61 research outputs found

    The Efficacy of Mitotane in Human Primary Adrenocortical Carcinoma Cultures

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    CONTEXT: Patients with adrenocortical carcinoma (ACC) often fail mitotane treatment and deal with severe toxicity, marking the relevance of predictive parameters for treatment outcome. OBJECTIVE: Determine the effects of mitotane in primary ACC cultures, and correlate sensitivity with patient and tumor characteristics. METHODS: In 32 primary ACC cultures, the effects of mitotane on cell growth and cortisol production were determined. RRM1, SOAT1, and CYP2W1 expression were assessed using reverse transcription-polymerase chain reaction and immunohistochemistry. RESULTS: The median percentage cell amount inhibition in primary ACC cultures at 50 µM mitotane was 57%. Seven patients were classified as nonresponders, 14 as partial responders, and 11 as responders. The mean median effective concentration (EC50) value of mitotane for inhibition of cell amount in responders was 14.2 µM (95% CI, 11.3-17.9), in partial responders 41.6 µM (95% CI, 33.5-51.8), and could not be calculated in nonresponders. The percentage cortisol-producing ACC was 14%, 43%, and 73% for nonresponders, partial responders, and responders (P = 0.068). Mitotane inhibited cortisol production with a mean EC50 of 1.4 µM (95% CI, 0.9-2.1), which was considerably lower than the EC5

    Interferon-beta enhances sensitivity to gemcitabine in pancreatic cancer

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    Background Adjuvant gemcitabine for pancreatic cancer has limited efficacy in the clinical setting. Impaired drug metabolism is associated with treatment resistance. We aimed to evaluate the chemosensitising effect of interferon-beta (IFN-β). Methods BxPC-3, CFPAC-1, and Panc-1 cells were pre-treated with IFN-β followed by gemcitabine monotherapy. The effect on cell growth, colony formation, and cell cycle was determined. RT-qPCR was used to measure gene expression. BxPC-3 cells were used in a heterotopic subcutaneous mouse model. Results IFN-β increased sensitivity to gemcitabine (4-, 7.7-, and 1.7-fold EC50 decrease in BxPC-3, CFPAC-1, and Panc-1, respectively; all P < 0.001). Findings were confirmed when assessing colony formation. The percentage of cells in the S-phase was significantly increased after IFN-β treatment only in BxPC-3 and CFPAC-1 by 12 and 7%, respectively (p < 0.001 and p < 0.05, respectively). Thereby, IFN-β upregulated expression of the drug transporters SLC28A1 in BxPC-3 (252%) and SLC28A3 in BxPC-3 (127%) and CFPAC-1 (223%) (all p < 0.001). In vivo, combination therapy reduced tumor

    Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors

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    Background:The mTOR-inhibitor everolimus improves progression-free survival in advanced pancreatic neuroendocrine tumours (PNETs). However, adaptive resistance to mTOR inhibition is described.Methods:QGP-1 and BON-1, two human PNET cell lines, were cultured with increasing concentrations of everolimus up to 22 weeks to reach a dose of 1 ÎĽM everolimus, respectively, 1000-fold and 250-fold initial IC 50. Using total DNA content as a measure of cell number, growth inhibitory dose-response curves of everolimus were determined at the end of resistance induction and over time after everolimus withdrawal. Response to ATP-competitive mTOR inhibitors OSI-027 and AZD2014, and PI3K-mTOR inhibitor NVP-BEZ235 was studied. Gene expression of 10 PI3K-Akt-mTOR pathway-related genes was evaluated using quantitative real-time PCR (RT-qPCR).Results:Long-term everolimus-treated BON-1/R and QGP-1/R showed a significant reduction in everolimus sensitivity. During a drug holiday, gradual return of everolimus sensitivity in BON-1/R and QGP-1/R led to complete reversal of resistance after 10-12 weeks. Treatment with AZD2014, OSI-027 and NVP-BEZ235 had an inhibitory effect on cell proliferation in both sensitive and resistant cell lines. Gene expression in BON-1/R revealed downregulation of MTOR, RICTOR, RAPTOR, AKT and HIF1A, whereas 4EBP1 was upregulated. In QGP-1/R, a downregulation of HIF1A and an upregulation of ERK2 were observed.Conclusions:Long-term everolimus resistance was induced in two human PNET cell lines. Novel PI3K-AKT-mTOR pathway-targeting drugs can overcome everolimus resistance. Differential gene expression profiles suggest different mechanisms of everolimus resistance in BON-1 and QGP-1

    Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells

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    Prolonged remission of hypercortisolism with steroidogenesis inhibitors has been described in patients with ectopic adrenocorticotropic hormone (ACTH) syndrome. The anti-proliferative and pro-apoptotic effect of ketoconazole in human cancer cells was previously suggested. The aim of this study was to explore the effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor (NET) cell lines. The effects of ketoconazole alone, and in combination with somatostatin analogs, were evaluated in two human cell lines: DMS-79 (ectopic ACTH-producing small cell lung carcinoma) and BON-1 (human pancreatic NET). Total DNA measurement, apoptosis, cell cycle, chromogranin A (CgA)/proopiomelanocortin (POMC) expression by qRT-PCR, serotonin, CgA, and ACTH secretion assays were performed. In both cell lines, ketoconazole significantly suppressed cell growth and colony formation in a dose and time-dependent manner. The effect in DMS-79 was primarily cytotoxic, while it was more apoptotic in BON-1 cells. Ketoconazole also induced increase in G0/G1 phase in both cell lines and arrest in phase G2/M of BON-1 cells. Ketoconazole did not affect the secretion of serotonin, CgA, ACTH, or the mRNA expression of CgA and POMC. Decreased serotonin secretion was observed after the combination treatment with pasireotide. These results suggest a direct effect of ketoconazole on cell proliferation, apoptosis, and cell cycle in both ACTH- and non-ACTH-producing NET cells

    Intérêt du bilan de thrombophilie dans les pathologies vasculaires placentaires et les fausses couches à répétition

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    OBJECTIF : Evaluer l intérêt du bilan de thrombophilie dans le cadre des fausses couches à répétition et/ou des pathologies vasculaires placentaires afin de cibler ses indications ainsi que l efficacité du traitement anti-thrombotique mis en place lors des grossesses ultérieures. MATERIEL ET METHODE: Il s agit d une étude rétrospective, mono-centrique, se déroulant au CHU de DIJON, entre 2006 et 2013. Nous avons inclus toutes patientes ayant eu une recherche de thrombophilie héréditaire et acquise pour un des antécédents suivants: 2 ou plus fausses couches précoces 15 SA , 1 mort fœtale in utéro au-delà de 22SA, une interruption médicale de grossesse ou de décès néonatal pour cause de pathologie vasculaire placentaire, un retard de croissance intra-utérin sévère ou non , une préeclampsie sévère ou non, compliquée ou non d éclampsie, de hellp syndrome, un hématome rétro-placentaire avec preuve histologique. RESULTAT: 300 patientes avaient un antécédent de pathologie vasculaire placentaire et 153 de fausses couches à répétition. 122 (27%) patientes étaient porteuses de thrombophilie. Nous n avons pas observé plus de fausses couches (p=0.11) ni plus de pathologies vasculaires placentaires sévères (p=0.08) en présence de thrombophilie. 206 patientes ont entamé une nouvelle grossesse dont 75 (36.4%) avec une thrombophilie. 93.3% des patientes thrombophiles ont reçu un traitement anti-thrombotique (aspirine : 22.6%, héparine : 12%, aspirine + héparine 58.6%) versus 73.3% des patientes non thrombophiles (aspirine : 48.9%, héparine : 2.3%, aspirine+héparine : 22.2%). 18 (24%) patientes thrombophiles dont 1 SAPL ont récidivé sous traitement versus 33 (25.1%) patientes non thrombophiles. Le taux de récidive de pathologie vasculaire placentaire non sévère, de pathologie vasculaire placentaire sévère et de fausse couche n est pas statistiquement différent chez les patientes thrombophiles par rapport aux patientes non thrombophiles quelque soit le traitement mis en place (p=0.30, p=0.97, p=0.56). Cependant la prescription d une bithérapie était plus fréquente en présence de thrombophilie. CONCLUSION : Nous proposons de réaliser un bilan de thrombophilie acquise en cas de fausses couches à répétition et de pathologie vasculaire placentaire sévère. Le bilan de thrombophilie héréditaire pourra être réalisé en cas de pathologie vasculaire placentaire atypique et très sévère. L aspirine devrait être prescrite en première intention dans tous les tableaux. Nous suggérons l introduction de lovenox 4000UI/j en cas d échec d aspirine seule en prévention d une récidive de fausse couche ou de pathologie vasculaire placentaire sévère en tenant compte de l évolution de la protéine S et des D-dimères au cours de la grossesse.DIJON-BU Médecine Pharmacie (212312103) / SudocSudocFranceF

    Qualité de vie après chirurgie de l’endométriose pelvienne profonde : évaluation d’une version française de l’EHP-30

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    International audienceOBJECTIVE:To evaluate the changes in the quality of life of patients after deep pelvic endometriosis surgery, with a French version of EHP-30 questionnaire, and the capacity of the EHP-30 to carry out this measurement.MATERIAL AND METHODS:Study prospective monocentric, conducted in the obstetrics and gynecology department of the CHU Dijon during the period of October 2012 from October 2013. A EHP-30 questionnaire was given to patients before surgery. The same questionnaire was sent to their homes, away from surgery (3-6 months) to inform about their postoperative quality of life. The difference in preoperative and postoperative scores was tested using the test Wilcoxon signed ranks. A difference was considered significant if the p-value was less than or equal to 0.05. Sensitivity to change was calculated by the method of effect size (ES). The size of the effect is defined as the difference in mean preoperative and postoperative scores divided by the standard deviation of preoperative scores. A size effet of 0.20 indicates less change scores, of 0.50 a moderate change and of 0.80 a material change.RESULTS:We included 22 patients in total in the prospective analysis. The majority of patients had gynecological symptoms of dysmenorrhea with 69.7%, 75.7% and 75.7% dyspareunia chronic pelvic pain. Nineteen patients (57.6%) had gastro-intestinal symptoms. Urinary symptoms were less frequent. The results of the EHP-30 showed a significant improvement for the items "pain" (P=0.01), "control and powerlessness" (P=0.02), "emotional well-being" (P<0,01) "social relations" (P<0.01), "sexual intercourse" (P=0.03) and "relationship with the medical world" (P=0.05). We observed a non-significant improvement for the items "self-image" (P=0.44), "work" (P=0.48) and "relationships with children" (P=0.50). The size of the effect (ES) was low to high for all dimensions of the questionnaire, ranging from 0.1 to 0.6 for the entire group. A significant sensitivity to change was found for the items "pain" (ES=0.60), "control and powerlessness" (ES=0.62), "social relations" (ES=0.57). A moderate sensitivity to change was found for the items "emotional well-being" (ES=0.29), "relationship with the medical world" (ES=0.26). A low sensitivity to change was found for the items "relationships with children" (ES=0.06), "self-image" (ES=0.16), "work" (ES=0.18), "sexual intercourse" (ES=0.20). A size that is important to moderate effect corresponded to a statistically significant improvement of the score EHP-30.CONCLUSION:This study showed that the EHP-30 is a sensitive tool to change the health status and an appropriate instrument for the assessment of treatment effects in patients with deep pelvic endometriosis

    Determination of the tectonic evolution of the Edremit Gulf based on seismic reflection studies

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    The Edremit Gulf, which developed during the Neogene-Quaternary, is a seismically active graben in NW Anatolia (Turkey) surrounded by the Sakarya continent. The sedimentary deposits in the gulf overlie the bedrock unconformably and can be separated into two parts as upper and lower deposits based on similarity of their seismic characteristics, and because the contact between them is clear. The lower deposits are characterized in the seismic profiles by the absence of well defined, continuous reflectors and are strongly disturbed by faults. A tectonic map and structural model of the Edremit Gulf was derived from interpreting 21 deep seismic profiles trending NE-SW and NW-SE within the gulf. Two fault systems were distinguished on the basis of this compilation. The NNW-SSE trending parallel faults are low-angle normal faults formed after compression. They controlled and deformed the lower basin deposits. A syncline and anticline with a broad fold-curvature length resulted in folds that developed parallel to basin boundaries in the lower basin deposits. The ENE-WSW trending high-angle faults have controlled and deformed the northern basin of the Edremit Gulf. The folds developed within the northern lower deposits originated from the listric geometry of the faults. These faults are normal faults associated with regional N-S extension in western Anatolia. The Edremit Gulf began to open under the control of low-angle NNW-SSE trending faults that developed after the compression of western Anatolia in an E-W direction in the early Neogene. Subsequently, regional N-S extensional stress and high-angle normal faults cut the previous structures, opened the northern basin, and controlled and deformed the lower basin deposits in the gulf. As a result, the Edremit Gulf has not been controlled by any strike-slip faults or the Northern Anatolian Fault. The basin developed in the two different tectonic regimes of western Anatolia as an Aegean type cross-graben from the Neogene to Holocene

    Influence of type-I Interferon receptor expression level on the response to type-I Interferons in human pancreatic cancer cells

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    Pancreatic cancer is a highly aggressive malignancy with limited treatment options. Type-I interferons (e.g. IFN-/-) have several anti-tumour activities. Over the past few years, clinical studies evaluating the effect of adjuvant IFN- therapy in pancreatic cancer yielded equivocal results. Although IFN- and - act via the type-I IFN receptor, the role of the number of receptors present on tumour cells is still unknown. Therefore, this study associated, for the first time, in a large panel of pancreatic cancer cell lines the effects of IFN-/- with the expression of type-I IFN receptors. The anti-tumour effects of IFN- or IFN- on cell proliferation and apoptosis were evaluated in 11 human pancreatic cell lines. Type-I IFN receptor expression was determined on both the mRNA and protein level. After 7days of incubation, IFN- significantly reduced cell growth in eight cell lines by 5-67%. IFN- inhibited cell growth statistically significant in all cell lines by 43-100%. After 3days of treatment, IFN- induced significantly more apoptosis than IFN-. The cell lines variably expressed the type-I IFN receptor. The maximal inhibitory effect of IFN- was positively correlated with the IFNAR-1 mRNA (P<0.05, r=0.63), IFNAR-2c mRNA (P<0.05, r=0.69) and protein expression (P<0.05, r=0.65). Human pancreatic cancer cell lines variably respond to IFN- and -. The expression level of the type-I IFN receptor is of predictive value for the direct anti-tumour effects of IFN- treatment. More importantly, IFN- induces anti-tumour effects already at much lower concentrations, is less dependent on interferon receptor expression and seems, therefore, more promising than IFN-
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