1. Toward precision medicine : molecular biomarkers of response to tofacitinib in inflammatory bowel diseaseAnja Bizjak, Boris Gole, Gregor Jezernik, Uroš Potočnik, Mario Gorenjak, 2025, review article Abstract: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), is a chronic, relapsing inflammatory condition that significantly impairs the patient’s quality of life. While biologics have transformed disease management, a substantial number of patients remain unresponsive or lose efficacy over time. Tofacitinib (TOFA), an oral Janus kinase (JAK) inhibitor, introduces a novel therapeutic class of small-molecule drugs with a unique oral administration route, offering enhanced patient convenience and broader accessibility compared to parenterally administered biologics. As the first oral treatment approved for moderate to severe UC in years, TOFA acts by modulating the JAK/STAT pathway, influencing critical inflammatory mediators such as IL-6, IL-17, and IFN-γ. However, response rates are variable and appear dose-dependent, with up to 60% of patients showing inadequate therapeutic outcomes. This review represents the first comprehensive synthesis focused specifically on biomarkers of TOFA response in UC. Drawing on multi-omics data—epigenomics, transcriptomics, proteomics, and cellular profiling, we highlight emerging predictors of responsiveness, including CpG methylation signatures (e.g., LRPAP1 and FGFR2), transcriptomic regulators (e.g., REG3A and CLDN3), immune and epithelial cell shifts, and the cationic transporter MATE1. TOFA demonstrates a dual mechanism by modulating immune responses while supporting epithelial barrier restoration. Despite being promising, TOFA’s dose-dependent efficacy and interpatient variability underscore the critical need for non-invasive, predictive biomarkers to guide personalized treatment. As the first review of its kind, this work establishes a basis for precision medicine approaches to optimize the clinical utility of TOFA in UC management.
Keywords: inflammatory bowel disease, ulcerative colitis, genomics, tofacitinib, transcriptomics, proteomics
Published in DKUM: 18.08.2025; Views: 0; Downloads: 10
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2. MFUM-BrTNBC-1, a newly established patient-derived triple-negative breast cancer cell line : molecular characterisation, genetic stability, and comprehensive comparison with commercial breast cancer cell linesKristijan Skok, Lidija Gradišnik, Helena Sabina Čelešnik, Marko Milojević, Uroš Potočnik, Gregor Jezernik, Mario Gorenjak, Monika Sobočan, Iztok Takač, Rajko Kavalar, Uroš Maver, 2022, original scientific article Abstract: Triple-negative breast cancer (TNBC) is a breast cancer (BC) subtype that accounts for
approximately 15–20% of all BC cases. Cancer cell lines (CLs) provide an efficient way to model the
disease. We have recently isolated a patient-derived triple-negative BC CL MFUM-BrTNBC-1 and
performed a detailed morphological and molecular characterisation and a comprehensive comparison
with three commercial BC CLs (MCF-7, MDA-MB-231, MDA-MB-453). Light and fluorescence
microscopy were used for morphological studies; immunocytochemical staining for hormone receptor,
p53 and Ki67 status; RNA sequencing, qRT-PCR and STR analysis for molecular characterisation; and
biomedical image analysis for comparative phenotypical analysis. The patient tissue-derived MFUMBrTNBC-1 maintained the primary triple-negative receptor status. STR analysis showed a stable and
unique STR profile up to the 6th passage. MFUM-BrTNBC-1 expressed EMT transition markers and
displayed changes in several cancer-related pathways (MAPK, Wnt and PI3K signalling; nucleotide
excision repair; and SWI/SNF chromatin remodelling). Morphologically, MFUM-BrTNBC-1 differed
from the commercial TNBC CL MDA-MB-231. The advantages of MFUM-BrTNBC-1 are its isolation
from a primary tumour, rather than a metastatic site; good growth characteristics; phenotype identical
to primary tissue; complete records of origin; a unique identifier; complete, unique STR profile;
quantifiable morphological properties; and genetic stability up to (at least) the 6th passage.
Keywords: hormonal receptors, MFUM-BrTNBC-1, MCF-7, MDA-MB-231, MDA-MB-453
Published in DKUM: 10.04.2025; Views: 0; Downloads: 4
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3. Genska ontologija farmakogenomike bioloških zdravil pri imunsko pogojenih boleznih : magistrsko deloTino Kovačič, 2024, master's thesis Abstract: V magistrskem delu smo z uporabo genske ontologije preučevali farmakogenomiko bioloških zdravil pri imunsko pogojenih boleznih, s poudarkom na atopijskem dermatitisu, astmi in multipli sklerozi. Namen raziskave je bil ugotoviti vpliv bioloških označevalcev na učinkovitost zdravljenja z biološkimi zdravili ter identificirati skupne in specifične molekularne poti teh bolezni. S sistematskim pregledom literature smo analizirali že objavljene članke, ki poročajo o genih povezanih z odzivom na zdravljenje z biološkimi zdravili pri vseh treh boleznih, nato pa smo izvedli analizo genske ontologije s pomočjo programske opreme Cytoscape.
Primerjali smo individualne analize za vsako bolezen posebej in izvedli komparativno analizo genske ontologije. Ugotovili smo, da so statistično najbolj pomembni pojmi za vse tri bolezni vključujejo: aktivacijo B celic (p vrednost = 1,16 × 10-17), diferenciacijo T celic (p vrednost = 2,15 × 10-33), diferenciacijo CD4+ alfa-beta T celic (p vrednost = 6,65 × 10-25) ter celično apoptozo (p vrednost = 5,28 × 10-18). Pri vseh posameznih analizah so se pojavili tudi statistično pomembni pojmi, kot so mikroglialna aktivnost, regulacija imunoglobulina E in vitamina D, ki posredno ali neposredno vplivajo na odziv na biološka zdravila. Diferenciacija Bergmannovih glialnih celic (p vrednost = 1,67 × 10-4) je bil statistično pomemben pojem, ki se je pojavil le pri analizi multiple skleroze.
Povzamemo lahko, da je v tej nalogi razkritih več GO izrazov, ki so vključeni v molekularne poti atopijskega dermatitisa, astme in multiple skleroze ter služijo kot pokazatelji odziva na zdravljenje z biološkimi zdravili za te bolezni.
Keywords: genska ontologija, biološka zdravila, biološki označevalci, atopijski dermatitis, astma, multipla skleroza
Published in DKUM: 16.01.2025; Views: 0; Downloads: 48
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4. Single-cell transcriptomic and targeted genomic profiling adjusted for inflammation and therapy bias reveal CRTAM and PLCB1 as novel hub genes for anti-tumor necrosis factor alpha therapy response in Crohn’s diseaseMario Gorenjak, Boris Gole, Larisa Goričan, Gregor Jezernik, Uršula Prosenc Zmrzljak, Cvetka Pernat Drobež, Pavel Skok, Uroš Potočnik, 2024, original scientific article Abstract: The lack of reliable biomarkers in response to anti-TNFα biologicals hinders
personalized therapy for Crohn’s disease (CD) patients. The motivation behind our study is to shift
the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using
single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression
signals, which may be masked due to the treatment or ongoing inflammation; Methods: The singlecell
RNA sequencing was performed on PBMC samples from CD patients either naïve to biological
therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive
to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and
independent cohort genomic profiling. Replication and meta-analyses were performed using publicly
available raw RNA sequencing files of sorted immune cells and an association analysis summary.
Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to
validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in
CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds
throughout the analyses. An additional assessment proved causal inference of both genes in response
to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered
novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy
or inflammation.
Keywords: inflammatory bowel diseases, Crohn’s disease, tumor necrosis factor alpha, adalimumab, single-cell gene expression analysis
Published in DKUM: 10.12.2024; Views: 0; Downloads: 13
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5. Discovery of novel biomarkers with extended non-coding RNA interactor networks from genetic and protein biomarkersGregor Jezernik, Damjan Glavač, Pavel Skok, Martina Krušič, Uroš Potočnik, Mario Gorenjak, 2024, original scientific article Abstract: Curated online interaction databases and gene ontology tools have streamlined the analysis of highly complex gene/protein networks. However, understanding of disease pathogenesis has gradually shifted from a protein-based core to complex interactive networks where non-coding RNA (ncRNA) is thought to play an essential role. As current gene ontology is based predominantly on protein-level information, there is a growing need to analyze networks with ncRNA. In this study, we propose a gene ontology workflow integrating ncRNA using the NPInter V5.0 database. To validate the proposed workflow, we analyzed our previously published curated biomarker datasets for hidden disease susceptibility processes and pharmacogenomics. Our results show a novel involvement of melanogenesis in psoriasis response to biological drugs in general. Hyperpigmentation has been previously observed in psoriasis following treatment with currently indicated biological drugs, thus calling attention to melanogenesis research as a response biomarker in psoriasis. Moreover, our proposed workflow highlights the need to critically evaluate computed ncRNA interactions within databases and a demand for gene ontology analysis of large miRNA blocks.
Keywords: gene ontology, non-coding RNA, ncRNA, disease pathogenesis, gene networks, protein networks, tools, psoriasis
Published in DKUM: 06.12.2024; Views: 0; Downloads: 13
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6. Meta-analytic comparison of global RNA transcriptomes of acute and chronic myeloid leukemia cells reveals novel gene candidates governing myeloid malignanciesStaša Jurgec, Gregor Jezernik, Mario Gorenjak, Tomaž Büdefeld, Uroš Potočnik, 2022, original scientific article Abstract: Despite advances in the understanding of genetic risk factors and molecular mechanisms underlying acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), clinical outcomes of current therapies in terms of disease relapse and mortality rate pose a great economic and social burden. To overcome this, the identification of new molecular prognostic biomarkers and pharmacological targets is crucial. Recent studies have suggested that AML and CML may share common pathogenic mechanisms and cellular substrates. To this end, in the present study, global transcriptome profiles of AML and CML at the molecular and cellular level were directly compared using a combination of meta-analysis and modern statistics, and novel candidate genes and specific biological processes associated with the pathogenesis of AML and CML were characterized. Our study significantly improves our current understanding of myeloid leukemia and will help develop new therapeutic targets and biomarkers for disease progression, management and treatment response.
Keywords: AML, CML, meta-analysis, lincRNA, spliceosome
Published in DKUM: 05.12.2024; Views: 0; Downloads: 10
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7. Identification of novel loci involved in adalimumab response in Crohn’s disease patients using integration of genome profiling and isoform-level immune-cell deconvoluted transcriptome profiling of colon tissueMario Gorenjak, Gregor Jezernik, Martina Krušič, Pavel Skok, Uroš Potočnik, 2022, original scientific article Abstract: Crohn’s disease is a consequence of dysregulated inflammatory response to the host’s microbiota. Although anti-TNF treatment improves the quality of the patient’s life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn’s disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn’s disease patients.
Keywords: Crohn’s disease, adalimumab, transcriptome, isoforms, deconvolution
Published in DKUM: 05.12.2024; Views: 0; Downloads: 4
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9. Genska ontologija za odkritje molekularno bioloških poti in procesov, povezanih s siringomielijo in chiari podobno malformacijo pri domačem psuTjaša Pečovnik, 2022, master's thesis Abstract: Uvod: Siringomielija (SM) in Chiari podobna malformacija (CPM)sta dve pogosti
bolezni, ki se pojavljata pri domačem psu in najpogosteje prizadeneta pse pasme
Cavalier King Charles španjel (CKCS) in bruseljski grifon (BG). Bolezni predstavljata
problem čistokrvne reje miniaturnih pasem. CKCS je pasma, pogosto podvržena
boleznim mitralne zaklopke, več kot 50% psov pasme CKCS pa naj bi trpelo za SM
Metode: S pomočjo do sedaj opravljenih raziskav, genske ontologije in
bioinformacijskih pristopov smo odkrili molekularno biološke poti, ki bi lahko v
prihodnosti prispevale k oblikovanju novih smernic za raziskave CPM in SM.CPM kot SM
smo obravnavali kot ločeni bolezni in za vsako naredili ločeno analizo genske
ontologije. Podrobneje smo si pogledali termine GO z visoko stopnjo statistične
značilnosti.
Rezultati: S CPM smo povezali 3 gene, ki so bili omenjeni v literaturi (CDX1, FBNI,
CSKD1) in 3 gene za SM (ILR6, PCDH17, ZWINT). Za konec smo preverili ali si bolezni
delita skupne termine genske ontologije, pri čemer smo dobili 6 skupnih terminov, ki
niso dovolj izčrpni, da bi jih lahko uporabili v nadaljnjih analizah.
Sklep in razprava: Potrdili smo ujemanje genov z posameznima boleznima, kar lahko
služi kot smernica za nadaljnje analize. Laboratorijske raziskave, bi lahko bile naslednji
korak, ki bi podale globlje informacije izbrane kompleksne bolezni.
Keywords: genska ontologija, siringomielija, Chiari podobna malformacija, domači pes.
genska ontologija, siringomielija, Chiari podobna malformacija, domači pes.
Published in DKUM: 15.02.2022; Views: 810; Downloads: 90
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10. Biološki procesi in napovedovanje neodzivnosti na zaviralce dejavnika tumorske nekroze pri Crohnovi bolezni z integracijo genomskih podatkovGregor Jezernik, 2020, doctoral dissertation Abstract: Razvoj bioloških zdravil je pomembno prispeval k možnostim zdravljenja raka in imunsko pogojenih bolezni. Med najpogosteje uporabljenimi biološkimi zdravili so zaviralci dejavnika tumorske nekroze (TNF). Crohnova bolezen je pogosta imunsko pogojena bolezen prebavil, ki se zdravi z zaviralci TNF. Kljub tarčnemu delovanju zaviralcev TNF del bolnikov s Crohnovo boleznijo žal ne doseže dobrega odziva na zaviralce TNF že ob uvedbi terapije ali pa sprva dober odziv na zaviralce TNF s časom izzveni. Neodzivnost na zaviralce TNF predstavlja pomeni izgubo nadzora nad pogosto hudim bolezenskim stanjem bolnika s Crohnovo boleznijo, ki je po nepotrebnem izpostavljen potencialno hudim neželenim stranskim učinkom bioloških zdravil, in tudi precejšnje finančno breme za zdravstveno blagajno. Ti razlogi utemeljujejo potrebo po napovedovanju odziva na biološka zdravila, po možnosti še pred uvedbo zdravljenja.
V doktorski disertaciji smo celostno raziskali biološke označevalce odziva na zaviralce dejavnika tumorske nekroze na ravni DNA in RNA ter maščobnih kislin v vzorcih periferne venske krvi skupine slovenskih bolnikov s Crohnovo boleznijo, ki se je zdravila z adalimumabom. Rezultate teh analiz smo uporabili za oblikovanje novih napovednih modelov s pristopi strojnega učenja, t.i. metode podpornih vektorjev. Za namene iskanja vzročnih bioloških procesov, ki pogojujejo neodzivnost na zaviralce dejavnika tumorske nekroze, smo sistematsko preučili gensko ontologijo že objavljenih bioloških označevalcev odziva na zaviralce dejavnika tumorske nekroze v kronični vnetni črevesni bolezni. Za primerjalno analizo genske ontologije smo zbrali tudi biološke označevalce odziva v revmatoidnem artritisu. Ker je neodzivnost pogostejša med pediatričnimi bolniki, smo analizo genske ontologije razširili še na vzročne gene pediatričnih dednih oblik kronične vnetne črevesne bolezni in sindrome s klinično sliko, skladno s kronično vnetno črevesno boleznijo. Dodatno smo tudi poskusili ponoviti že objavljen napovedni model odziva na infliksimab, ki temelji na izražanju petih genov v črevesni sluznici.
Rezultati genske ontologije že objavljenih označevalcev kažejo na povezavo med krvnimi lipoproteini in odzivom na zaviralce dejavnika tumorske nekroze pri kronični vnetni črevesni bolezni, kot tudi pri revmatoidnem artritisu. Na osnovi rezultatov genske ontologije pediatričnih dednih oblik kronične vnetne črevesne bolezni lahko sklepamo, da so zelo zgodnje pediatrične oblike z nastopom bolezni pred šestim letom starosti ločena genetska entiteta in je neodzivnost pogojena z drugimi procesi, npr. s primarno imunsko pomanjkljivostjo.
Analiza bioloških podatkov na ravni DNA in RNA ter maščobnih kislin ni pokazala biološkega označevalca, ki bi dosegel statistično značilnost, kar odraža tudi analiza napovedne moči s pristopi strojnega učenja. Profili maščobnih kislin nimajo napovedne moči za določevanje odziva na zaviralce dejavnika tumorske nekroze, genomski in transkripromski podatki pa imajo le nizko napovedno moč. Napovedni model na osnovi že objavljenega modela izražanja genov v črevesni sluznici smo uspešno ponovili in prenesli na drugo učinkovino (adalimumab). Na osnovi izražanja štirih genov v vneti in nevneti črevesni sluznici je možno napovedati odziv na zaviralce dejavnika tumorske nekroze s natančnostjo do 100 %. Nato smo še analizirali diagnostično napovedno moč bioloških podatkov s vključitvijo bioloških podatkov zdravih prostovoljcev, ki so že bili na voljo. Napovedni model na osnovi dednega zapisa in profilov maščobnih kislin je z natančnostjo do 100 % ločil med zdravimi prostovoljci in bolniki s Crohnovo boleznijo.
Keywords: Crohnova bolezen, genomika, transkriptomika, adalimumab, izid zdravljenja, genska ontologija
Published in DKUM: 20.01.2021; Views: 1462; Downloads: 160
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