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Item A Retrospective Multicenter Evaluation of Cutaneous Melanomas in Turkey(ASIAN PACIFIC ORGANIZATION CANCER PREVENTION, 2014-01-01) Gamsizkan, Mehmet; Yilmaz, Ismail; Buyukbabani, Nesimi; Demirkesen, Cuyan; Demiriz, Murat; Cetin, Emel Dikicioglu; Ince, Umit; Akalin, Taner; Demirkan, Nese Calli; Lebe, Banu; Erdem, Ozlem; Gokoz, Ozay; Sakiz, Damlanur; Demireli, Peyker Temiz; Astarci, Hesna Muzeyyen; Adim, Saduman Balaban; Zemheri, Itir Ebru; Acikalin, Arbil; Yaman, Banu; Aydin, Ovgu; Bassorgun, Cumhur IbrahimBackground: We defined melanoma distribution in a large series of Turkish patients and evaluated the prognostic parameters of melanomas. Materials and Methods: A total of 1574 patients' data was retrospectively collected at 18 centers in Turkey. Demographic characteristics were questioned and noted. Prognostic parametres were evaluated based on sentinel lymph node involvement. Results: Mean age was 56.7 (4-99) years. While 844 (53.6\%) cases were male, 730 (46.4\%) cases were female. One thousand four hundred forty-seven (92\%) cases were invasive melanoma and 127 (8\%) cases were in-situ melanoma. The most common histopathological form was the superficial spreading melanoma (SSM) which was found in 549 patients (37.9\%). It was followed by nodular melanoma in 379 (26.2\%), acral lentiginous melanoma (ALM) in 191 (13.2\%) and lentigo maligna melanoma in 132 (9.1\%), respectively. On univariate analysis, lymphovascular invasion (p<0.001), tumor thickness (p<0.001), histopathological subtype (p<0.001), Clark level (p=0.001), ulceration (p<0.001), >= 6/mm(2) mitosis (p=0.005), satellite formation (p=0.001) and gender (p=0.03) were found to be associated with sentinel lymph node positivity. Regression was associated with sentinel lymph node negativity (p=0.017). According to multivariate analysis, lymphovascular invasion and tumor thickness were significant independent predictive factors of SLN positivity. Patient age, tumor localization, precursor lesions, lymphocytic infiltration and neurotropism were not related with sentinel lymph node involvement. Conclusions: In this retrospective analysis, it was found that the prevalence of SSM is at a lower rate while the prevalence of ALM is at a higher rate when compared to western countries. According to Breslow indexItem The magnitude of gonadotoxicity of chemotherapy drugs on ovarian follicles and granulosa cells varies depending upon the category of the drugs and the type of granulosa cells(OXFORD UNIV PRESS, 2015-01-01) Yuksel, Aytac; Bildik, Gamze; Senbabaoglu, Filiz; Akin, Nazli; Arvas, Macit; Unal, Fehmi; Kilic, Yagmur; Karanfil, Isil; Eryilmaz, Baldan; Yilmaz, Pelin; Ozkanbas, Can; Taskiran, Cagatay; Aksoy, Senai; Guzel, Yilmaz; Balaban, Basak; Ince, Umit; Iwase, Akira; Urman, Bulent; Oktem, OzgurSTUDY QUESTION: Do different chemotherapy drugs exert the same magnitude of cytotoxicity on dormant primordial follicles and the growing follicle fraction in the ovary in vivo and on mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro? SUMMARY ANSWER: Cyclophosphamide (alkylating agent) and cisplatin (alkylating like) impacted both primordial and pre-antral/antral follicles and both mitotic and non-mitotic granulosa cells, whereas the anti-metabolite cancer drug gemcitabine was detrimental only to pre-antral/antral follicles and mitotic non-luteinized granulosa cells. WHAT IS KNOWN ALREADY: It is already known that anti-metabolite cancer drugs are less detrimental to the ovary than alkylating and alkylating like agents, such as cyclophosphamide and cisplatin. This assumption is largely based on the results of clinical reports showing lower rates of amenorrhea in women receiving anti-metabolite agent-based regimens compared with those treated with the protocols containing an alkylating drug or a platinum compound. But a quantitative comparison of gonadotoxicity with a histomorphometric proof of evidence has not been available for many chemotherapy drugs. Therefore, we combined in this study in vivo and in vitro models of human and rat origin that allows a comparative analysis of the impact of different chemotherapy agents on the ovary and granulosa cells using real-time quantitative cell indices, histomorphometry, steroidogenesis assays, and DNA damage and cell death/viability markers. We also aimed to investigate if there is a difference between mitotic and non-mitotic granulosa cells in terms of their sensitivity to the cytotoxic actions of chemotherapy drugs with different mechanisms of action. This issue has not been addressed previously. STUDY DESIGN, SIZE, DURATION: This translational research study involved in vivo analyses of ovaries in rats and in vitro analyses of granulosa cells of human and rat origin. PARTICIPANTS/MATERIALS, SETTING, METHODS: For the in vivo assays, 54 4- to 6-week old Sprague-Dawley young female rats were randomly allocated into four groups of 13 to receive a single IP injection of: saline (control), gemcitabine (200 mg/kg), cisplatin (50 mg/kg) or cyclophosphamide (200 mg/kg). The animals were euthanized 72 h later. Follicle counts and serum AMH levels were compared between the groups. In vitro cytotoxicity studies were performed using mitotic non-luteinized rat (SIGC) and human (COV434, HGrC1) granulosa cells, and non-mitotic luteinized human (HLGC) granulosa cells. The cells were plated at a density of 5000 cells/well using DMEM-F12 culture media supplemented with 10\% FBS. Chemotherapy agents were used at their therapeutic blood concentrations. The growth of mitotic granulosa cells was monitored real-time using xCelligence system. Live/dead cell and apoptosis assays were also carried out using intravital Yo-Pro-1 staining and cleaved caspase-3 expression, respectively. Estradiol (E2), progesterone (P) and anti-Mullerian hormone (AMH) levels were assayed with ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: Cyclophosphamide and cisplatin caused massive atresia of both primordials and growing follicles in the rat ovary whereas gemcitabine impacted pre-antral/antral follicles only. Cyclophosphamide and cisplatin induced apoptosis of both mitotic non-luteinized and non-mitotic luteinized granulosa cells in vitro. By contrast, cytotoxicity of gemcitabine was confined to mitotic non-luteinized granulosa cells. LIMITATIONS, REASONS FOR CAUTION: This study tested only three chemotherapeutic agents. The experimental methodology described here could be applied to other drugs for detailed analysis of their ovarian cytotoxicity. WIDER IMPLICATIONS OF THE FINDINGS: These findings indicate that in vivo and in vitro cytotoxic actions of chemotherapy drugs on the ovarian follicles and granulosa cells vary depending upon the their mechanism of action and the nature of the granulosa cells.Item GnRH agonist leuprolide acetate does not confer any protection against ovarian damage induced by chemotherapy and radiation in vitro(OXFORD UNIV PRESS, 2015-01-01) Bildik, Gamze; Akin, Nazli; Senbabaoglu, Filiz; Sahin, Gizem Nur; Karahuseyinoglu, Sercin; Ince, Umit; Taskiran, Cagatay; Selek, Ugur; Yakin, Kayhan; Guzel, Yilmaz; Ayhan, Cem; Alper, Ebru; Cetiner, Mustafa; Balaban, Basak; Mandel, Nil Molinas; Esen, Tarik; Iwase, Akira; Urman, Bulent; Oktem, OzgurSTUDY QUESTION: Is there any in vitro evidence for or against ovarian protection by co-administration of a GnRH agonist with chemotherapy in human? SUMMARY ANSWER: The co-administration of GnRH agonist leuprolide acetate with cytotoxic chemotherapy agents does not preserve ovarian reserve in vitro. WHAT IS KNOWN ALREADY: Randomized controlled trials of the co-administration of gonadotrophin-releasing hormone (GnRH) agonists with adjuvant chemotherapy to preserve ovarian function have shown contradictory results. This fact, together with the lack of a proven molecular mechanism of action for ovarian protection with GnRH agonist (GnRHa) places this approach as a fertility preservation strategy under scrutiny. We therefore aimed in this study to provide in vitro evidence for or against the role of GnRHa in the prevention of chemotherapy-induced damage in human ovary. STUDY DESIGN, SETTINGS, SIZE AND DURATION: This translational research study of ex vivo and in vitro models of human ovary and granulosa cells was conducted in a university hospital between 2013 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian cortical pieces (n = 15, age 14-37) and mitotic non-luteinized (COV434 and HGrC1) and non-mitotic luteinized human granulosa cells (HLGC) expressing GnRH receptor were used for the experiments. The samples were treated with cyclophosphamide, cisplatin, paclitaxel, 5-FU, or TAC combination regimen (docetaxel, adriamycin and cyclophosphamide) with and without GnRHa leuprolide acetate for 24 h. DNA damage, apoptosis, follicle reserve, hormone markers of ovarian function and reserve (estradiol (E2), progesterone (P) and anti-mullerian hormone (AMH)) and the expression of anti-apoptotic genes (bcl-2, bcl-xL, bcl-2L2, Mcl-1, BIRC-2 and XIAP) were compared among control, chemotherapy and chemotherapy + GnRHa groups. MAIN RESULTS AND THE ROLE OF CHANCE: The greatest magnitude of cytotoxicity was observed in the samples treated with cyclophosphamide, cisplatin and TAC regimen. Exposure to these drugs resulted in DNA damage, apoptosis and massive follicle loss along with a concurrent decline in the steroidogenic activity of the samples. GnRHa co-administered with chemotherapy agents stimulated its receptors and raised intracellular cAMP levels. But it neither activated anti-apoptotic pathways nor prevented follicle loss, DNA damage and apoptosis induced by these drugs. LIMITATIONS, REASONS FOR CAUTION: Our findings do not conclusively rule out the possibility that GnRHa may offer protection, if any, through some other mechanisms in vivo. WIDER IMPLICATIONS OF THE FINDINGS: GnRH agonist treatment with chemotherapy does not prevent or ameliorate ovarian damage and follicle loss in vitro. These data can be useful when consulting a young patient who may wish to receive GnRH treatment with chemotherapy to protect her ovaries from chemotherapy-induced damage.Item High Cholesterol Diet-Induced Changes in Oxysterol and Scavenger Receptor Levels in Heart Tissue(HINDAWI LTD, 2018-01-01) Sozen, Erdi; Yazgan, Burak; Sahin, Ali; Ince, Umit; Ozer, Nesrin KartalInvolvement of high cholesterol and oxidative stress in cardiovascular diseases is well studied, as it can be hypothesized that various products originated from lipid peroxidation, such as oxysterols, or affected protein expression might lead to cardiomyocyte damage followed by the pathological modifications. Although oxidation of excessive cholesterol to oxysterols in elevated stress conditions is identified by a number of studies, the role of a high cholesterol diet in regulating fatty acid and oxysterol accumulation, together with scavenger receptor mRNA levels, in the heart remains little investigated. Our study provides a detailed analysis of the changes in fatty acid, oxysterol, and scavenger receptor profiles and its relation with histological alterations in the heart tissue. We evaluated alterations of fatty acid composition, by the GC-MS method, while 4 beta-, 25-, and 27-hydroxycholesterol and 7-ketocholesterol levels by means of LC-MS/MS in high cholesterol diet-fed rabbits. Additionally, a number of proteins related to lipid metabolism and scavenger receptor mRNA expressions were evaluated by Western blotting and RT-PCR. According to our in vivo results, a high cholesterol diet enhances a number of unsaturated fatty acids, oxysterols, and LXR alpha, in addition to CD36, CD68, CD204, and SR-FI expressions while alpha-tocopherol supplementation decreases LXR alpha and SR expressions together with an increase in 27-hydroxycholesterol and ABCA1 levels. Our results indicated that the high cholesterol diet modulates proteins related to lipid metabolism, which might result in the malfunction of the heart and alpha-tocopherol shows its beneficial effects. We believe that this work will lead the generation of different theories in the development of heart diseases.Item The mammalian target of rapamycin protein expression in human granulosa cell tumors(GALENOS YAYINCILIK, 2019-01-01) Guralp, Onur; Bese, Tugan; Bildik, Gamze; Demikiran, Fuat; Ince, Umit; Malik, Eduard; Arvas, Macit; Oktem, OzgurObjective: To investigate the role of mammalian target of rapamycin (mTOR) in human granulosa cell ovarian tumors and the therapeutic effect of rapamycin in COV434 mitotic granulosa cell lines. Material and Methods: A retrospective evaluation of the medical records and pathologic sections of patients with granulosa cell ovarian carcinoma was performed. mTOR and p-mTOR expression was immunohistochemically investigated. A COV434 cell culture were treated with 0.5, 1, 2, and 5 mu M rapamycin. Real-time growth curve analysis via xCELLigence system and apoptotic cell analysis via YO-PROT-1 Iodide were performed to assess the therapeutic effect of rapamycin on cancer cells. Results: A total of twenty patients were evaluated. mTOR staining was detected in 18 (90\%) patients. Mild, moderate, intense, and very intense staining was observed in three (15\%), eight (40\%), six (30\%), and one (5\%) sample, respectively. The mean mTOR staining ratio was 59 +/- 41\%. P-mTOR staining was observed in two ( 10\%) patients. One (5\%) patient had 5\% staining, and one (5\%) patient had 100\% staining for p-mTOR. Both of the latter patients had very intense staining. Rapamycin caused a dose-dependent growth arrest and induced apoptosis in COV434 mitotic granulosa cells. The real-time growth curves of the cells treated with these drugs were distinguished by a marked reduced slope after exposure for several hours, indicating a rapid onset of apoptosis. Live/dead cell analysis with YO-PRO-1 staining showed that rapamycin induced apoptosis in 24\% of the cells when used at 1 mu M concentration, whereas the rate increased to 61\% and 72\% when the cells were treated with 2 mu M and 5 mu M rapamycin, respectively. Conclusion: mTOR expression is observed in various degrees in 90\%, and p-mTOR expression is observed in only 10\% of patients with granulosa cell ovarian carcinoma. Rapamycin caused a dose-dependent growth arrest and apoptosis in COV434 mitotic granulosa cells.Item Effects of Ozone on Spinal Cord Recovery via the Wnt/beta-Catenin Pathway Following Spinal Cord Injury in Rats(TURKISH NEUROSURGICAL SOC, 2017-01-01) Tural Emon, Selin; Uslu, Serap; Ilgaz Aydinlar, Elif; Irban, Arzu; Ince, Umit; Orakdogen, Metin; Gulec Suyen, GuldalAIM: At the cellular level, spinal cord injury (SCI) provokes an inflammatory response that generates substantial secondary damage within the spinal cord but may also contribute to its repair. Besides intracellular antioxydant increase after exactly estimated oxidative stressItem Vacuum-assisted stereotactic breast biopsy in the diagnosis and management of suspicious microcalcifications(TURKISH SOC RADIOLOGY, 2016-01-01) Esen, Gul; Tutar, Burcin; Uras, Cihan; Calay, Zerrin; Ince, Umit; Tutar, OnurPURPOSE We aimed to present our biopsy method and retrospectively evaluate the results, upgrade rate, and follow-up findings of stereotactic vacuum-assisted breast biopsy (VABB) procedures performed in our clinic. METHODS Two hundred thirty-four patients with mammographically detected nonpalpable breast lesions underwent VABB using a 9 gauge biopsy probe and prone biopsy table. A total of 195 patients (median age 53 years, range 32-80 years) with 198 microcalcification-only lesions with a follow- up of at least one year were included in the study. The location of the lesion relative to the needle was determined from the postfire images, and unlike the conventional technique, tissue retrieval was predominantly performed from that location, followed by a complete 360 degrees rotation, if needed. RESULTS The median core number was 8.5. Biopsy results revealed 135 benign, 24 atypical, and 39 malignant lesions. The total upgrade rate at surgery was 7.7\% (6.1\% for ductal carcinomas in situ and 10.5\% for atypical lesions). Patients with benign lesions were followed up for a median period of 27.5 months, with no interval change. At the follow-up, scar formation was seen in 23 patients (17\%)Item Endogenous c-Jun N-terminal kinase (JNK) activity marks the boundary between normal and malignant granulosa cells(NATURE PUBLISHING GROUP, 2018-01-01) Bildik, Gamze; Akin, Nazli; Senbabaoglu, Filiz; Esmalian, Yashar; Sahin, Gizem Nur; Urman, Defne; Karahuseyinoglu, Sercin; Ince, Umit; Palaoglu, Erhan; Taskiran, Cagatay; Arvas, Macit; Guzel, Yilmaz; Yakin, Kayhan; Oktem, OzgurGranulosa cell tumor of the ovary (GCT) is a very rare tumor, accounting for only 2\% of all ovarian tumors. It originates from sex cords in the ovary and can be divided into adult (95\%) and juvenile (5\%) types based on histologic findings. To date, no clear etiologic process has been identified other than a missense point mutation in the FOXL2 gene. Our previous works showed that c-Jun N-terminal kinase (JNK) pathway plays critical role in cell cycle progression and mitosis of normal and immortalized granulosa cells and follicle growth in rodent ovaries. These findings led us to investigate the role of JNK pathway in the granulosa cell tumor of the ovary. We used two different GCT cell lines (COV434 and KGN) and fresh GCT samples of adult and juvenile types obtained from the patients during surgery. We have discovered that endogenous kinase activity of JNK is markedly enhanced in the GCT samples and cell lines, whereas it was almost undetectable in mitotic non-malignant human granulosa cells. The inhibition of JNK pathway in GCT cell lines with two different pharmacologic inhibitors (SP600125 and AS601245) or siRNA resulted in a dose-dependent reduction in in vitro cell growth, increased apoptosis and diminished estradiol and AMH productions. JNK inhibition was also associated with a decrease in the number of cells positive for mitosis marker phospho-histone H3(Ser) 10 in the asynchronous cellsItem EML4-ALK-positive lung adenocarcinoma presenting an unusual metastatic pattern in a 29-year-old woman who is alive and well in her third year follow up: A case report(ELSEVIER SCIENCE BV, 2017-01-01) Tokat, Fatma; Zeren, Handan; Barut, Pinar; Tansan, Sualp; Ince, UmitNon-small cell lung cancer (NSCLC) is a frequent tumor entity with high mortality. Although several newly discovered chromosomal translocations and mutations opened new horizons for targeted therapy, literature still lacks large series of NSCLC with chromosomal abberations and their correlations with histological and clinical features. We present a case of echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) translocation positive adenocarcinoma of the lung with an unusual metastatic pattern in a 29-year-old young woman. Conclusion: Young adult non-smoker female patients with an unexplained pleural effusion and signs of metastatic disease should alert the physicians straight away for all types of malignancies including lung cancer. Any skin lesions should be evaluated carefully, biopsies should be done to exclude metastasis in urgency. On the other hand, an uncommon clinical presentation of a lung cancer requires corresponding molecular testing rapidly in order to offer the best treatment option. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license.Item Association of B7-H4 gene polymorphisms in urothelial bladder cancer(TUBITAK SCIENTIFIC \& TECHNICAL RESEARCH COUNCIL TURKEY, 2017-01-01) Ozgoz, Asuman; Samli, Murat; Dincel, Deniz; Sahin, Ahmet; Ince, Umit; Saglican, Yesim; Balci, Faruk; Samli, HaleBackground/aim: We aimed to study polymorphisms of the B7-H4 gene in order to evaluate a possible association in urothelial carcinoma, as it is highly expressed in cancer tissues. Materials and methods: In this study B7-H4 gene rs10754339, rs10801935, and rs3738414 SNPs were studied by PCR-RFLP method in paraffin-embedded tumor specimens from 62 urothelial carcinoma patients and in a control group including 30 patients without bladder cancer. Results: We detected that the rs10754339 polymorphism was more frequent in the cancer patients when compared with the control group (P < 0.05). Only the rs3738414 polymorphism showed a statistically significant difference in frequency between pathologic diagnostic groups. Conclusion: The rs10754339 AA genotype distribution was found to have a higher frequency whereas the rs3738414 AG genotype distribution was lower in the bladder cancer group (P < 0.05). None of the genotype distributions showed a significant difference from the control group for the rs10801935 polymorphism. We conclude that B7-H4 has the potential to be a useful prognostic marker in urothelial carcinoma.