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Item Influence of Radiation Exposure During Radiotherapy Evidence for the Increase of Versican and Heparin-Binding EGF-like Growth Factor Concentrations(SCI PRINTERS & PUBL INC) Ozbilgin, MK; Aktas, C; Uluer, ET; Buyukuysal, MC; Gareveran, MS; Kurtman, COBJECTIVE: To investigate the reaction of versican and heparin-binding EGF-like growth factor (HB-EGF) molecule concentrations to acute radiation exposure in normal bladder and rectal tissue samples in order to gain more insight into the effects of cancer radiotherapy. STUDY DESIGN: Four groups with 6 male adult Swiss Albino mice per group were investigated. The mice bladder and rectum tissue samples were subjected to a 10-Gy single-dose radiation exposure in the pelvic region with a Co-60 teletherapy device and investigated 1, 2, and 7 days after radiation exposure, with 1 reference group which was not exposed to radiation. RESULTS: In the immunohistochemical examination of the tissue samples with anti-versican and anti-HB-EGF primary antibodies was observed a statistically significant increase 7 days after radiation exposure. CONCLUSION: The observed increase of versican and HB-EGF concentrations in the normal tissue matrix after radiation exposure may play a role in the side effects of radiotherapy.Item Neurotoxic effect of Caulerpa racemosa var. cylindracea by neurite inhibition on the neuroblastoma cell line(MAIK NAUKA/INTERPERIODICA/SPRINGER) Kurt, O; Ozdal-Kurt, F; Tuglu, I; Deliloglu-Gurhan, SI; Ozturk, MIn the present study, antiproliferative, apoptotic and especially neurotoxic effects of Caulerpa racemosa var. cylindracea dry and wet extracts on mouse neuroblastoma cell line, NA2B were investigated by neurotoxicity screening test (NST). C. racemosa var. cylindracea wet and dry extracts were obtained by methanol (MT) extraction. The effect of the extracts on viability and proliferation was measured by MTT. NA2B cells were induced to differentiate using 1 mu M dcAMP and the amount of inhibition of growing neurites in different dilutions (50, 35, 25, 15, 10 and 5 mu l/ml) by extracts was measured. The number of apoptotic cells was computed by TUNEL method using cells in culture. It was found that majority of the cells died with dry extract above the level of 15 mu l/ml due to the MT effect. Below this level, on the other hand, presence of cell death and antiproliferative effect was noted due to the toxic effects of C. racemosa var. cylindracea which was independent of MT. In all doses of wet extracts, similar but less prominent dose-dependent effects were observed. Below the level of 15 mu l/ml, mild toxic effect presented itself with neurite inhibition. In addition to the toxic, apoptotic and antiproliferative effects of C. racemosa var. cylindracea, its neurotoxic effects possessing property at low concentrations which manifesting itself by neurite inhibition was also showed. This species offers a potential for developing new drugs due to its antiproliferative, toxic and apoptotic effects. Nevertheless, its neurotoxic effect is a factor to be considered as multifunctional agents especially in neuronal metabolism.Item Tumor Budding Should Be in Oral Cavity Cancer Reporting: A Retrospective Cohort Study Based on Tumor Microenvironment(MDPI) Tan, AY; Taskin, TSimple Summary In our study, which started with the hypothesis that there is a histopathological marker that can be used to predict prognosis in oral squamous cell carcinomas, we found that tumor budding is quite significant. The fact that this finding will provide us with very important data in routine practice and play a key role in the treatment management of patients will be a significant finding and contribution to the literature. The utility of histological grading, which is useful in predicting prognosis in many tumors, is controversial for oral squamous cell carcinoma (OSCC). Therefore, new histopathological parameters should be added to histopathology reports of OSCCs. The study aimed to evaluate the parameters of worst invasion pattern (WPOI) and tumor budding in patients with OSCC, to compare them with other histopathological parameters, clinical data and overall survival, and to evaluate these results within the literature. A total of 73 OSCC cases with excisional biopsies were included in this study. WPOI, tumor budding, cell nest size, tumor-stroma ratio, stromal lymphocyte infiltration and stroma type, as well as classical histopathological parameters, were evaluated on hematoxylin-eosin-stained sections. Perineural invasion, lymph node metastases, advanced stage, presence of more than five buds and single cell invasion pattern in univariate survival analyses are characterized by a shortened overall survival time. While there was no significant difference between WPOI results and survival in the survival analysis, WPOI 5 was associated with more frequent lymph node metastasis and advanced stage at the time of diagnosis compared to WPOI 4. We concluded that tumor budding and single-cell invasion should be considered prognostic histopathologic parameters in OSCC.Item Staged-surgery with permanent pathology for the management of high-risk nonmelanoma skin cancer of the nose(SPRINGER) Eskiizmir, G; Gençoglan, G; Temiz, P; Hirçin, Z; Ermertcan, AThe objective of the study was to investigate the effect of staged-surgery with permanent pathology on tumour recurrence of high-risk nonmelanoma skin cancers (NMSCs) of the nose and to determine the factors associated with subclinical spread and deep-margin involvement. Twenty-one patients who underwent staged-surgery with permanent pathology for high-risk NMSCs of the nose between 2007 and 2008 were prospectively followed-up for tumour recurrence. The incidence of tumour recurrence after staged-surgery with permanent pathology was 0%. A positive correlation between perineural involvement and subclinical spread (p = .012); and a statistically significant relationship between infiltrative type basal cell carcinoma (BCC) and deep-margin involvement (p = .033) was detected. Staged-surgery with permanent pathology is a reliable surgical method for complete excision of high-risk NMSCs of the nose and provides a significant decrease in tumour recurrence. Perineural involvement may cause subclinical spread, and infiltrative type BCC may invade deeper structures of the nose.Item A Src/Abl kinase inhibitor, bosutinib, downregulates and inhibits PARP enzyme and sensitizes cells to the DNA damaging agents(WALTER DE GRUYTER GMBH) Kirmizibayrak, PB; Ilhan, R; Yilmaz, S; Gunal, S; Tepedelen, BEBackground: Poly(ADP-ribosyl)ation (PARylation) catalyzed mainly by PARP1 is a highly regulated posttranslational modification associated with several pathways in cellular physiology and genotoxic deoxyribonucleic acid (DNA) damage response. PAR polymers and PARP enzyme function in DNA integrity maintenance and several PARP inhibitors have entered clinical phase studies for cancer therapies. Material and methods: The effect of bosutinib, a dual Src/Abl kinase inhibitor, on PARylation was fluorometrically measured. The cytotoxic and chemosensitizing effects were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The levels of DNA repair proteins and PARP enzyme were examined by immunoblotting. Results: In this study, bosutinib is characterized as a novel PARP inhibitor. Bosutinib inhibited oxidative stress-induced cellular PARylation and nuclear foci formation by downregulating PARP1 levels. Bosutinib was found to be more cytotoxic on Capan1 cells with BRCA2 mutation. Furthermore by acting as a chemosensitizer, bosutinib enhanced the cytotoxicity of doxorubicin (DOXO) and etoposide (ETP) by decreasing phosphorylation of DNA repair enzymes checkpoint kinase 1 (Chk1) and ataxia-telangiectasia mutated (ATM). Conclusion: By inhibition of both PARP and DNA damage checkpoint kinases, bosutinib increased the phospho-H2AX levels, an early indicator of DNA double strand breaks.Item Potential role of chromatin remodeling factor genes in atrophic gastritis/gastric cancer risk(AVES) Bilgiç, F; Gerçeker, E; Boyacioglu, SÖ; Kasap, E; Demirci, U; Yildinm, H; Baykan, AR; Yüceyar, HBackground/Aims: Atrophic gastritis (AG), intestinal metaplasia (IM), and Helicobacter pylori (HP) are the risk factors for the development of gastric cancer (GC). Chromatin remodeling is one of the epigenetic mechanisms involved in the carcinogenesis of GC. The purpose of this study was to investigate the expression profiles of defined chromatin remodeling genes in gastric mucosal samples and their values as gastric carcinogenesis biomarkers. Materials and Methods: In total, 95 patients were included in the study. Patients were divided into 3 groups as: GC group (n=34), AG group (n=36), and control group (n=25). AG group was further divided into subgroups based on the presence of HP and IM in gastric mucosa. Chromatin remodeling gene expressions were analyzed using real-time PCR (RT-PCR) array in all groups. Data were evaluated using the RT-gPCR primer assay data analysis software. Results: EED, CBX3, and MTA1 were more overexpressed, whereas ARID1A ING5, and CBX7 were more underexpressed in the AG and GC groups compared with the controls. No significant differences were observed between the AG and GC groups concerning the expression of these 6 genes, although the fold change levels of these genes in the GC group were well above than in the AG group. EEO, CBX3, and MTA1 were significantly more overexpressed in HP- and IM-positive AG subgroup compared with the HP- or IM-negative AG subgroup. Conclusion: In conclusion, our results provide an evidence of epigenetic alterations in AG. Expressions of EED, CBX3, MTA1, ARID1A, ING5, and CBX7 may be considered as promising markers to be used in GC screening for patients with AG.Item Immunohistochemical staining of IGF-I, IGF-binding proteins-1 and-3, and transforming growth factor beta-3 in the umbilical cords of preeclamptic patients(BLACKWELL MUNKSGAARD) Inan, S; Vatansever, S; Kuscu, NK; Laçin, S; Ozbilgin, K; Koyuncu, FBackground. To detect the immunoreactivity of insulin-like growth factor-I, insulin-like growth factor-binding proteins-1 and -3 and transforming growth factor beta-3 in the umbilical cords of normal and preeclamptic patients. Methods. Umbilical cords were obtained from 15 normal and 15 preeclamptic patients. Immunoreactivities were determined using either indirect immunofluorescence or immunoperoxidase techniques on formalin-fixed, paraffin-embedded sections. Staining intensity was graded by a semiquantitative scoring method. The results were compared by Mann-Whitney U -test. Results. The umbilical cords were thinner and the vessels were hypoplastic in the preeclamptic group. Moderate staining intensity for insulin-like growth factor-I, insulin-like growth factor binding protein-1 and -3 and transforming growth factor-beta 3 was observed in normal patients. The preeclamptic group had mild and strong intensities for insulin-like growth factor-I and insulin-like growth factor binding protein-1, respectively, and intensity for insulin-like growth factor binding protein-3 did not change, but diffuse and increased intensity was observed for transforming growth factor-beta 3. Conclusion. Changes in the intensity of insulin-like growth factor-I and its major binding protein and the transformation of growth factor-beta 3 may play a role in the pathogenesis of preeclampsia by altering the structure and responsiveness of the umbilical cordItem The effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells lines(ELSEVIER) Özgürbüz, U; Gencür, S; Kurt, FÖ; Özkalkanli, M; Vatansever, HSOpioids are widely used in the treatment of cancer related pain. They mainly exert their effects on opioid receptors. The most common opioid in the treatment of pain is morphine. Previous studies show that they may have effects on cancer cell behavior. These may include apoptosis, angiogenesis, invasion, inflammation and immune reactions. Tramadol, also an opioid is widely used in the treatment of cancer pain and is not well studied in cancer behavior. We aimed to investigate the effects of tramadol on cancer stem cells and metabolic changes in colon carcinoma cells. We used Co1o320 (ATCC, CCL-220), Colo741 (ECACC, 93052621) and HCT116 (ATCC, CCL-247) colon cancer cell lines. CD133 was considered colon cancer stem cell marker and used to sort CD133+ and CD133- cells by magnetic cell sorting. Dm (mitochondria-targeted therapeutics) technique was used to detect tramadol's cytotoxic effect on cells in the study groups. Cells were treated with 1 mg/kg, 1.5 mg/kg and 2 mg/kg tramadol for 24 h at 37 degrees C and 5% CO2.Caspase-3, Ki-67, Bcl-2 and VGEF distributions were performed using indirect immunoperoxidase staining for immunohistochemical analysis. The study showed that tramadol has triggering effect on apoptosis in Colo320 colon cancer stem cells.Item Tumor Microenvironment in Head and Neck Squamous Cell Carcinomas(GALENOS YAYINCILIK) Eskiizmir, GRecent studies about solid tumors demonstrated that tumor microenvironment has an important role in tumor progression, aggressivity, and metastasis process, in addition to genetic aberrations and molecular alterations of cancer cells. Therefore, the crosstalks between cancerous and noncancerous cells and metabolic changes in tumor microenvironment cause significant detrimental effects. The purpose of this review is to present the role and effect of noncancerous cells and their crosstalks with cancer cells, metabolic changes in tumor microenvironment, and to discuss the clinical significance of all these factors with respect to the current literature.Item Effect of apoptosis and response of extracellular matrix proteins after chemotherapy application on human breast cancer cell spheroids(PROFESSOR D A SPANDIDOS) Oktem, G; Vatansever, S; Ayla, S; Uysal, A; Aktas, S; Karabulut, B; Bilir, AMulticellular Tumor Spheroid (NITS) represents a three-dimentional structural form of tumors in laboratory conditions, and it has the characteristics of avascular micrometastases or intervascular spaces of big tumors. Recent studies indicate that extracellular matrix (ECM) proteins play a critical role in tumor metastasis, therefore normal and cancer cells require an ECM for survival, proliferation and differentiation. Doxorubicin and Docetaxel are widely used in the therapy of breast cancer, as well as in in vivo and in vitro studies. In this study, we examined the effect of apoptosis and proliferation of cells on the human breast cancer cell line, MCF-7, by using p53, bcl-2 and Ki67 gene expression, and the tendency to metastasis with extracellular matrix proteins, laminin and type IV collagen after chemotherapy in the spheroid model. The apoptotic cell death in situ was detected by TUNEL method. TUNEL-positive cells and positive immunoreactivities of laminin, type IV collagen, p53 and, bel-2 were detected in the control group. There was no laminin and type IV collagen immunoreactivities in spheroids of drug groups. While TUNEL-positive cells and p53 immunoreactivity were detected in Docetaxel, Doxorubicin and Docetaxel/Doxorubicin groups, p53 immunoreactivity was not observed in the Docetaxel group. There was no bcl-2 immunoreactivity in either drug group. In addition, we did not detect Ki67 immunoreactivity in both control and drug treatment groups. However, the absence of Ki67 protein in MCF-7 breast multicellular tumor spheroids is possibly related to the cells in GO or S phase. These agents may affect the presence of ECM proteins in this in vitro model of micrometastasis of spheroids. These findings suggest that the possible mechanism of cell death in Doxorubicin and Docetaxel/Doxorubicin treatment groups is related to apoptosis through the p53 pathway. However, we considered the possiblity that there is another control mechanism for the Docetaxel group.Item Effects of leptin on the viability of human ovarian cancer cells and changes in cytokine expression levels(PEERJ INC) Dincer, F; Atmaca, H; Akman, L; Oktay, LM; Karaca, B; Terek, MCBackground: Obesity is associated with increased mortality among ovarian cancer and is a poor prognostic factor. There are significant links between the leptin hormone, a product of the obesity gene, and the development of ovarian cancer. Leptin is a vital hormone-like cytokine secreted from adipose tissue and is mainly involved in the maintenance of energy homeostasis. It regulates several intracellular signaling pathways and also interacts with various hormones and energy regulators. It acts as a growth factor by stimulating cell proliferation and differentiation and in this way contributes to cancer cell development. The aim of the study was to investigate the effects of leptin on human ovarian cancer cells. Methods: In this study, the effects of increasing the concentration of leptin were investigated on the cell viability of OVCAR-3 and MDAH-2774 ovarian cancer lines by MTT assay. Moreover, to elucidate the molecular mechanisms of leptin in ovarian cancer cells, changes in the expression levels of 80 cytokines were evaluated after leptin treatment via a human cytokine antibody array. Results: Leptin increases the proliferation of both ovarian cancer cell lines. IL-1 level was increased in OVCAR-3 cells and TGF-beta level was increased in MDAH-2774 cells after leptin treatment. A decrease in IL-2, MCP-2/CCL8 and MCP-3/CCL7 levels was detected in both ovarian cancer cell lines with leptin administration. An increase in IL-3 and IL-10 expressions, insulin-like growth factor binding proteins (IGFBP) IGFBP-1, IGFBP-2 and IGFBP-3 levels were detected in both ovarian cancer cell lines with leptin administration. In conclusion; leptin has a proliferative effect on human ovarian cancer cell lines and affects different cytokines in different types of ovarian cancer cells.Item Piperlongumine inhibits cell growth and enhances TRAIL-induced apoptosis in prostate cancer cells(WOLTERS KLUWER MEDKNOW PUBLICATIONS) Kismali, G; Ceylan, A; Meral, O; Alpay, M; Kosova, F; Cakir, DU; Yurdakok-Dikmen, B; Tascene, N; Sel, TObjective: To investigate whether piperlongumine can sensitize prostate cancer cells to tumor necrosis factor-related apoptosis- inducing ligand (TRAIL) and trigger apoptosis in prostate cells. Methods: Human prostate cancer cell lines PC3, LNCaP, and VCaP were cultured with piperlongumine and TRAIL. Then, cell proliferation, migration, caspase activation, apoptotic protein expressions, and death receptor expressions were measured. Results: Piperlongumine inhibited cell proliferation at low doses (<10 mu M) alone and in combination with TRAIL (25 ng/mL), induced apoptosis, and suppressed cyclooxygenase activation. Additionally, piperlongumine induced expression of death receptors which potentiated TRAIL-induced apoptosis in cancer cells but did not affect decoy receptors. Piperlongumine also downregulated tumor cell-survival pathways, inhibited colony formation and migration of cancer cells alone or in combination with TRAIL. The combination of piperlongumine with TRAIL was found to be synergistic. Conclusions: Our findings indicate that piperlongumine can sensitize cancer cells to TRAIL through the upregulation of death receptors and can trigger apoptosis with the downregulation of anti- apoptotic proteins.Item Immunolocalization of αV, α3 and β1 integrins in the human placenta with pre-eclampsia(URBAN & FISCHER VERLAG) Vatansever, HS; Inan, VS; Lacin, S; Koyuncu, FSigns of pre-eclampsia are considered to be caused by maternal endothelial dysfunction due to circulating factors of placental origin. Integrins are a large family of cell surface proteins that serve as receptors involved in cell-cell and cell-matrix interactions during placentation. Therefore, low expression of integrins or the lack of it may be encountered during pre-eclampsia. In the present study, we investigated the immunolocalisation of integrins alphaV, alpha3 and beta1 in placentas of normal and preeclamptic women. Thirty-two placentas from pre-eclamptic (n = 14) and normotensive (n = 18) women were used. Immunohistochemical staining was performed on formalin-fixed, paraffin-embedded tissue specimens, using anti-alphaV, anti-alpha3 and anti-beta1 antibodies and the indirect immunoperoxidase technique. A semi-quantitative grading system (HSCORE) was used to compare immunohistochemical staining intensities. Distribution patterns of alphaV, alpha3 and beta1 integrins were detected in cytotrophoblasts and Hofbauer cells in normal and pre-eclamptic placentas. Immunostaining of alphaV and beta1 integrins was slightly decreased in pre-eclamptic samples but alpha3 integrin immunostaining was similar in pre-eclamptic and normal placentas. Decreased immunostaining of integrins in the cytotrophoblasts may considered to be a structural basis for decreased placental perfusion in pre-eclampsia.Item The immunohistochemical evaluation of VEGF in placenta biopsies of pregnancies complicated by preeclampsia(SPRINGER HEIDELBERG) Akercan, F; Cirpan, T; Terek, MC; Ozcakir, HT; Giray, G; Sagol, S; Karadadas, NObjective The study was designed to determine the protein levels of vascular endothelial growth factor (VEGF) in the placenta biopsies of patients with preeclampsia and compare with normal controls. Design Prospective cohort study. Methods The placental biopsies were obtained from ten patients with preeclampsia and ten patients of control group at the time of delivery. Avidin-biotin-peroxidase immunohistochemistry was then performed to identify levels of VEGF protein within the tissue and a semi-quantitative method was devised to score the amount of staining present in the sample. Two histopathologists who were blinded to the groups were asked to score each sample for the intensity of staining and the number of cells stained in a randomly selected per high-power fields of each sample. The resulting H-score was computed as a product of intensity and percent of cells stained. Results The VEGF expression was significantly higher in placenta biopsies of preeclamptic patients compared to that of controls (271.2 +/- 22.65 vs. 201.9 +/- 12.33, P = 0.000). Conclusion Immunostaining of VEGF is significantly higher in placenta biopsies of patients with preeclampsia.Item Apoptosis-mediated Cytotoxic Effects of Ibandronic Acid on Hormone- and Drug-refractory Prostate Cancer Cells and Human Breast Cancer Cells(FIELD HOUSE PUBLISHING LLP) Kucukzeybek, Y; Gorumlu, G; Cengiz, E; Karabulut, B; Sezgin, C; Atmaca, H; Sanli, UA; Uzunoglu, S; Uslu, ROver 80% of patients with advanced breast and prostate cancer ultimately develop bone metastases. Ibandronic acid has proven efficacy for treatment of bone metastasis secondary to breast cancer. This study was designed to investigate the cytotoxic and apoptotic effects of ibandronic acid on hormone- and drug-refractory prostate carcinoma DU-145 and human breast cancer MCF-7 cell lines. Cytotoxicity was evaluated using an XTT cell proliferation kit, and apoptosis was assessed by enzyme-linked immunosorbent assay (histone-DNA fragmentation) and measurement of caspase 3/7 activity. With increasing concentrations of ibandronic acid there was a dose- and time-dependent decrease in cell numbers. MCF-7 cells were more resistant than DU-145 cells (half maximal inhibitory concentrations of 122 and 90 mu M, respectively). Ibandronic acid induced apoptosis in both cell lines. The study showed an apoptosis-mediated cytotoxic effect for ibandronic acid (in addition to the already known osteoclast inhibiting effect) in breast cancer patients with bone metastases; which was also observed in prostate cancer cells. Further clinical studies involving breast and prostate cancer patients with bone metastases are warranted to confirm these findings.Item A Star of Connection Between Pancreatic Cancer and Diabetes: Adrenomedullin(E S BURIONI RICERCHE BIBLIOGRAFICHE) Görgülü, K; Diakopoulos, KN; Vatansever, HSPancreatic cancer belongs to the most aggressive cancer types, with an incidence rate equallig mortality rate. It is well-known that type 2 diabetes is a significant risk factor for pancreatic cancer. Interestingly, several studies have shown that pancreatic cancer can also lead to type 2 diabetes, as part of the pancreatic cancer induced paraneoplastic syndrome. Multiple factors have been proposed to be involved in the interaction between pancreatic cancer and diabetes. Adrenomedullin, a multifunctional hormone, is nominated as a strong candidate influencing the connection of pancreatic cancer with diabetes. Evidence so far suggest that adrenomedullin upregulation is linked with pancreatic cancer growth, invasion, metastasis, and angiogenesis. Most importantly, adrenomedullin exerts paracrine effects on pancreatic beta cells impairing insulin secretion, causing glucose intolerance, and thus leading to beta cell dysfunction. This review will explain recent advances regarding the involvement of adrenomedullin in pancreatic cancer and pancreatic cancer-associated diabetes.