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Öğe A Novel Mutation in the Promoter Region of the -Globin Gene: HBB: c.-127G > C(Taylor & Francis Ltd, 2016) Bilgen, Türker; Canatan, Duran; Delibas, Serpil; Keser, İbrahimNovel -globin gene mutations are still occasionally being reported, especially when evaluating milder phenotypes. We report here a novel putative mutation in the promoter region of the -globin gene and assess its clinical implications. A family, parents and four siblings, with hematological and clinical features suspected of being -globin gene mutation(s), were involved in this study. In addition to hematological and clinical evaluations of the whole family, molecular analyses of the -globin gene were performed by direct sequencing. Sequencing of the -globin gene revealed a novel genomic alteration in the regulatory region of the gene. This novel genomic alteration was defined as HBB: c.-127G>C according to the Human Genome Variation Society (HGVS) nomenclature. Two siblings were found to be carriers of the HBB: c.-127G>C mutation, while the other two siblings were carriers of the codon 8 (-AA) (HBB: c.25_26delAA) deletion of the -globin gene. The mother was a compound heterozygote for the codon 8 and HBB: c.-127G>C mutations. Based on hematological and clinical evaluations, we conclude that this novel -globin gene promoter region change would be associated with a mild phenotype of -thalassemia (-thal).Öğe Alloreactive memory B cell detection by flow cytometric cross match using polyclonally activated memory B cell culture supernatants(Elsevier, 2022) Akalan, Hande; Şirin, Duygu Yaşar; Yılmaz, İpek; Ata, Pınar; Kara, Veli Melih; Taşdemir, Nicel; Bilgen, Türker; Titiz, Mesut İzzetIn addition to alloantibodies, alloreactive memory B cell (mBC) evaluation has a potential for immunological risk assessment during transplantation processes. For the alloreactive mBCs evaluation currently, direct Flow Cytometric (FC) analysis using the HLA tetramer staining is an option. Evaluation of alloantibodies produced by the polyclonally stimulated alloreactive mBCs in in vitro culture system seems to be another useful approach, but this needs further downstream applications. In this study, we investigated the usefulness of the Flow Cytometric Cross Match (FCXM-supernatant) in which in vitro polyclonally activated mBCs culture supernatants and potential donor's lymphocytes being used for the mBC detection. FCXM-supernatant assays were performed between culture supernatants of polyclonally activated mBCs obtained from 4 allosensitized multiparous women and 14 renal transplant patients, and their non-alloimmunized spouses' or donors' lymphocytes, and vice versa. HLA typing was performed by SSP method. Anti-HLA antibodies produced by in vitro activated alloreactive mBCs were also evaluated by the Luminex assays. The success of in vitro polyclonal activation of mBCs was evaluated by a total IgG ELISA test and antibody secreting cell analyses by FC. Donor specific alloreactive mBCs were detected by FCXM-supernatant in 45% of the 18 allosensitized cases. Detection rate was 85% (6 out of 7) in the strongly allosensitized cases. No alloreactive mBCs was detected in control cases without allosensitization. FCXMsupernatant negative results of the allosensitized cases were related to low level of allosensitization and insufficient polyclonal stimulation evaluated by total IgG antibody tests of the supernatants. We herein report a practical methodology for alloreactive mBC detection as a donor specific manner using the FCXM-supernatant assay so that this would easily be transformed into a routine test performed in tissue typing laboratories.Öğe Comparison of Cytotoxic Flow Cytometric Cross Match With Complement Dependent Lymphocytotoxicity and Flow Cytometric Cross Match in Renal Transplant Patients(Elsevier USA, 2019) Bilgen, Türker; Canbakan, Mustafa; Şahin, G.; Titiz, Mesut İzzetCytotoxic flow cytometric crossmatch (cFCXM), identified by detecting complement-mediated cytotoxic cell death in addition to the capability of showing the alloantibodies binding onto lymphocytes at the same time, can reduce the necessary time and workload in evaluating alloantibodies. More data from clinical samples are needed for cFCXM to be accepted by tissue typing laboratories. In this study, we compared cFCXM with complement-dependent lymphocytotoxicity and standard flow cytometric crossmatch in 41 renal pretransplant patients. A comparison of the obtained data was performed using Spearman's correlation test. We found that cFCXM showed no statistically significant differences with complement-dependent lymphocytotoxicity and flow cytometric crossmatch. We believe that cFCXM can be used in clinical laboratories in the near future following intra-laboratory validation. © 2019 Elsevier Inc.Öğe Copy number increase of oncoprotein CIP2A is associated with poor patient survival in human head and neck squamous cell carcinoma(Wiley, 2016) Routila, Johannes; Bilgen, Türker; Saramaki, Outi; Grenman, Reidar; Visakorpi, Tapio; Westermarck, Jukka; Ventela, SamiBackgroundCIP2A, an inhibitor of PP2A tumour suppressor function, is a widely overexpressed biomarker of aggressive disease and poor therapy response in multiple human cancer types. MethodsCIP2A and DPPA4 copy number alterations and expression were analysed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in different cell lines and a tissue microarray of 52 HNSCC patients. Results were correlated with patient survival and other clinicopathological data. ResultsCIP2A and DPPA4 copy number increase occurred at a relatively high frequency in human HNSCC patient samples. CIP2A but not DPPA4 FISH status was significantly associated with patient survival. CIP2A detection by combining IHC with FISH yielded superior resolution in the prognostication of HNSCC. ConclusionsCIP2A copy number increase is associated with poor patient survival in human HNSCC. We suggest that the reliability and prognostic value of CIP2A detection can be improved by performing FISH analysis to CIP2A IHC positive tumours.Öğe Cytotoxic Antibody Detection by Means of Flow-Cytometric Cross-Match(Elsevier Science Inc, 2017) Bilgen, Türker; Ata, P.; Tozkir, J.; Tozkır, Hilmi; Titiz, Mesut İzzetBackground. Complement-dependent lymphocytotoxicity (CDC-XM) and flowcytometric (FCXM) cross-match are analyzed individually for each donor and recipient pair, because these techniques have fundamental differences for the evaluation of histocompatibility. Lately, cytotoxic flow-cytometric cross-match (cFCXM) has been developed as an alternative to both CDC-XM and FCXM techniques. We evaluated the limits of cFCXM with the use of different positive serum dilutions. Methods. CDC-XM, FCXM, and cFCXM tests were performed with the use of commercially available negative and positive serum samples and lymphocytes from healthy donors. Results. Complement-dependent cell death was successfully detected with the use of cFCXM. Complement-dependent cell death ratios in cFCXM were similar those in CDCXM. With cFCXM, not only complement-dependent cell death but also IgG binding could be detected within a single assay. At higher concentrations of the positive serum, IgG-fluorescein isothiocyanate (FITC) mean fluorescent intensity (MFI) values detected with the use of cFCXM were less than those of conventional FCXM. Correspondingly, for dead cells, MFI values of IgG-FITC were less than those of live cells in higher positive serum concentrations in the cFCXM assay. Moreover, our results demonstrated that in cFCXM analysis, the decreasing ratio of dead cells at increasing positive serum dilutions was not in parallel with the same decrease in IgG-FITC MFI values. Conclusions. The cFCXM technique detects complement-mediated cytotoxic cell death with the additional ability to show IgG binding in the same tube and therefore may reduce the necessary bench time and workload.Öğe Effects of idiopathic erythrocytosis on the left ventricular diastolic functions and the spectrum of genetic mutations: A case control study(Lippincott Williams & Wilkins, 2022) Yeşilaltay, Alpay; Değirmenci, Hasan; Bilgen, Türker; Şirin, Duygu Yaşar; Bayır, Duygu; Değirmenci, Pelin; Turgut, BurhanBackground: We have aimed at exposing left ventricular diastolic functions and the presence of known genetic mutations for familial erythrocytosis, in patients who exhibit idiopathic erythrocytosis. Methods: Sixty-four patients with idiopathic erythrocytosis (mean age, 46.4 +/- 2.7 years) and 30 age-matched healthy subjects were prospectively evaluated. The regions of interest of the erythropoietin receptor, hemoglobin beta-globin, von Hippel-Lindau, hypoxia-inducible factor 2 alpha, and Egl-9 family hypoxia-inducible factor genes were amplified by PCR. Left ventricular (LV) mass was measured by M-mode and 2-dimensional echocardiography. LV diastolic functions were assessed by conventional echocardiography and tissue Doppler imaging. Results: As a result of genetic analyses, genetic mutations for familial erythrocytosis were detected in 5 patients. It has been observed in our study that the risk of cardiovascular disorders is higher in patients. Interventricular septum thickness, left atrial diameter, and some diastolic function parameters such as deceleration time and isovolumetric relaxation time have been found to be significantly higher in idiopathic erythrocytosis group than in the controls. Conclusion: This study has shown that LV diastolic functions were impaired in patients with idiopathic erythrocytosis. In this patient group with increased risk of cardiovascular disorders, the frequent genetic mutations have been detected in 5 patients only. Therefore, further clinical investigations are needed as novel genetic mutations may be discovered in patients with idiopathic erythrocytosis because of cardiovascular risk.Öğe First observation of hemoglobin G-waimanalo and hemoglobin fontainebleau cases in the Turkish population(Turkish Society of Hematology, 2016) Canatan, D.; Bilgen, Türker; Çiftçi, V.; Yazıcı, G.; Delibaş, S.; Keser, İ.[No abstract available]Öğe First Observation of Hemoglobin Kansas [beta 102(G4)Asn -> Thr, AAC > ACC] in the Turkish Population(Galenos Yayincilik, 2015) Keser, İbrahim; Öztaş, Alev; Bilgen, Türker; Canatan, Duran[No Abstract Available]Öğe FMR1 Gene Mutation Analysis and CGG Repeat Number Distribution from a Single Center(Gazi Univ, Fac Med, 2022) Arıkan, Yunus; Bilgen, Türker; Mıhcı, Ercan; Duman, Özgür; Karaman, Tuğba; Keser, İbrahimBackground: Mutation occurring in fragile X mental retardation 1 (FMR1) gene is acknowledged as the most common cause for X chromosome linked intellectual disability/mental retardation (XLID/XLMR). This gene harbors unstable CGG triplet repeats within its 5'UTR (untranslated region). Loss of function of the FMR1, which is mostly due to the hypermethylation of the CpG islands on its promoter region, causes fragile X syndrome (FXS). Displaying different frequencies, the FXS is a common phenomenon all over the world, the studies focus mostly on the Caucasian population. Purpose: We aimed to reveal the CGG repeat number distribution and the mutation profile of the FMR1 gene in clinically pre-diagnosed FXS patients and in family members of the patients who were diagnosed as full mutation. Methods: We evaluated the copy number of the CGG triplets in 767 FXS patients and their family members in Antalya province by employing fragment analysis molecular technique. We also assessed, by segregation analysis, whether there is unusual genetic transmission pattern of CGGs. Results: The molecular analysis shows the most common copy numbers of CGGs are thirty, twenty-nine and thirty-one. Present study is the first report concerning Antalya city of Turkey about the frequencies of the normal CGG repeats number, grey-zone, pre-mutation and full mutations, we updated our molecular test results with two unusual transmittance patterns of the CGG repeats. Conclusion: Since the potential of CGG repeat properties may cause differential intergenerational transmission patterns, its' population specific evaluation can contribute to provide a better genetic diagnosis and genetic counseling services for the related clinical entities.Öğe Gap-PCR Screening for Common Large Deletional Mutations of beta-Globin Gene Cluster Revealed a Higher Prevalence of the Turkish Inversion/Deletion (delta beta)(0) Mutation in Antalya(Galenos Yayincilik, 2016) Bilgen, Türker; Clark, Özden Altıok; Öztürk, Zeynep; Yesilipek, M. Akif; Keser, İbrahimObjective: Although the calculated carrier frequency for point mutations of the beta-globin gene is around 10% for Antalya Province, nothing is known about the profile of large deletional mutations involving the beta-globin gene. In this study, we aimed to screen common deletional mutations in the beta-globin gene cluster in patients for whom direct DNA sequencing was not able to demonstrate the mutation(s) responsible for the disease phenotype. Materials and Methods: Thirty-one index cases selected with a series of selection events among 60 cases without detected beta-globin gene mutation from 580 thalassemia-related cases tested by direct sequencing over the last 4 years in our diagnostic center were screened for the most common 8 different large deletional mutations of the beta-globin gene cluster by gap-PCR. Results: We detected 1 homozygous and 9 heterozygous novel unrelated cases for the Turkish inversion/deletion (delta beta)(0) mutation in our series of 31 cases. Our study showed that the Turkish inversion/deletion (delta beta)(0) mutation per se accounts for 16.6% of the unidentified causative alleles and also accounts for 1.5% of all detected mutations over the last 4 years in our laboratory. Conclusion: Since molecular diagnosis of deletional mutations in the beta-globin gene cluster warrants different approaches, it deserves special attention in order to provide prenatal diagnosis and prevention opportunities to the families involved. We conclude that the Turkish inversion/deletion (delta beta)(0), as the most prevalent deletional mutation detected so far, has to be routinely tested for in Antalya, and the gap-PCR approach has valuable diagnostic potential in the patients at risk.Öğe GTG Banded Karyotype of Anatolian River Buffalo (Bubalus bubalis, 2n=50)(Namık Kemal Üniversitesi, Ziraat Fakültesi, 2016) Soysal, Mehmet İhsan; Bilgen, Türker; Perucattı, Angela; Lannuzzı, LeopoldoThe water buffalo (Bubalus bubalis) is one of the most important farm animals of Turkey. There are two types of the water buffalo: river and swamp. While the chromosome number of the river type is 2n=50, that of swamp type is 2n=48. It was reported that the Anatolian water buffalo has 2n=50 chromosomes as being river type but the GTG banded karyotype has not been reported so far. We here report for the first time a GTG banded karyotype of the Anatolian water buffalo.Öğe Induction of fetal hemoglobin by modulation of epigenetic and genetic factors in beta thalassemia major patients(Nature Publishing Group, 2018) Keser, İbrahim; Arikan, Y.; Kupesiz, A.; Bilgen, Türker; Kurtoglu, E.[No Abstract Available]Öğe Investigation of alpha globin gene mutations by complementary methods in Antalya(Yuzuncu Yil Universitesi Tip Fakultesi, 2021) Keser, İbrahim; Mercan, T.K.; Bilgen, Türker; Kupesiz, O.A.; Arikan, Y.; Canatan, D.Alpha (?) thalassemia is one of the hemoglobinopaties that is inherited by autosomal recessive mode. It is caused by mutations on alpha-1 and alpha-2 globin genes. Deletional type mutations of globin genes have commonly been seen in alpha thalassemias. While small deletional mutations such as-3.7 cause ?+-thalassemia, large deletions such as-26.5-20.5 cause ?0-thalassemia. The objective of our study was to determine the profile of deletional and non-deletional ?-globin gene mutations in the Antalya population, Turkey. In present study, the presence of ?-thalassemia mutations were investigated by RDBH (reverse dot blot hybridization) among 250 patients with microcytic anemia and beta globin normal. Some positive and negative cases were confirmed by MLPA (multiplex ligation dependent probe amplification) and at the latest DNA sequencing. Eight different mutations were determined in 112 (44.8%) of patients in our study. The-??3.7 deletion was the most common mutation(73.3%). Others common mutations were the – ?20.5 (13.0%) and –MED (6.5%),--FIL (2.4%), Hb Adana (2.4%). The 97.5 % of total mutations consisted of these five mutations. Three patients with Hb H disease were found related with-? 3.7 /-(?)-20.5 genotype. One patient (2.04%) had the ??? anti-3.7 gene triplication. Two rare mutations, ?2 codon 64 (G>C) (Hb Fontainebleau) and ?2 codon 193 (G>A) (Hb G-Waimanalo), were determined by DNA sequencing firstly in Antalya Province, Turkey. Our results may be valuable to give accurate premarital genetic counseling and to apply classical prenatal and preimplantation genetic diagnosis by the complementary methods such as RDBH, MLPA and DNA sequencing for the screening of alpha thalassemia carriers. © 2021, Yuzuncu Yil Universitesi Tip Fakultesi. All rights reserved.Öğe Investigation of the Effects of Piperlongumine and Doxorubicin Combined Treatment on Cell Death via PTEN in HeLa Cells(2024) Güzelel, Gonca; Akalan, Hande; Bilgen, Türker; Şirin, Duygu YaşarDoxorubicin (Dox), which is used in treating many types of cancer including cervix cancer nevertheless, its effect alone is low especially in recurrent cases. Therefore, investigating of agents that can increase the impact of Dox continues. The aim of the present study is to answer the question: Can Piperlongumine (PL) a natural alkaloid cause an increase in the efficacy of Dox in the HeLa cell line? In this study, the effects of Dox and PL on cell viability by MTT and Acridine orange/propidium iodide staining, and expression levels of the PTEN (Phosphatase and tensin homolog 10) gene by Real-Time PCR and Western-Blot were evaluated in HeLa cells. It was determined that PL combined with Dox increased cell death and suppressed cell proliferation. The PTEN gene expression was decreased in all experimental groups, but the PTEN protein phosphorylation increased in cultures treated with PL and when Dox/PL was combined. The fact that PL application increases the activation of PTEN, which is a tumor suppressor. This indicates that it can be used to increase the effectiveness of Dox in the treatment.Öğe Piperlongumine increases the apoptotic effect of doxorubicin and paclitaxel in a cervical cancer cell line(Wolters Kluwer Medknow Publications, 2020) Şeber, Erdoğan Selçuk; Şirin, Duygu Yaşar; Yetişyiğit, Tarkan; Bilgen, TürkerObjective: Piperlongumine (PL) is an alkaloid derived from the edible pepper (Piper longum L) and it has been described to have various biologic activities including anticancer effects. Our aim in this study was to assess the cytotoxic role of PL on a cervical cancer cell line (HeLa) and to evaluate the effects of PL/doxorubicin and PL/paclitaxel combination therapies on apoptotic cancer cell death. Material and Methods: The cytotoxicity, IC50 doses by MTT assay confirmed by fluorescent imaging, and apoptotic cell rates by Annexin V staining using flow cytometry were determined for PL, doxorubicin, paclitaxel, and for their combinations. Results: It was shown that the PL by itself induced the apoptosis in HeLa cells. PL in combination with doxorubicin and paclitaxel increased apoptotic cell death compared to either chemotherapeutic agent alone. Conclusion: We conclude that the PL inhibits cancer cell growth by inducing apoptosis and has a potential anticancer activity in cervical cancer, especially when combined with doxorubicin and paclitaxel. © 2020 Wolters Kluwer Medknow Publications. All rights reserved.Öğe Protective effects of Acetobacter ghanensis against gliadin toxicity in intestinal epithelial cells with immunoregulatory and gluten-digestive properties(Springer Heidelberg, 2022) Doğuer, Çaglar; Akalan, Hande; Demirok, Nazan Tokatlı; Erdal, Berna; Mete, Rafet; Bilgen, TürkerPurpose The aim of this study was to establish whether Acetobacter ghanensis, the probiotic characteristics of which were evaluated previously, attenuates gliadin-induced toxicity in intestinal epithelial cells with gluten-digestive and immunoregulatory properties. Methods A co-culture model of human intestinal epithelial cell (Caco-2) monolayers on top of peripheral blood mononuclear cells (PBMCs) obtained from patients with celiac disease (CD) was established. The gluten-digestive properties of A. ghanensis were determined by checking bacterial growth in a medium containing gluten as the main nitrogen source. The mRNA levels of genes encoding TJ-associated proteins were measured by quantitative real-time PCR (qRT-PCR). The concentrations of IL-6 and TNFac were determined by enzyme-linked immunosorbent assay (ELISA). Results We found that PT-gliadin disrupted intestinal barrier integrity by modulating the expression of TJ-associated genes encoding zonulin (increased by similar to 60%), zonula occludens-1 (ZO-1) (decreased by similar to 22%), and occludin (decreased by similar to 28%) in Caco-2 cells. Furthermore, PT-gliadin treatment in Caco-2 cells was associated with increased concentrations of IL-6 (similar to 1.6-fold) and TNFac (similar to twofold) from PBMCs. These modulatory effects of PT-gliadin, however, were suppressed when Caco-2 cells were subjected to A. ghanensis in the presence of PT-gliadin. As a factor underlying these protective effects, we showed that A. ghanensis could digest gluten peptides. Conclusions To our knowledge, the current study is the first to demonstrate that A. ghanensis improves intestinal barrier functions by attenuating the modulatory effects of PT-gliadin with immunoregulatory and gluten-digestive properties.Öğe Why Crossmatch Tests are Very Important and What Do They Tell Us?(Turkish Society of Nephrology, 2020) Titiz, Mesut İzzet; Bilgen, TürkerOrgan transplantation is a very complex procedure that can save lives. It is a very useful procedure if the concepts of immunology, gained through bitter experience over the years, are kept in mind during practice. Allogeneic sensitization due to previous exposure(s) to alloantigens can hamper the procedure and remains the main obstacle to organ transplantation. Allosensitization and its level in a patient can be revealed before transplantation using the crossmatch test performed by incubating the patient’s serum with the possible donor’s lymphocytes in a laboratory environment. Crossmatch tests are routinely used prior to transplantation to prevent acute humoral reactions to the allograft tissue following reperfusion and also for long-term monitoring of the patient’s humoral status during the pre- and post-transplantation periods. © 2020 Turkish Society of Nephrology. All rights reserved.Öğe Yumurtalık Kanseri Hücre Soylarında CIP2A Onkogeni Mutasyonlarının Taranması(2019) Şirin, Duygu Yaşar; Bilgen, TürkerAmaç: Kanserle ilişkili genetik değişimlerin belirlenmesi erken tanı, hastalığın takibi ve hedefe yöneliktedavi yaklaşımlarının geliştirilmesi açısından önem taşımaktadır. CIP2A, birçok insan kanserleri ileilişkilendirilmiş yeni tanımlanmış bir onkoproteindir. Birçok kanserde CIP2A gen ekspresyonununartışı gösterilmiştir ancak bu güne kadar AGS, HeLa, HT1080 kanser hücre soylarında CIP2A promotorbölge mutasyonlarının araştırıldığı ve tarafımızdan yapılmış olan bir çalışma dışında herhangibir kanser tipinde CIP2A geninin kodlayan dizilerindeki mutasyonlarını araştıran bir çalışma yapılmamıştır.Bu çalışmamızda CIP2A gen ekspresyonunun kanserdeki artışına ilişkin moleküler mekanizmalarınaydınlatılmasına katkıda bulunmak amacı ile bu genin onkogenik etkisinin oluşmasında rolüolması muhtemel regülatör bölge ve gen içi mutasyonlar araştırılmıştır.Gereç ve Yöntemler: CIP2A geninin kodlayan dizileri, ekzon-intron bağlantı bölgeleri ve promotorbölgesi DNA dizi analizi yöntemiyle SK-OV-3, Ov-CAR3 ve Caov-3 insan yumurtalık kanseri hücresoylarında taranmıştır.Bulgular: Ov-CAR3 hücre soyunda ekson 3, intron 6 ve intron 8’de, Caov-3 hücre soyunda ise sadeceintron 6 ve intron 8’de genomik değişimler saptanmıştır.Sonuç: Bulgularımız, yumurtalık kanseri için CIP2A ekspresyonundaki artışta CIP2A’daki genomikdeğişimlerin etkisini dışlamaktadır. CIP2A onkoproteinini yüksek düzeylerde ekspresyon eden hücrelerdebu duruma neden olabilecek diğer mekanizmaların da araştırıldığı fonksiyonel çalışmalaragereksinim vardır.
