91 research outputs found
Pharmacogenetics of 6-mercaptopurine and methotrexate in childhood acute lymphoblastic leukemia
Farmakogenomika prouÄava odnos izmeÄu genetiÄkog sklopa individue i njegovog odgovora
na lekove i jedan je od stubova personalizovane medicine. DosadaÅ”nji princip leÄenja da se
standardna doza leka daje svim pacijentima sa istom dijagnozom po unapred utvrÄenom
protokolu se napuÅ”ta. Za veliki broj pacijenta ta doza leka Äesto nije efikasna i/ili sigurna za
upotrebu. Cilj farmakogenomiÄkih studija je da identifikuju farmakogenomiÄke markere,
varijacije u genomu koje mogu pouzdano da predvide odgovor na terapiju, Ŕto je osnov za
individualizaciju terapije.
Model sistemi bolesti za analizu farmakogenomiÄkih markera koriÅ”Äeni u ovom radu su deÄja
akutna limfoblastna leukemija (ALL) i reumatoidni artritis (RA). LeÄenje ovih bolesti
ukljuÄuje imunosupresivne i citotoksiÄne lekove 6-merkaptopurin (6-MP), metotreksat
(MTX), antibiotik baktrim, antimikotik nistatin, kao i anti-TNF lekove. GenetiÄke varijacije
koje moduliÅ”u metaboliÄke puteve povezane sa ovim lekovima su kandidati za
farmakogenomiÄke markere.
Cilj ove studije je da ispita uÄestalosti genetiÄkih varijanti u genima TPMT, ITPA, ABCB1,
ABCC4, TYMS, MTHFR, SLC19A1, DHFR, TNF i IL-6, kao i da oceni farmakogenomiÄki
potencijal ovih varijanti u srpskoj populaciji. BiÄe ispitana i uloga ovih farmakogenomiÄkih
markera kao faktora rizika za razvoj deÄje ALL. IspitaÄe se i uticaj terapije održavanja, gde
okosnicu terapije Äine lekovi 6-MP i MTX, kao i pola i uzrasta dece sa ALL na ekspresiju
gena TPMT. BiÄe funkcionalno okarakterisane varijante u genu TPMT, potencijalni
modulatori ekspresije gena TPMT, sa posebnom pažnjom na ulogu VNTR regiona u
promotoru gena TPMT.
U studiju je bilo ukljuÄeno 174 pedijatrijskih ALL pacijenata, 73 RA pacijenata i 104
kontrolnih zdravih ispitanika. GenetiÄke varijacije u svim gorepomenutim genima su
odreÄene metodama baziranim na PCR-u...Pharmacogenomics is focused on exploring the relation between the genomic signature of an
individual and their drug response. It is the basis for implementation of personalized
medicine. The old-fashioned therapeutic paradigm of Ā»one protocol dose fits all patients with
the same diagnosisĀ« is getting abandoned. The standard drug dose is often not efficient and/or
safe for many of patients. Pharmacogenomic studies identify pharmacogenomic markers,
genomic variations that could reliably predict the drug response, which is the basis for
therapy individualization.
In order to analyze pharmacogenomic markers, childhood acute lymphoblastic leukemia
(ALL) and rheumatoid arthritis (RA) are used as disease model systems. ALL and RA
therapy protocols include cytotoxic and immunosuppressive drugs 6-mercaptopurine (6-MP)
and methotrexate (MTX), antibiotic bactrim and antimycotic nystatin, as well as anti-TNF
drugs. Genetic variations that modulate metabolic pathways related to these drugs are
candidate pharmacogenomic markers.
The aim of this study is to analyze frequencies of genetic variants in TPMT, ITPA, ABCB1,
ABCC4, TYMS, MTHFR, SLC19A1, DHFR, TNF and IL-6 genes in Serbian population and
to evaluate the pharmacogenomic potential of these variants. Also, the role of these
pharmacogenomic markers as risk factors for development of childhood ALL will be
assessed. Influence of the maintenance therapy, which includes 6-MP and MTX as most
important drugs, as well as the age and gender of patients will be analyzed in regard to TPMT
gene expression. Functional assays will be carried out in order to identify potential modifiers
of TPMT expression with a special focus on VNTR region in promoter of TPMT gene.
In this study, 174 pediatric ALL patients, 73 RA patients and 104 healthy subjects were
enrolled. Genetic variants in above-mentioned genes were detected using PCR-based
methodology..
Precision medicine and COVID-19: importance of host genome profiling and bioinformatics
Clinical picture and course of the disease in patients with COVID-19 vary from asymptomatic to lethal.
Precision medicine could discover the cause of this phenomenon by analyzing the individual genomic
profiles of the patients.
We aimed to understand a host genetic component of COVID-19 focusing on variants in genes encoding
proteases and genes involved in innate immunity, important for susceptibility and resistance to SARS-CoV-2
infection. Also, we wanted to identify phamracogenes and pharmacogenomics markers associated with
drugs used for COVID-19 treatment in different clinical protocols in Serbia, and to compare the results
with various world populations.
Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained
using TruSight One Gene Panel (Illumina). Variants in genes encoding proteases and genes involved in innate
immunity were identified and analysed in silico (PolyPhen-2, SIFT, MutPred2, Swiss-Pdb Viewer) to predict
the impact of the variants to the structure and/or function of proteins. Genotype data from Serbian population
was compared with European and 4 super-populations (total 2504 subjects). Data were extracted from
VCF files of Phase 3 variant calls of the 1000 Genomes Project (1kGP) sample collection via Ensembl Data
Slicer Tool. The level of population genetic variability at each selected loci was examined using the maximal
global differences in minor allele frequencies (delta MAF) calculated by subtracting the maximum and the
minimum MAF across analyzed population groups, and Fst statistics. Fisher exact test was used to measure
differences in genotypes distributions between Serbian and 1kGP populations, applying Bonferoni correction.
R software was utilized for genotype data manipulation and statistical calculations.
Based on high alternative allele frequencies in population and the functional effect of the variants, we identified
variants in genes encoding proteases and involved in the innate immunity that might be relevant for the
host response to SARS-CoV-2 infection. The potential pharmacogenomics markers in pharmacogenes relevant
for COVID-19 treatment were also identified. Bioinformatics tools integrated into precision medicine
could contribute to better understanding of inter-individual and population-specific genetic susceptibility and
resistance to the SARS-CoV-2 infection, therapy response inconsistencies, and could be applied to improve
the outcome of the COVID-19 patients.Book of Abstracts: Belgrade BioInformatics Conference 202
Personalized medicine and COVID-19: the importance of genomic host profiling and bioinformatics
Novi koronavirus SARS-CoV-2, uzroÄnik upale pluÄa, sposoban je da zarazi ljude i izazove novu bolest COVID- 19 koja je preopteretila zdravstvene sisteme Å”irom planete i izazvala globalnu ekonomsku krizu. KliniÄka slika i tok bolesti kod pacijenata obolelih od COVID-19 varira od asimptomatske do letalnog ishoda. Kako se radi o istom uzroÄniku bolesti, individualni genomski profil pacijenta krije odgovor na pitanje medicinske nauke o uzroku ovog fenomena. U radu su sumirana dosadaÅ”nja znanja o genetiÄkim markerima koji su odgovorni za Å”iroki spektar kliniÄkih slika, kao i da li se veÄ može primeniti individualizovan pristup leÄenju. Prikazane su dosada istraživane varijante u genima (sa osvrtom na populacione specifiÄnosti) odgovorne za predispoziciju i odgovor na SARS-CoV-2 virusnu infekciju, farmakogenetiÄke varijante od znaÄaja za lekove koji se koriste u leÄenju pacijenata obolelih od COVID-19, kao i nutrigenetiÄki markeri u genima važnim za metabolizam mikronutrijenata, vitamina D, selena i cinka, koji se takoÄe koriste u terapiji pacijenata sa COVID-19. Udruženi napor istraživaÄa, multidisciplinarni pristup, dostupnost modernih tehnologija koje imaju kapacitet analize celokupnih genoma, buduÄe sveobuhvatnije studije sa dobro okarakterisanim grupama pacijenata, kao i razvoj robusnijih bioinformatiÄkih alata koji koriste maÅ”insko uÄenje i napredne statistiÄke metode, omoguÄiÄe identifikaciju novih genetiÄkih markera Äoveka povezanih sa COVID-19, bolje razumevanje same patofiziologije bolesti, razvoj prave ciljane terapije kao i istaÄi znaÄaj nutrigenomike i farmakogenomike za primenu personalizovane medicine u leÄenju 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
Machine Learning Modeling from Omics Data as Prospective Tool for Improvement of Inflammatory Bowel Disease Diagnosis and Clinical Classifications
Research of inflammatory bowel disease (IBD) has identified numerous molecular players involved in the disease development. Even so, the understanding of IBD is incomplete, while disease treatment is still far from the precision medicine. Reliable diagnostic and prognostic biomarkers in IBD are limited which may reduce efficient therapeutic outcomes. High-throughput technologies and artificial intelligence emerged as powerful tools in search of unrevealed molecular patterns that could give important insights into IBD pathogenesis and help to address unmet clinical needs. Machine learning, a subtype of artificial intelligence, uses complex mathematical algorithms to learn from existing data in order to predict future outcomes. The scientific community has been increasingly employing machine learning for the prediction of IBD outcomes from comprehensive patient data-clinical records, genomic, transcriptomic, proteomic, metagenomic, and other IBD relevant omics data. This review aims to present fundamental principles behind machine learning modeling and its current application in IBD research with the focus on studies that explored genomic and transcriptomic data. We described different strategies used for dealing with omics data and outlined the best-performing methods. Before being translated into clinical settings, the developed machine learning models should be tested in independent prospective studies as well as randomized controlled trials
Pharmacogenomic and Pharmacotranscriptomic Profiling of Childhood Acute Lymphoblastic Leukemia: Paving the Way to Personalized Treatment
Personalized medicine is focused on research disciplines which contribute to the individualization of therapy, like pharmacogenomics and pharmacotranscriptomics. Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. It is one of the pediatric malignancies with the highest cure rate, but still a lethal outcome due to therapy accounts for 1-3% of deaths. Further improvement of treatment protocols is needed through the implementation of pharmacogenomics and pharmacotranscriptomics. Emerging high-throughput technologies, including microarrays and next-generation sequencing, have provided an enormous amount of molecular data with the potential to be implemented in childhood ALL treatment protocols. In the current review, we summarized the contribution of these novel technologies to the pharmacogenomics and pharmacotranscriptomics of childhood ALL. We have presented data on molecular markers responsible for the efficacy, side effects, and toxicity of the drugs commonly used for childhood ALL treatment, i.e., glucocorticoids, vincristine, asparaginase, anthracyclines, thiopurines, and methotrexate. Big data was generated using high-throughput technologies, but their implementation in clinical practice is poor. Research efforts should be focused on data analysis and designing prediction models using machine learning algorithms. Bioinformatics tools and the implementation of artificial i Lack of association of the CEP72 rs924607 TT genotype with intelligence are expected to open the door wide for personalized medicine in the clinical practice of childhood ALL
The pharmacogenomics of vincristine-induced peripheral neuropathy in pediatric acute lymphoblastic leukemia patients in Serbia: A single center experience
Uvod/Cilj Vinkristin je jedan od kljuÄnih lekova u protokolima leÄenja deÄje akutne limfoblastne leukemije (ALL). Vinkristin dovodi do destabilizacije mikrotubula, Äime se Äelija zaustavlja u metafazi i indukuje apoptoza. TakoÄe dovodi do degradacije aksona i poremeÄaja aksonskog transporta, uzrokujuÄi vinkristinom indukovanu perifernu neuropatiju (VIPN). Cilj ove studije bio je da istraži povezanost pet varijanti u farmakogenima ukljuÄenim u metabolizam vinkristina kod dece obolele od ALL koja su razvila VIPN, u Srbiji. TakoÄe, cilj nam je bio da otkrijemo kandidate za nove farmakogenomske markere VIPN-a u srpskoj populaciji. Metode Detekcija varijanti gena CYP3A5, CEP72, ACTG1, MIR3117 i MIR4481 izvedena je metodologijom zasnovanom na PCR-u i sekvenciranju. StatistiÄkim metodama je ispitana njihova asocijacija sa VIPN-om kod 56 pedijatrijskih bolesnika obolelih od ALL. UraÄena je i populaciona vinkristin farmakogenomska analiza 17 farmakogena iz postojeÄih podataka dobijenih sekvenciranjem nove generacije u srpskoj populaciji. Podaci o distribuciji frekvencija alela za evropsko stanovniÅ”tvo preuzeti su iz javnih baza podataka. Rezultati Tokom leÄenja, 17,86% bolesnika je razvilo VIPN. Asocijativne analize pokazale su da nijedna genetiÄka varijanta nije bila povezana sa VIPN-om u naÅ”oj studiji. NaÅ”e populaciono farmakogenomsko istraživanje nije otkrilo validne farmakovarijante za VIPN. NaÅ”i rezultati ne preporuÄuju preventivno farmakogenetiÄko ispitivanje vinkristina u Srbiji. ZakljuÄak Potreban je sveobuhvatniji pristup kako bi se identifikovao panel gena kojim bi se mogao objasniti razvoj VIPN-a posle primene vinkristina kod pedijatrijskih bolesnika obolelih od ALL. Bolje osmiÅ”ljene studije asocijacija na nivou genoma (GWAS) i robusniji alati koji koriste veÅ”taÄku inteligenciju doveli bi do dizajniranja panela farmakogena za preventivno testiranje predispozicije za razvoj VIPN-a, doprinoseÄi individualizaciji i unapreÄenju terapije dece obolele od ALL.Introduction/Objective Vincristine (VCR) is one of the key drugs in current treatment protocols for pediatric acute lymphoblastic leukemia (ALL). By destabilizing microtubules, VCR arrests cells in metaphase, inducing apoptosis of malignant cells. VCR also causes axonal degradation and impairment of axonal transport, which leads to VCR-induced peripheral neuropathy (VIPN). This study aimed to investigate the association of five variants in pharmacogenes involved in VCR metabolism with VIPN in Serbian ALL children. We also wanted to discover candidate pharmacogenomic markers of VIPN in Serbian population. Methods PCR and sequencing-based methodology was used to detect variants in CYP3A5, CEP72, ACTG1, MIR3117, and MIR4481 genes. Statistical analyses were performed for investigating their association with VIPN in 56 pediatric ALL patients. Population VCR pharmacogenomics analysis of 17 pharmacogenes from in-house next-generation sequencing data was also done. Data on allele frequency distribution for the European population were extracted from public databases. Results During the treatment, 17.86% of patients developed VIPN. Association analyses have shown that none of the genetic variants contributed to the occurrence of VIPN in our study. Population pharmacogenomics study did not reveal valid candidate pharmacovariants for VIPN. Our results suggested that pre-emptive pharmacogenetic testing for VCR is not applicable presently. Conclusion More comprehensive approaches are needed to identify the panel of genes that could explain the VIPN development after VCR administration in ALL patients. Utilizing better designed genome-wide association studies and more robust artificial intelligence-based tools would provide a panel of pharmacogenes for pre-emptive tests of VIPN to individualize therapy for ALL in children
Pharmacogenomics landscape of COVID-19 therapy response in Serbian population and comparison with worldwide populations
Uvod: Kako ne postoje odobreni terapeutici za leÄenje pacijenata sa COVID-19, moguÄnost upotrebe postojeÄih lekova je postala važna. U nedostatku vremena za testiranje farmakogenomskih markera kod pojedinaca, populaciona farmakogenomika bi mogla biti od koristi u predviÄanju poveÄanog rizika za pojavu neželjenih reakcija i neuspeha leÄenja kod pacijenata sa COVID-19. Cilj naÅ”e studije bio je identifikovanje farmakogena i farmakogenomskih markera povezanih sa lekovima koji se preporuÄuju za leÄenje COVID-19, hlorokin/hidroksihlorokin, azitromicin, lopinavir i ritonavir, u populaciji Srbije i drugim svetskim populacijama. Metode: Podaci o genotipu 143 osobe srpskog porekla dobijeni su iz baze podataka prethodno formirane analizama genoma koriÅ”Äenjem TruSight One Gene Panel (Illumina). Podaci o genotipu pojedinaca iz razliÄitih svetskih populacija dobijeni su iz Projekta 1000 genoma. FiÅ”erov egzaktni test koriÅ”Äen je za poreÄenje uÄestalosti alela. Rezultati: Identifikovali smo 11 potencijalnih farmakogenomskih markera u 7 farmakogena znaÄajnih za leÄenje COVID-19. Na osnovu visoke alterativne uÄestalosti alela u populaciji Srbije i funkcionalnog efekta varijanti, ABCB1 rs1045642 i rs2032582 mogu biti znaÄajne za smanjeni klirens lekova azitromicina, lopinavira i ritonavira, a varijanta UGT1A7 rs17868323 za hiperbilirubinemiju kod bolesnika sa COVID-19 koji se leÄe ritonavirom. SLCO1B1 rs4149056 je potencijalni marker odgovora na lopinavir, posebno u populaciji Italije. NaÅ”i rezultati potvrdili su da se farmakogenomski profil afriÄke populacije razlikuje od ostatka sveta. ZakljuÄak: UzimajuÄi u obzir farmakogenomski profil specifiÄan za populaciju, preventivno testiranje farmakogena znaÄajnih za lekove koji se koriste u leÄenju COVID-19 moglo bi doprineti boljem razumevanju interindividualnih razlika u odgovorima na terapiju i poboljÅ”anju ishoda leÄenja pacijenata sa COVID-19.Background: Since there are no certified therapeutics to treat COVID-19 patients, drug repurposing became important. With lack of time to test individual pharmacogenomics markers, population pharmacogenomics could be helpful in predicting a higher risk of developing adverse reactions and treatment failure in COVID-19 patients. Aim of our study was to identify pharmacogenes and pharmacogenomics markers associated with drugs recommended for COVID-19 treatment, chloroquine/hydroxychloroquine, azithromycin, lopinavir and ritonavir, in population of Serbia and other world populations. Methods: Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained using TruSight One Gene Panel (Illumina). Genotype data of individuals from different world populations were extracted from the 1000 Genome Project. Fisher's exact test was used for comparison of allele frequencies. Results: We have identified 11 potential pharmacogenomics markers in 7 pharmacogenes relevant for COVID-19 treatment. Based on high alternative allele frequencies in population and the functional effect of the variants, ABCB1 rs1045642 and rs2032582 could be relevant for reduced clearance of azithromycin, lopinavir and ritonavir drugs and UGT1A7 rs17868323 for hyperbilirubinemia in ritonavir treated COVID-19 patients in Serbian population. SLCO1B1 rs4149056 is a potential marker of lopinavir response, especially in Italian population. Our results confirmed that pharmacogenomics profile of African population is different from the rest of the world. Conclusions: Considering population specific pharmacogenomics landscape, preemptive testing for pharmacogenes relevant for drugs used in COVID-19 treatment could contribute to better understanding of the inconsistency in therapy response and could be applied to improve the outcome of the COVID-19 patients
The in vitro antioxidative and cytotoxic effects of selected Salvia species water extracts
The current paper presents antioxidant and cytotoxic activities and total phenolic and flavonoid content of the selected species of genus Salvia (Lamiaceae) growing wild in Macedonia (S. jurisicii Kosanin, S. amplexicaulis Lam., S. ringens Sibth. & Sm.) and Libya (S. fruticosa Mill. and S. lanigera Poir.). Crude water extracts, obtained from aerial parts, were yielded from 6.50 to 14.32%. Total phenolic content was the highest in water extracts of S. amplexicaulis and S. ringens (226.30 and 189.01 mg GAE/g, respectively), while the flavonoids were the most abundant in S. jurisicii extract (32.36 mg QE/g). Antioxidant activities of extracts were measured using DPPH, ABTS and FRAP assays. S. amplexicaulis and S. ringens extracts showed the strongest antioxidant activity, measured using DPPH (14.21 and 23.44 mu g/mL, respectively) and ABTS assays (2.91 and 2.42 mg AAE/g, respectively). In FRAP assay, S. amplexicaulis and S. fruticosa extracts exhibited strongest activity (1406.73 and 1191.51 mu mol Fe(II)/g). Water extract of S. amplexicaulis and S. ringens performed the strongest cytotoxic activity against K562 cells (151.07 and 173.06 mu g/mL, respectively). Based on these findings, it can be concluded that S. amplexicaulis and S. ringens water extracts could be considered as possible source of antioxidant and cytotoxic agents
The in vitro antioxidative and cytotoxic effects of selected Salvia species water extracts
The current paper presents antioxidant and cytotoxic activities and total phenolic and flavonoid content of the selected species of genus Salvia (Lamiaceae) growing wild in Macedonia (S. jurisicii KoÅ”anin, S. amplexicaulis Lam., S. ringens Sibth. & Sm.) and Libya (S. fruticosa Mill. and S. lanigera Poir.). Crude water extracts, obtained from aerial parts, were yielded from 6.50 to 14.32%. Total phenolic content was the highest in water extracts of S. amplexicaulis and S. ringens (226.30 and 189.01 mg GAE/g, respectively), while the flavonoids were the most abundant in S. jurisicii extract (32.36 mg QE/g). Antioxidant activities of extracts were measured using DPPH, ABTS and FRAP assays. S. amplexicaulis and S. ringens extracts showed the strongest antioxidant activity, measured using DPPH (14.21 and 23.44 Ī¼g/mL, respectively) and ABTS assays (2.91 and 2.42 mg AAE/g, respectively). In FRAP assay, S. amplexicaulis and S. fruticosa extracts exhibited strongest activity (1406.73 and 1191.51 Āµmol Fe(II)/g). Water extract of S. amplexicaulis and S. ringens performed the strongest cytotoxic activity against K562 cells (151.07 and 173.06 Ī¼g/mL, respectively). Based on these findings, it can be concluded that S. amplexicaulis and S. ringens water extracts could be considered as possible source of antioxidant and cytotoxic agents
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