Tıp Fakültesi / Faculty of Medicine
Permanent URI for this collectionhttps://hdl.handle.net/11727/1403
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Item An Exploratory, Single-Center Study of Factors Associated with Child Marriage Among Syrian Female Adolescents Residing in Turkey(2022) Kutuk, Meryem Ozlem; Kilicaslan, Fethiye; Tufan, Ali Evren; Celik, Fatma; Gokcen, Cem; Bag, Harika Gozukara; Servi, Gulay; Karali, Mehtap; Bahsi, Gamze; Servi, Ceyhun; Alatli, Resat; Kandemir, Betul; Aytekin, Neslihan; Kutuk, Ozgur; https://orcid.org/0000-0001-9854-7220; AAH-1671-2019This exploratory study aimed to evaluate factors related with child marriage compared to unmarried status in female adolescent residents in a refugee camp in Turkey. The rate of child marriage and developmental status of offspring from those marriages were reported. A research team evaluated married female youth and their offspring for psychopathologies according to DSM-5 criteria and ascertained lifetime traumatic events among mothers. We compared the traumatic experiences and psychopathologies of married females and controls. Post-traumatic stress disorder (PTSD) was the most common diagnosis in both groups and child brides reported greater cumulative traumatic experiences and elevated rates of PTSD. More than one-tenth (i.e., 15.1%) of offspring of child brides displayed developmental delays and 12.1% were diagnosed with global developmental delay.Item Distinct Apoptotic Blocks Mediate Resistance to Panher Inhibitors in HER2+Breast Cancer Cells(2018) Karakas, Bahriye; Ozmay, Yeliz; Basaga, Huveyda; Gul, Ozgur; Kutuk, Ozgur; https://orcid.org/0000-0001-9854-7220; 29733883; AAH-1671-2019Despite the development of novel targeted therapies, de novo or acquired chemoresistance remains a significant factor for treatment failure in breast cancer therapeutics. Neratinib and dacomitinib are irreversible panHER inhibitors, which block their autophosphorylation and downstream signaling. Moreover, neratinib and dacomitinib have been shown to activate cell death in HER2-overexpressing cell lines. Here we showed that increased MCL1 and decreased BIM and PUMA mediated resistance to neratinib in ZR-75-30 and SKBR3 cells while increased BCL-XL and BCL-2 and decreased BIM and PUMA promoted neratinib resistance in BT474 cells. Cells were also cross-resistant to dacomitinib. BH3 profiles of HER2 + breast cancer cells efficiently predicted antiapoptotic protein dependence and development of resistance to panHER inhibitors. Reactivation of ERK1/2 was primarily responsible for acquired resistance in SKBR3 and ZR-75-30 cells. Adding specific ERK1/2 inhibitor SCH772984 to neratinib or dacomitinib led to increased apoptotic response in neratinib-resistant SKBR3 and ZR75-30 cells, but we did not detect a similar response in neratinib-resistant BT474 cells. Accordingly, suppression of BCL-2/BCL-XL by ABT-737 was required in addition to ERK1/2 inhibition for neratinib- or dacomitinib-induced apoptosis in neratinib-resistant BT474 cells. Our results showed that different mitochondrial apoptotic blocks mediated acquired panHER inhibitor resistance in HER2 + breast cancer cell lines as well as highlighted the potential of BH3 profiling assay in prediction of panHER inhibitor resistance in breast cancer cells.Item Sociodemographic and Clinical Features of Obsessive Compulsive Disorder in a Large Sample of Children and Adolescents from Turkey(2018) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Erden, Sema; Aksu, Gulen Guler; Kilicaslan, Fethiye; Sogut, Figen; Kutuk, Ozgur; Toros, Fevziye; https://orcid.org/0000-0001-9854-7220; AAH-1671-2019Objective: Obsessive compulsive disorder (OCD) is a time-consuming and chronic disorder characterized by obsessions and compulsions that can start before age of eighteen and can be associated with significant impairments in academic, social and family functioning. In this study, our aim was to evaluate sociodemographic characteristics, clinical pictures and comorbid diagnoses of a large sample of children and adolescents who were diagnosed with OCD according to diagnostic criteria of DSM-IV-TR in a child and adolescent psychiatry outpatient clinic of a University Hospital. Methods: Patients who were first diagnosed at the study center with OCD according to DSM-IV-TR criteria were included. For inclusion, the primary diagnosis should be OCD as per DSM-IV-TR criteria and there must be concordance between at least 2 clinicians (one resident and the head of department) for diagnosis. Results: 440 cases were included in our study and the most common obsessions in our sample were contamination with dirt (48.8%), and exactness (23.8%) and most common compulsions were ordering/checking (42.4%) and washing/cleaning (32.0%). Most of the patients in our sample (78.0%) had a comorbid diagnosis and most common comorbidities were Attention-Deficit/ Hyperactivity Disorder (26.6%) and Generalized Anxiety Disorder (20.5%). Discussion: Accordingly, our results in terms of comorbidity, obsessions and compulsions are consistent with the literature. In conclusion, this is the largest study on a clinical sample of pediatric OCD from Turkey that we are aware of in terms of sample size, time frame and statistical power.Item A Novel Homozygous Nonsense Mutation in The Calpastatin (CAST) Gene Associated with Peeling Skin Phenotype in A Child(2018) Saricaoglu, Hayriye; Temel, Sehime; Zorlu, Ozge; Turkgenc, Burcu; Kutuk, Ozgur; Karakas, Bahriye; Kiran, Ummuhan; Erguner, Bekir; Yakicier, Cengiz; https://orcid.org/0000-0001-9854-7220; AAH-1671-2019Item Migraine and Associated Comorbidities are Three Times More Frequent in Children With ADHD and Their Mothers(2018) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Guler, Gulen; Yalin, Osman Ozgur; Altintas, Ebru; Bag, Harika Gozukara; Uluduz, Derya; Toros, Fevziye; Aytan, Nurgul; Kutuk, Ozgur; Ozge, Aynur; https://orcid.org/0000-0002-2918-7871; https://orcid.org/0000-0001-5207-6240; https://orcid.org/0000-0003-2735-4805; https://orcid.org/0000-0001-9854-7220; 29921473; AAI-9626-2021; C-5074-2015; G-8832-2015; AAH-1671-2019Objective: Attention deficit and hyperactivity disorder (ADHD) is a neuro-developmental disorder related to internalizing and externalizing disorders as well as somatic complaints and disorders. This study was conducted to evaluate the prevalence of headache subtypes, epilepsy, atopic disorders, motion sickness and recurrent abdominal pain among children and adolescents with ADHD and their parents. Methods: In a multi-center, cross-sectional, familial association study using case-control design, treatment na ve children and adolescents between 6 and 18 years of age diagnosed with ADHD according to the DSM-5 criteria as well as age- and gender matched healthy controls and their parents were evaluated by a neurologist and analyzed accordingly. Results: 117 children and adolescents with ADHD and 111 controls were included. Headache disorder diagnosis was common for both patients and healthy controls (59.0% vs. 37.8%), with a significantly elevated rate in the ADHD group (p = 0.002). Migraine was found in 26.0% of ADHD patients and 9.9% of healthy controls. Tension headache was found in 32.4% of ADHD patients and 27.9% of healthy controls. Headache diagnosis was also found to be significantly more common in mothers of children with ADHD than control group mothers (90.5% vs. 36.6%, p < 0.001). Conclusion: Headache diagnoses and specifically migraines were significantly more common among children with ADHD and their mothers, while recurrent abdominal pain was elevated in both parents and ADHD patients. Migraine is an important part of ADHD comorbidity, not only for children but also for mothers. Motion sickness may be reduced among families of ADHD probands. (C) 2018 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.Item Cytotoxic and Apoptotic Effects of Novel Pyrrolo[2,3-d]Pyrimidine Derivatives Containing Urea Moieties on Cancer Cell Lines(2018) Kilic-Kurt, Zuhal; Bakar-Ates, Filiz; Karakas, Bahriye; Kutuk, Ozgur; 0000-0003-2809-8946; 0000-0001-9616-4656; 0000-0001-9854-7220; 29866023; AAS-5399-2020; AAG-3843-2020; AFW-5486-2022; AAH-1671-2019Background: Pyrrolo[2,3-d]pyrimidines have been recently reported to have anticancer activities through inhibition of different targets such as, Epidermal Growth Factor Receptor (EGFR) tyrosine kinase, Janus Kinase (JAK), mitotic checkpoint protein kinase (Mps1), carbonic anhydrase, MDM-2. On the other hand, aryl urea moieties which are found in some tyrosine kinase inhibitors such as Sorafenib and Linifanib have aroused recent attention as responsible for anticancer activities. The aims of this paper are to synthesize pyrrolo[2,3-d]pyrimidine derivatives containing urea moiety and evaluate their anti-cancer activity against human lung cancer cell line (A549), prostate cancer cell line (PC3), human colon cancer cell line (SW480) and human breast cancer cell line (MCF-7). Methods: A series of new pyrrolo[2,3-d]pyrimidines containing urea moieties have been synthesized as Scheme 1. In vitro cytotoxicity of target compounds were evaluated against, SW480, PC3, A549 and MCF-7 human cancer cell lines using a MTT assay. In order to evaluate the mechanism of cytotoxic activity of compounds 9e, 10a and 10b, having the best cytotoxic activity, Annexin V binding assay, cell cycle analysis and western blot analysis were performed. Results: Among the target compounds, 10a (IC50 = 0.19 mu M) was found to be the most potent derivative against PC3 cells. Compound 10b and 9e showed the strong cytotoxic activity against MCF-7 and A549 cells with IC50 value of 1.66 mu M and 4.55 mu M, respectively. Flow cytometry data suggest that the cytotoxic activity of the compounds on cancer cells might be mediated by apoptosis revealing a significant increase in the percentage of late apoptotic cells and causing a cell cycle arrest at different stages. Western blot analysis of apoptosis marker demonstrated that these compounds induce apoptosis through the intrinsic pathway. Conclusion: Compound 9e displayed the strongest cytotoxicity against A549 cancer cell line, and induced late apoptosis in A549, as confirmed by cell cycle arrest in G0/G1 phase. In addition, compound 9e reduced expression of the anti-apoptotic protein Bcl-2 and enhanced expression of the pro-apoptotic protein Bax, besides increased caspase-9 and caspase-3, as well as cleavage of PARP levels. These results suggest that compound 9e showed a cytotoxic effect in A549 cells through activation of the mitochondrial apoptotic pathway. Further studies will be undertaken in our laboratory to improve cytotoxic activity of compound 9e and to identify the biological targets of 9e which are responsible for anticancer activity.Item Kinome-wide RNAi screening for mediators of ABT-199 resistance in breast cancer cells identifies Wee1 as a novel therapeutic target(2021) Aka, Yeliz; Acikbas, Ufuk; Kutuk, Ozgur; 34171479Antiapoptotic and proapoptotic BCL-2 protein family members regulate mitochondrial apoptotic pathway. Small molecule inhibitors of antiapoptotic BCL-2 proteins including BCL-2-specific inhibitor ABT-199 (Venetoclax) are in clinical development. However, the efficiency of ABT-199 as a single agent in solid tumors is limited. We performed a high-throughput RNAi kinome screen targeting 691 kinases to identify potentially targetable kinases to enhance ABT-199 response in breast cancer cells. Our studies identified Wee1 as the primary target kinase to overcome resistance to ABT-199. Depletion of Wee1 by siRNA-mediated knockdown or inhibition of Wee1 by the small molecule Wee1 inhibitor AZD1775 sensitized SKBR3, MDA-MB-468, T47D and CAMA-1 breast cancer cells to ABT-199 along with decreased MCL1. BH3-only proteins PUMA and BIM functionally contribute to apoptosis signaling following co-targeting BCL-2 and Wee1. Suppression of Wee1 function increased mitochondrial cell death priming. Furthermore, we found that Wee1 inhibition altered MCL1 phosphorylation and protein stability, which led to HUWE1-mediated MCL1 degradation. Our findings suggest that Wee1 inhibition can overcome resistance to ABT-199 and provide a rationale for further translational investigation of BCL-2 inhibitor/Wee1 inhibitor combination in breast cancer.Item Novel inflammatory targets for immunotherapies in pediatric patients with trichotillomania(2020) Kutuk, Meryem Ozlem; Tufan, Ali Evren; Kilicaslan, Fethiye; Mutluer, Tuba; Gokcen, Cem; Karadag, Mehmet; Yektas, Cigdem; Kandemir, Hasan; Buber, Ahmet; Aksu, Gulen Guler; Topal, Zehra; Giray, Asli; Celik, Fatma; Acikbas, Ufuk; Kutuk, Ozgur; 0000-0002-2918-7871; 32113788; AAI-9626-2021Immune dysregulation may be important in the etiology of obsessive-compulsive and related disordersandbody-focusedrepetitivebehaviors, such as Trichotillomania (TTM). The role of inflammation and inflammatory markers in TTM has received relatively little attention. This study was aimed to determine the expression levels of inflammatory markers (i.e. IL-1 beta, IL-1 alpha, IL-4, IL-6, IL-17, TNF-alpha and TGF-5) in peripheral blood mononuclear cells of children with TTM and healthy controls and to evaluate their association with clinical variables. Seventy-seven patients with TTM and 107 healthy controls were enrolled in the study. Peripheral blood was collected in standardized conditions. The mean age of patients and controls did not differ significantly (10.8 +/- 4.4 and 12.0 +/- 3.2 years; respectively). The majority of patients with TTM and controls were females (n = 55, 71.4 % and n = 55, 51.4 %; respectively); with a greater preponderance of females among TTM. Patients with TTM had significantly elevated expression levels of TNF-alpha, IL-6 and IL-17 compared to controls. However, the expression level of IL-4 was significantly reduced in TTM patients compared to controls. Accordingly, we found a proinflammatory state in TTM and those findings may suggest novel treatment options for TTM and further, crossdisciplinary studies focusing on neuro- inflammation in TTM conducted on larger samples are needed.Item Cytokine expression profiles in Autism spectrum disorder: A multi-center study from Turkey(2020) Kutuk, Meryem Ozlem; Tufan, Evren; Gokcen, Cem; Kilicaslan, Fethiye; Karadag, Mehmet; Mutluer, Tuba; Yektas, Cigdem; Coban, Nurdan; Kandemir, Hasan; Buber, Ahmet; Coskun, Seyma; Acikbas, Ufuk; Guler, Gulen; Topal, Zehra; Celik, Fatma; Altintas, Ebru; Giray, Asli; Aka, Yeliz; Kutuk, Ozgur; 0000-0002-2918-7871; 0000-0001-9854-7220; 0000-0003-2735-4805; 32563959; AAI-9626-2021; AAH-1671-2019; G-8832-2015Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in communication and social interaction as well as restricted interests and repetitive behaviors. The pathogenesis of ASD is not completely understood, but a growing body of research has demonstrated that the immune response may be a contributing factor in the etiology and/or ontogeny of ASD. The aim of this study was to determine the expression levels of IL-1 beta, IL-1 alpha, IL-4, IL-6, IL-17, TNF-alpha and TGF-beta in peripheral blood mononuclear cells of children with ASD and healthy controls in order to determine the contributions of cytokines to ASD. Within the study timeframe, 195 children with ASDs (80.5% male) and 162 controls (73.6% male) were enrolled. Most children with ASD had a comorbid disorder (n = 114, 58.5%), with the most common diagnoses as Intellectual Developmental Disorder (IDD, n = 64, 32.8%) and ADHD (n = 64, 32.8%). The majority of children with ASD had severe autistic symptoms as evaluated via Childhood Autism Rating Scale (CARS, n = 130, 64.6%). The mean CARS score in the ASD sample was 40.8 (S.D. = 7.6). The patients with ASD were found to have significantly higher levels of IL-6 (p < 0.001) and significantly lower levels of IL-17 (p < 0.05, all Bonferroni corrected). Treatment tended to affect IL-4 levels. Lastly, discriminant function analysis (DFA) revealed that a combination of IL-6, IL-17 and IL-1 alpha correctly classified 56.6% of cases. Despite extensive immunological evidence suggesting immune system aberrations, further research is required to clarify the relationship between immune profiles and ASD symptoms.Item RAB25 confers resistance to chemotherapy by altering mitochondrial apoptosis signaling in ovarian cancer cells(2020) Temel, Sehime Gulsun; Giray, Asli; Karaka, Bahriye; Gul, Ozgur; Kozanoglu, Ilknur; Celik, Husnu; Basaga, Huveyda; Acikbas, Ufuk; Sucularli, Ceren; Oztop, Sidika; Aka, Yeliz; Kutuk, Ozgur; 0000-0001-5653-6080; 0000-0001-9854-7220; 0000-0002-5268-1210; 32901335; AAJ-7911-2020; AAH-1671-2019; AAE-1241-2021Ovarian cancer remains one of the most frequent causes of cancer-related death in women. Many patients with ovarian cancer suffer from de novo or acquired resistance to chemotherapy. Here, we report that RAB25 suppresses chemotherapy-induced mitochondrial apoptosis signaling in ovarian cancer cell lines and primary ovarian cancer cells. RAB25 blocks chemotherapy-induced apoptosis upstream of mitochondrial outer membrane permeabilization by either increasing antiapoptotic BCL-2 proteins or decreasing proapoptotic BCL-2 proteins. In particular, BAX expression negatively correlates with RAB25 expression in ovarian cancer cells. BH3 profiling assays corroborated that RAB25 decreases mitochondrial cell death priming. Suppressing RAB25 by means of RNAi or RFP14 inhibitory hydrocarbon-stapled peptide sensitizes ovarian cancer cells to chemotherapy as well as RAB25-mediated proliferation, invasion and migration. Our data suggest that RAB25 is a potential therapeutic target for ovarian cancer.