Browsing by Author "Kutbay, NO"
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Item Effects of metformin and pioglitazone combination on apoptosis and AMPK/mTOR signaling pathway in human anaplastic thyroid cancer cellsKutbay, NO; Avci, CB; Yurekli, BS; Kurt, CC; Shademan, B; Gunduz, C; Erdogan, MAnaplastic cancer constitutes 1% of thyroid cancers, and it is one of the most aggressive cancers. Treatment options are external radiation therapy and/or chemotherapy. The success rate with these treatment modalities is not satisfactory. We aimed to evaluate the effects of metformin (MET) and pioglitazone (PIO) combination on apoptosis and AMP-activated protein kinase/mammalian target of rapamycin (mTOR) signaling pathway in human anaplastic thyroid cancer cells. In this study, we evaluated the effects of MET and PIO individually and the combination of the two drugs on the cellular lines SW1736 and C643 ATC. Genes contained in the mTOR signaling pathway were examined using human mTOR Signalization RT(2)Profiler PCR Array. In C643 and SW1736 cell lines, IC(50)doses of MET and PIO were found out as 17.69 mM, 11.64 mM, 27.12 mu M, and 23.17 mu M. Also, the combination of MET and PIO was determined as an additive according to isobologram analyses. We have found the downregulation of the expression levels of oncogenic genes:AKT3, CHUK, CDC42, EIF4E, HIF1A, IKBKB, ILK, MTOR, PIK3CA, PIK3CG, PLD1, PRKCA, andRICTORgenes, in the MET and PIO combination-treated cells. In addition, expression levels of tumor suppressorgenes, DDIT4, DDIT4L, EIF4EBP1, EIF4EBP2, FKBP1A, FKBP8, GSK3B, MYO1C, PTEN, ULK1, andULK2, were found to have increased significantly. The MET + PIO combination was first applied to thyroid cancer cells, and significant reductions in the level of oncogenic genes were detected. The decreases, particularly, inAKT3, DEPTOR, EIF4E, ILK, MTOR, PIK3C, andPRKCAexpressions indicate that progression can be prevented in thyroid cancer cells and these genes could be selected as therapeutic targets.Item AN UNUSUAL CASE OF ACQUIRED PARTIAL LIPODYSTROPHY PRESENTING WITH ACANTHOSIS NIGRICANSKutbay, NO; Yurekli, BS; Yasar, Z; Akinci, BAbout 250 patients with acquired partial lipodystrophy (Barraquer-Simons) syndrome have been reported so far. It is characterized by the loss of adipose tissue from the face and upper extremities, and accumulated fat in the rest of the body. The disease usually starts in females during childhood or adolescence, and usually after a febrile illness. Fat loss often comes into view in months or years. We present a 23-year-old female patient with acquired partial lipodystrophy, which is rarely seen.Item A case of familial partial lipodystrophy caused by a novel lamin A/C (LMNA)mutation in exon 1 (D47N)Kutbay, NO; Yurekli, BS; Onay, H; Altay, CT; Atik, T; Hekimsoy, Z; Saygili, F; Akinci, BBackground: Familial partial lipodystrophy (FPL) is a rare genetic disorder characterized by selective lack of subcutaneous fat which is associated with insulin resistant diabetes. The Dunnigan variety (FPL2) is caused by several missense mutations in the lamin A/C (LMNA) gene, most of which are typically located in exon 8 at the codon position 482. Case report: Here, we report on a Turkish family with FPL2 which is caused by a novel heterozygous missense LMNA mutation in exon 1 (D47N, c. 139G N A), in the rod domain of lamins A/C. Fat distribution and metabolic features of LMNA D47N mutation were similar to typical codon 482 mutation. Metabolic abnormalities were observed as a form of insulin resistant diabetes, hypertriglyceridemia, low HDL cholesterol and hepatic steatosis. There was no evidence for neuromuscular and cardiac involvement. Conclusion: Although it is previously known that alterations in the rod domain of type A lamins are involved in cardiac and neuromuscular diseases, our current observation shows that exon 1 LMNA mutationsmay be associated with partial lipodystrophy without any cardiac and neurological abnormalities, at least at the time of the presentation. (C) 2015 European Federation of Internal Medicine. Published by Elsevier B. V. All rights reserved.Item Plasma Levels of Antioxidant Vitamins in Patients with Acromegaly: A Case-Control StudyKutbay, NO; Yurekli, BS; Simsir, IY; Suner, A; Seckiner, S; Kucukerdonmez, O; Saygili, FOBJECTIVE: The aim of this study was to compare antioxidant vitamin C and vitamin E levels in the non-acromegaly control group and in patients with acromegaly with and without remission. MATERIAL AND METHODS: In this study, 100 cases, acromegaly patients of 57% (n=57, 29F, 28M, mean ages of 49.5 +/- 12.1) and control subjects of 43% (n=43, 29F, 14M, mean ages of 49.6 +/- 9.2). Acromegaly patients were classified into two groups; active acromegaly (AA; n=33) and controlled acromegaly (CA; n=24). RESULTS: Vitamin C levels were significantly lower in the acromegaly group [7.6 (4.7) mg/L, as median (IQR)] when compared to the control group [12.2 (5.5) mg/L, as median (IQR)] (p <0.001). Vitamin E levels didn't show a significant difference between the acromegaly and the control groups (14.2 +/- 3.6 vs. 14.8 +/- 3.7, as mean +/- SD, respectively, p = 0.439). Correlation analysis showed that vitamin C levels were not significantly associated with clinical, anthropometric and laboratory parameters in the acromegaly group. Vitamin E levels were significantly associated with the total cholesterol, triglyceride, LDL-C, HDL-C, APO A1, APO B both in the acromegaly and the control groups. CONCLUSION: This study is the first one to investigate the relationship between the levels of vitamin C & E and anthropometric & metabolic parameters in acromegaly patients and control group. In our study, vitamin C level was significantly lower in the acromegaly group compared to the level in the control group. There was no significant difference in vitamin E levels between the acromegaly and control group.Item Assesment of attainment of recommended TSH levels and levothyroxine compliance in differentiated thyroid cancer patientsYavuz, DG; Yazan, CD; Hekimsoy, Z; Aydin, K; Gokkaya, N; Ersoy, C; Akalin, A; Topaloglu, O; Aydogan, BI; Dilekci, ENA; Uc, ZA; Cansu, GB; Ozsari, L; Iyidir, OT; Olgun, ME; Keskin, L; Mert, M; Can, B; Gungor, K; Galip, T; Cantürk, Z; Elbuken, G; Pekkolay, Z; Kutbay, NO; Yorulmaz, G; Kalkan, AT; Unsal, YA; Yay, A; Karagun, B; Bozkur, EObjective Thyroid-stimulating hormone (TSH) suppression treatment can induce signs and symptoms of hyperthyroidism and hypothyroidism due to inappropriate treatment or poor compliance to the treatment. The current study aimed to investigate TSH levels, frequency of being on target TSH, adherence to levothyroxine (LT4) suppression treatment in differentiated thyroid cancer (DTC) patients after surgery in a multicentric setting. Design and Patients This multicentric cross-sectional study was conducted at 21 medical centres from 12 cities in Turkey. DTC patients followed at least one year in the same center included in the study. Clinical data, serum TSH, free thyroxine (FT4), thyroglobulin (Tg) and anti-Tg levels were recorded during the most recent visit. Body mass index, systolic and diastolic blood pressures, pulse rate were measured. LT4 doses were recorded and doses per kilogram of bodyweight were calculated. Pill ingestion habits recorded and adherence to the therapy were evaluated using the Morisky Medication Adherence Scale and categorized as good, moderate or poor compliant based on their scores. Risk stratification forpredicting the disease persistance and/or reccurence was assessed using the American Joint Committee on Cancer-7th edition thyroid cancer staging calculator. TSH serum concentrations were classified as severe suppression (TSH < 0.01 mU/L), moderate suppression (TSH: 0.01-0.1 mU/L), mild suppression (TSHL 0.1-0.5 mU/L), euthyroid (TSH: 0.5-4 mU/L) and hypothyroid (TSH > 4 mU/L). TSH levels can also be classified as on being on target, under the target, or beyond over the target, according to the American Thyroid Association recommendations. Results A group of 1125 patients (F/M: 941/184, 50.7 +/- 11.7 years) were included in the study. The mean LT4 daily dosage was 132.4 +/- 39.6 mcg/day. TSH levels showed severe suppression in 99 (%8.8) patients, moderate suppression in 277 (%24.6) patients and mild suppression in 315 (%28) patients and euthyroid range in 332 (%29.5) patients and hypothyroid range in 97 (8.6%). TSH levels were in target in 29.2% of the patients 20.4% of the patients were undertreated, 50.4% overtreated. The daily LT4 dose and LT4 dose/kg were significantly higher in the severe suppression group (p < .001, p < .001). According to the Morisky scale, 564 patients (50.1%) were good compliant, 368 patients (32.7%) were moderate compliant, and 193 patients (17.1%) were noncompliant. Patients with poor compliance need a higher dose of LT4 compared to the good compliance group (p < .001). TSH levels of patients with good compliance were 0.67 +/- 1.96 mU/L and TSH with poor compliance was 2.74 +/- 7.47 mU/L (p < .001). TSH levels were similar in patients on fixed and alternating dosages. Conclusion In 29.2% of the DTC patients, serum TSH levels were at target levels. Remaining of the study group have TSH levels under or over treatment range, exposing the patient to medication side effects. Majorty of the study group 82.8% have good or moderate adherence to LT4 therapy. Reaching TSH targets requires simplified and applicable guidelines and following the guideline recommendations.Item Dopamine Agonist-Induced Impulse Control Disorders in Patients With Prolactinoma: A Cross-Sectional Multicenter StudyDogansen, SC; Cikrikcili, U; Oruk, G; Kutbay, NO; Tanrikulu, S; Hekimsoy, Z; Hadzalic, A; Gorar, S; Omma, T; Mert, M; Akbaba, G; Yalin, GY; Bayram, F; Ozkan, M; Yarman, SContext: Dopamine agonist (DA)-induced impulse control disorder (ICD) in patients with prolactinomas is not sufficiently known. Objective: To evaluate the prevalence of DA-induced ICDs and possible risk factors related to these disorders in patients with prolactinoma. Design, Setting, and Participants: This is a cross-sectional multicenter study involving 308 patients with prolactinoma followed up in tertiary referral centers who received at least three months of DA therapy. DA-induced ICDs (pathological gambling, hypersexuality, compulsive shopping, and compulsive eating) and impulsivity were assessed using the Questionnaire for ImpulsiveCompulsive Disorders in Parkinson Disease and the Barratt Impulsiveness Scale-11, respectively. Patients were evaluated in terms of parameters related to ICD development. Results: Any ICD prevalence was 17% (n = 51). Hypersexuality was most common (6.5%). Although any ICD and hypersexuality were more common in male patients (P = 0.009, P < 0.001, respectively), compulsive eating was more common in female patients (P = 0.046). Current smoking, alcohol use, and gambling history were more frequent (P = 0.033, P = 0.002, P = 0.008, respectively) in patients with any ICD. In Barratt Impulsiveness Scale-11 total, attentional, motor, and nonplanning scores were higher in patients with any ICD (P < 0.001). Current smoking and alcohol use were more frequent (P = 0.007, P = 0.003, respectively) and percentage increase of testosterone levels at last visit was higher (P = 0.021) in male patients with prolactinomas with hypersexuality. Conclusion: Any ICD may be seen in one of six patients with prolactinoma who are receiving DA therapy. Endocrinology specialists should be aware of this side effect, particularly in male patients with a history of gambling, smoking, or alcohol use.Item Cardiac phenotype in familial partial lipodystrophyEldin, AJ; Akinci, B; da Rocha, AM; Meral, R; Simsir, IY; Adiyaman, SC; Ozpelit, E; Bhave, N; Gen, R; Yurekli, B; Kutbay, NO; Siklar, Z; Neidert, AH; Hench, R; Tayeh, MK; Innis, JW; Jalife, J; Oral, H; Oral, EAObjectives LMNA variants have been previously associated with cardiac abnormalities independent of lipodystrophy. We aimed to assess cardiac impact of familial partial lipodystrophy (FPLD) to understand the role of laminopathy in cardiac manifestations. Study design Retrospective cohort study. Methods Clinical data from 122 patients (age range: 13-77, 101 females) with FPLD were analysed. Mature human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from a patient with an LMNA variant were studied as proof-of-concept for future studies. Results Subjects with LMNA variants had a higher prevalence of overall cardiac events than others. The likelihood of having an arrhythmia was significantly higher in patients with LMNA variants (OR: 3.77, 95% CI: 1.45-9.83). These patients were at higher risk for atrial fibrillation or flutter (OR: 5.78, 95% CI: 1.04-32.16). The time to the first arrhythmia was significantly shorter in the LMNA group, with a higher HR of 3.52 (95% CI: 1.34-9.27). Non-codon 482 LMNA variants were more likely to be associated with cardiac events (vs. 482 LMNA: OR: 4.74, 95% CI: 1.41-15.98 for arrhythmia; OR: 17.67, 95% CI: 2.45-127.68 for atrial fibrillation or flutter; OR: 5.71, 95% CI: 1.37-23.76 for conduction disease). LMNA mutant hiPSC-CMs showed a higher frequency of spontaneous activity and shorter action potential duration. Functional syncytia of hiPSC-CMs displayed several rhythm alterations such as early afterdepolarizations, spontaneous quiescence and spontaneous tachyarrhythmia, and significantly slower recovery in chronotropic changes induced by isoproterenol exposure. Conclusions Our results highlight the need for vigilant cardiac monitoring in FPLD, especially in patients with LMNA variants who have an increased risk of developing cardiac arrhythmias. In addition, hiPSC-CMs can be studied to understand the basic mechanisms for the arrhythmias in patients with lipodystrophy to understand the impact of specific mutations.Item Identifying Clinical Characteristics of Hypoparathyroidism in Turkey: HIPOPARATURK-NET StudyDegertekin, CK; Yavuz, DG; Pekkolay, Z; Saygili, E; Ugur, K; Koca, AO; Unubol, M; Topaloglu, O; Aydogan, BI; Kutbay, NO; Hekimsoy, Z; Yilmaz, N; Balci, MK; Tanrikulu, S; Unsal, YA; Ersoy, C; Omma, T; Keskin, M; Yalcin, MM; Yetkin, I; Soylu, H; Karakose, M; Yilmaz, M; Karakilic, E; Piskinpasa, H; Batman, A; Akbaba, G; Elbuken, G; Bahadir, CT; Kilinc, F; Bilginer, MC; Iyidir, OT; Canturk, Z; Yilmaz, BA; Sayiner, ZA; Eroglu, MHypoparathyroidism is an orphan disease with ill-defined epidemiology that is subject to geographic variability. We conducted this study to assess the demographics, etiologic distribution, treatment patterns and complication frequency of patients with chronic hypoparathyroidism in Turkey. This is a retrospective, cross-sectional database study, with collaboration of 30 endocrinology centers located in 20 cities across seven geographical regions of Turkey. A total of 830 adults (mean age 49.6 +/- 13.5 years; female 81.2%) with hypoparathyroidism (mean duration 9.7 +/- 9.0 years) were included in the final analysis. Hypoparathyroidism was predominantly surgery-induced (n = 686, 82.6%). The insulting surgeries was carried out mostly due to benign causes in postsurgical group (SG) (n = 504, 73.5%) while patients in nonsurgical group (NSG) was most frequently classified as idiopathic (n = 103, 71.5%). The treatment was highly dependent on calcium salts (n = 771, 92.9%), calcitriol (n = 786, 94.7%) and to a lower extent cholecalciferol use (n = 635, 76.5%) while the rate of parathyroid hormone (n = 2, 0.2%) use was low. Serum calcium levels were most frequently kept in the normal range (sCa 8.5-10.5 mg/dL, n = 383, 46.1%) which might be higher than desired for this patient group. NSG had a lower mean plasma PTH concentration (6.42 +/- 5.53 vs. 9.09 +/- 7.08 ng/l, p < 0.0001), higher daily intake of elementary calcium (2038 +/- 1214 vs. 1846 +/- 1355 mg/day, p = 0.0193) and calcitriol (0.78 +/- 0.39 vs. 0.69 +/- 0.38 mcg/day, p = 0.0057), a higher rate of chronic renal disease (9.7% vs. 3.6%, p = 0.0017), epilepsy (6.3% vs. 1.6%, p = 0.0009), intracranial calcifications (11.8% vs. 7.3%, p < 0.0001) and cataracts (22.2% vs. 13.7%, p = 0.0096) compared to SG. In conclusion, postsurgical hypoparathyroidism is the dominant etiology of hypoparathyroidism in Turkey while the nonsurgical patients have a higher disease burden with greater need for medications and increased risk of complications than the postsurgical patients.