Browsing by Author "Gulbas, Zafer"

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    Development of Small Molecule MEIS Inhibitors that modulate HSC activity
    (NATURE RESEARCH, 2020-01-01) Turan, Raife Dilek; Albayrak, Esra; Uslu, Merve; Siyah, Pinar; Alyazici, Lamia Yazgi; Kalkan, Batuhan Mert; Aslan, Galip Servet; Yucel, Dogacan; Aksoz, Merve; Tuysuz, Emre Can; Meric, Neslihan; Durdagi, Serdar; Gulbas, Zafer; Kocabas, Fatih
    Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34(l)degrees (w) cells) and human (CD34(+), CD133(+), and ALDH(hi) cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including Hif-1 alpha, Hif-2 alpha and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.
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    GUT MICROBIOTA EFFECTS IN HEMATOPOIETIC STEM CELL TRANSPLANT PATIENTS
    (ISTANBUL UNIV, FAC MEDICINE, PUBL OFF, 2022-01-01) Gurer, Ekin Ece; Oguz, Fatma S. A. V. R. A. N.; Kalayoglu, Sevgi BEsIsIK.; Aktas, Zerrin; Gulbas, Zafer; Oncul, Mustafa Oral; Sezerman, Ugur
    Objective: In our study, we analyzed gut microbiota in allo-HSCT patients and aimed to evaluate the relationship of gut microbio-ta with transplant complications, mainly GVHD. Materials and Methods: A total of 25 adult recipients and do-nors who underwent allo-HSCT at Istanbul Anadolu Medical Center were included in the study. Stool samples were collected twice, before chemotherapy regimen and after allo-HSCT. Sam-ples were analyzed by High Melting (HRM) Analysis and Next Generation Sequencing (NGS) methods after nucleic acid iso-lation. Sequencing was done with Illumina MiSeq. Bacteria Silva database was used for taxonomic classification and QIIME 2 pro-grams were used for analysis. Statistical analyses were carried out with the R statistical programming language. Results: Twenty-five allo-HKHN recipients were included in the study. The mean age was 46.24 +/- 14.86 years in recipients and 43.40 +/- 13.20 years in donors. Gender distribution was M/F: 15/10 in patients and M/F: 17/8 in donors. Recipient and donor sib-ling HLA match was 10/10. The rate of GVHD associated with Allo-HSCT was 16\%, and the relapse rate was 16\%. It was ob-served that the Firmicutes and Proteobacteria phyla changed significantly before and after transplantation. The number of Entereccocus species was found to be higher in patients who developed GVHD and died. The loss of diversity was found to be statistically significant in the pre-transplant and post-engraft-ment samples of the patients. Conclusion: Gut microbiota diversity may guide the monitoring of GVHD and also may be manipulated for the treatment of GVHD. It is thought that increasing the diversity of commensal bacteria can also positively affect the prognosis of the disease.