47 research outputs found
Pharmacogenomic and pharmacotranscriptomic markers in glucocorticoid treatment of pediatric acute lymphoblastic leukemia: molecular mechanism of action, clinical and population aspects
Personalizovana medicina, medicina XXI veka, nastoji da individualizuje terapiju za svakog pacijenta, kako bi leÄenje bilo Å”to efikasnije i sa Å”to manje rizika od toksiÄnosti. Personalizovana medicina se danas najviÅ”e oslanja na farmakogenomiku i farmakotranskriptomiku, koje su veÄ dale svoj doprinos unapreÄenju leÄenja mnogih bolesti, a posebno maligniteta.
Akutna limfoblastna leukemija (ALL) predstavlja najÄeÅ”Äi hematoloÅ”ki malignitet pedijatrijskog uzrasta. Mada stopa izleÄenja dostiže 80-90%, ALL je i dalje glavni uzrok mortaliteta u ovih pacijenata. Terapija izaziva neželjene efekte u 75% pacijenata. Pored toga, u 1-3% pedijatrijskih pacijenata sa ALL smrtni ishod nije posledica bolesti, veÄ je uzrokovan terapijom. LeÄenje pedijatrijske ALL nije napredovalo uvoÄenjem novih lekova, veÄ nastojanjem da se smanje neželjena dejstva onih lekova koji su veÄ sastavni delovi postojeÄih terapijskih protokola, zbog Äega su farmakogenomika i farmakotranskriptomika dobile kljuÄno mesto u ovoj oblasti.
Glukokortikoidni lekovi (GK) se koriste u poÄetnoj fazi leÄenja ALL u dece, u fazi indukcije remisije. Od poÄetka leÄenja do 8. dana se primenjuju iskljuÄivo GK. Ipak, farmakogenomske i farmakotranskriptomske studije za glukokortikoidne lekove joÅ” uvek nisu dovele do algoritma koji bi mogao biti primenjen u leÄenju deÄje ALL. Stoga je izuzetno znaÄajno nastaviti sa istraživanjima farmakogenomskih i farmakotranskriptomskih markera relevantnih za uspeÅ”nost GK terapije u dece sa ALL. Razumevanje molekularnog mehanizma dejstva GK vodi ka otkrivanju novih markera koji mogu biti iskoriÅ”Äeni za optimizaciju GK terapije. Nove tehnologije, kao Å”to je sekvenciranje nove generacije (eng, next generation sequencing, NGS) su omoguÄile dizajniranje panela za farmakogenomske i farmakotranskriptomske markere za razliÄite
lekove...Personalized medicine, the medicine of the XXI century, aims to individualize therapy for each patient, in order for the treatment to be as efficient and safe as possible. Today, personalized medicine is the most reliant on pharmacogenomics and pharmacotranscriptomics, which have already given their contribution to enhancing treatment of many diseases, especially malignancies.
Acute lymphoblastic leukemia (ALL) is the most common hematological malignancy of childhood. Even though the percentage of cured patients reaches 80-90%, ALL is still the main cause of mortality in this group of patients. Therapy causes side effects in 75% of patients. Aside from that, 1-3% of pediatric ALL patients die because of therapy side effects rather than the disease itself. Treatment of pediatric ALL wasnāt improved by the introduction of new drugs, but by decreasing the side effects of the drugs which are already included in existing protocols. Due to this fact, pharmacogenomics and pharmacotranscriptomics have gained key positions in this field.
Glucocorticoid drugs (GC) are used in the initial phase of childhood ALL treatment, in the phase of remission induction therapy. From the beginning of the treatment until day 8, GCs are exclusively applied. Pharmacogenomic and pharmacotranscriptomic studies for GC drugs have yet to produce an algorithm that could be applied in childhood ALL treatment. Therefore, it is of extreme importance to continue researching pharmacogenomic and pharmacotranscriptomic markers relevant to the success of the GC therapy of children with ALL. Understanding the molecular mechanism of action of GC can lead to discovery of new markers that could be used for the optimization of GC therapy. New technologies, such as next generation sequencing (NGS) have created a possibility for designing panels for pharmacogenomic and pharmacotranscriptomic markers of response to different drugs. Utilization of these panels in population pharmacogenomic studies can lead to new knowledge that could open wide the doors to predictive pharmacogenomic testing..
long noncoding rna gaS as a new biomarker in oncology
Growth arrest specific 5 (GAS5) je duga nekodirajuÄa RNK koja zaustavlja Äelijski ciklus i promoviÅ”e apoptozu.
PonaÅ”ajuÄi se kao signalni protein, kao mamac za druge molekule ili kao transportni molekul, ova regulatorna
RNK utiÄe na niz puteva i molekula koji su bitni za rast Äelije i apoptozu, meÄu kojima se istiÄu p53 mreža,
mTOR signalni put, AKT signalni put, kao i molekuli mikro RNK, PTEN i sliÄni. Brojne studije na razliÄitim tipovima
karcinoma su pokazale da nivo ekspresije GAS5 utiÄe na razvoj i tok bolesti kod hematoloÅ”kih maligniteta,
ginekoloŔkih karcinoma, glioma, karcinoma dojke, karcinoma gastrointestinalnog trakta, bubrega,
beÅ”ike, prostate i pluÄa. Shodno tome, GAS5 je novi biomarker u onkologiji, koji ima dijagnostiÄki i prognostiÄki
znaÄaj.Growth arrest specific 5 (GAS5) is a long noncoding RNA which halts the cell cycle and promotes apoptosis.
Acting as a signal protein, as a decoy for other molecules or as a transport molecule, this regulatory RNA influences
a number of pathways and molecules relevant for the growth of the cell and apoptosis, among
them the most important being the p53 network, the mTOR signal pathway, the AKT signal pathway, as well
as molecules of microRNA, PTEN and others.
Numerous studies on diverse cancer types have confirmed that the expression of GAS5 influences the development
and the course of hematological malignancies, gynecologic carcinoma, gliomas, breast cancer,
gastrointestinal cancer, kidney cancer, bladder cancer, prostate cancer and lung cancer. Therefore, GAS5 is
a promising new diagnostic and prognostic biomarker in oncology
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
Genetic basis of otosclerosis
Uvod Otoskleroza je poremeÄaj koÅ”tane kapsule lavirinta i sluÅ”nih koÅ”Äica uva, koji dovodi do gubitka sluha zbog nemoguÄnosti provoÄenja zvuka. GenetiÄki uzrok otoskleroze je nepoznat. Cilj ovog rada je bio da se saÄini sveobuhvatni pregled savremenih saznanja o genetiÄkoj osnovi otoskleroze. Metode Za prikaz podataka o genetici otoskleroze koriÅ”Äen je narativni pregled literature. Rezultati Genetika otoskleroze nije mnogo izuÄavana i literaturni podaci o genetiÄkoj osnovi otoskleroze su oskudni. MeÄutim, u novije vreme, proÅ”iruju se znanja o genetiÄkoj osnovi otoskleroze. Ovde je prikazan pregled znanja o asocijaciji genetiÄkih markera i otoskleroze, koja su rezultat analiza genetiÄke povezanosti, kao i asocijativnih studija gena kandidata i sveobuhvatnih analiza genoma. ZakljuÄak Otoskleroza zbog svoje kompleksnosti nije bolest Äija Äe genetiÄka osnova biti lako rasvetljena. Analize omika i bioinformatika Äe doprineti razumevanju genetiÄke osnove otoskleroze.Introduction Otosclerosis is a disorder of the bone labyrinth and stapes resulting in conductive hearing loss. The genetic basis of otosclerosis still remains unknown. We aimed at reporting a comprehensive review of up-to-date knowledge on genetic basis of otosclerosis. Methods Narrative literature review was undertaken to summarize the data about genetics of otosclerosis. Results Genetics of otosclerosis has not been studied extensively and the literature on this topic is scarce. However, knowledge of genetic basis of otosclerosis is recently increasing. We have presented an overview of the knowledge of association of genetic markers with otosclerosis, gained from linkage analyses, candidate-gene studies, and modern high-throughput genomic studies. Conclusion Due to its complex pathophysiology, otosclerosis is not a disease whose genetic base will be easily understood. Multiple omics analysis and bioinformatics will lead to elucidation of genetic basis of otosclerosis
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
Expression Profiles of Long Non-Coding RNA GAS5 and MicroRNA-222 in Younger AML Patients
Acute myeloid leukemia (AML) is a heterogeneous malignant disease both on clinical and genetic levels. AML has poor prognosis and, therefore, there is a constant need to find new prognostic markers, as well as markers that can be used as targets for innovative therapeutics. Recently, the search for new biomarkers has turned researchers' attention towards non-coding RNAs, especially long non-coding RNAs (lncRNAs) and micro RNAs (miRNAs). We investigated the expression level of growth arrest-specific transcript 5 (GAS5) lncRNA in 94 younger AML patients, and also the expression level of miR-222 in a cohort of 39 AML patients with normal karyotype (AML-NK), in order to examine their prognostic potential. Our results showed that GAS5 expression level in AML patients was lower compared to healthy controls. Lower GAS5 expression on diagnosis was related to an adverse prognosis. In the AML-NK group patients had higher expression of miR-222 compared to healthy controls. A synergistic effect of GAS5(low)/miR-222(high) status on disease prognosis was not established. This is the first study focused on examining the GAS5 and miR-222 expression pattern in AML patients. Its initial findings indicate the need for further investigation of these two non-coding RNAs, their potential roles in leukemogenesis, and the prognosis of AML patients
Polyphenols as Possible Agents for Pancreatic Diseases
Pancreatic cancer (PC) is very aggressive and it is estimated that it kills nearly 50% of patients within the first six months. The lack of symptoms specific to this disease prevents early diagnosis and treatment. Today, gemcitabine alone or in combination with other cytostatic agents such as cisplatin (Cis), 5-fluorouracil (5-FU), irinotecan, capecitabine, or oxaliplatin (Oxa) is used in conventional therapy. Outgoing literature provides data on the use of polyphenols, biologically active compounds, in the treatment of pancreatic cancer and the prevention of acute pancreatitis. Therefore, the first part of this review gives a brief overview of the state of pancreatic disease as well as the procedures for its treatment. The second part provides a detailed overview of the research regarding the anticancer effects of both pure polyphenols and their plant extracts. The results regarding the antiproliferative, antimetastatic, as well as inhibitory effects of polyphenols against PC cell lines as well as the prevention of acute pancreatitis are presented in detail. Finally, particular emphasis is given to the polyphenolic profiles of apples, berries, cherries, sour cherries, and grapes, given the fact that these fruits are rich in polyphenols and anthocyanins. Polyphenolic profiles, the content of individual polyphenols, and their relationships are discussed. Based on this, significant data can be obtained regarding the amount of fruit that should be consumed daily to achieve a therapeutic effect
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