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  1. Prediction of Postchemotherapy Ovarian Function Using Markers of Ovarian Reserve

    PubMed Central

    Xia, Rong; Schott, Anne F.; McConnell, Daniel; Banerjee, Mousumi; Hayes, Daniel F.

    2014-01-01

    Background. Reproductive-aged women frequently receive both chemotherapy and endocrine therapy as part of their treatment regimen for early stage hormone receptor-positive breast cancer. Chemotherapy results in transient or permanent ovarian failure in the majority of women. The difficulty in determining which patients will recover ovarian function has implications for adjuvant endocrine therapy decision making. We hypothesized that pretreatment serum anti-Müllerian hormone (AMH) and inhibin B concentrations would predict for ovarian function following chemotherapy. Methods. Pre- and perimenopausal women aged 25–50 years with newly diagnosed breast cancer were enrolled. Subjects underwent phlebotomy for assessment of serum AMH, inhibin B, follicle-stimulating hormone, and estradiol prior to chemotherapy and 1 month and 1 year following completion of treatment. Associations among hormone concentrations, clinical factors, and biochemically assessed ovarian function were assessed. Results. Twenty-seven subjects were evaluable for the primary endpoint. Median age was 41. Twenty subjects (74.1%) experienced recovery of ovarian function within 18 months. Of the 26 evaluable subjects assessed prior to chemotherapy, 19 (73.1%) had detectable serum concentrations of AMH. The positive predictive value of a detectable baseline serum AMH concentration for recovery of ovarian function was 94.7%, and the negative predictive value was 85.7%. On univariate analysis, younger age and detectable serum AMH concentration at chemotherapy initiation were predictive of increased likelihood of recovery of ovarian function. Conclusion. Prechemotherapy assessment of serum AMH may be useful for predicting postchemotherapy ovarian function. This finding has implications for decision making about adjuvant endocrine therapy in premenopausal women treated with chemotherapy. PMID:24319018

  2. Ovarian Cancer Risk Prediction Models

    Cancer.gov

    Developing statistical models that estimate the probability of developing ovarian cancer over a defined period of time will help clinicians identify individuals at higher risk of specific cancers, allowing for earlier or more frequent screening and counseling of behavioral changes to decrease risk.

  3. Predictive and therapeutic markers in ovarian cancer

    DOEpatents

    Gray, Joe W.; Guan, Yinghui; Kuo, Wen-Lin; Fridlyand, Jane; Mills, Gordon B.

    2013-03-26

    Cancer markers may be developed to detect diseases characterized by increased expression of apoptosis-suppressing genes, such as aggressive cancers. Genes in the human chromosomal regions, 8q24, 11q13, 20q11-q13, were found to be amplified indicating in vivo drug resistance in diseases such as ovarian cancer. Diagnosis and assessment of amplification levels certain genes shown to be amplified, including PVT1, can be useful in prediction of poor outcome of patient's response and drug resistance in ovarian cancer patients with low survival rates. Certain genes were found to be high priority therapeutic targets by the identification of recurrent aberrations involving genome sequence, copy number and/or gene expression are associated with reduced survival duration in certain diseases and cancers, specifically ovarian cancer. Therapeutics to inhibit amplification and inhibitors of one of these genes, PVT1, target drug resistance in ovarian cancer patients with low survival rates is described.

  4. KRAS Genomic Status Predicts the Sensitivity of Ovarian Cancer Cells to Decitabine | Office of Cancer Genomics

    Cancer.gov

    Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma, and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low-grade and high-grade serous ovarian cancer cells.

  5. KRAS genomic status predicts the sensitivity of ovarian cancer cells to decitabine

    PubMed Central

    Stewart, ML; Tamayo, P; Wilson, AJ; Wang, S; Chang, YM; Kim, JW; Khabele, D; Shamji, AF; Schreiber, SL

    2015-01-01

    Decitabine, a cancer therapeutic that inhibits DNA methylation, produces variable antitumor response rates in patients with solid tumors that might be leveraged clinically with identification of a predictive biomarker. In this study, we profiled the response of human ovarian, melanoma and breast cancer cells treated with decitabine, finding that RAS/MEK/ERK pathway activation and DNMT1 expression correlated with cytotoxic activity. Further, we showed that KRAS genomic status predicted decitabine sensitivity in low and high-grade serous ovarian cancer cells. Pre-treatment with decitabine decreased the cytotoxic activity of MEK inhibitors in KRAS-mutant ovarian cancer cells, with reciprocal downregulation of DNMT1 and MEK/ERK phosphorylation. In parallel with these responses, decitabine also upregulated the pro-apoptotic BCL-2 family member BNIP3, which is known to be regulated by MEK and ERK, and heightened the activity of pro-apoptotic small molecule navitoclax, a BCL-2 family inhibitor. In a xenograft model of KRAS-mutant ovarian cancer, combining decitabine and navitoclax heighted antitumor activity beyond administration of either compound alone. Our results define the RAS/MEK/DNMT1 pathway as a determinant of sensitivity to DNA methyltransferase inhibition, specifically implicating KRAS status as a biomarker of drug response in ovarian cancer. PMID:25968887

  6. Recreational Physical Activity and Ovarian Cancer Risk and Survival

    PubMed Central

    Moorman, Patricia G.; Jones, Lee W.; Akushevich, Lucy; Schildkraut, Joellen M.

    2010-01-01

    Purpose Physical activity may influence ovarian cancer risk and outcomes through effects on ovulation, inflammatory markers and other processes. We examined associations between self-reported physical activity and ovarian cancer risk and survival in a population-based, case-control study in North Carolina. Methods The analyses involved 638 epithelial ovarian cancer cases and 683 controls recruited between 1999-2008. Logistic regression analyses were used to assess ovarian cancer risk in relation to reported average physical activity at various time periods. Kaplan-Meier analyses and proportional hazards modeling were used to assess associations between physical activity and survival among ovarian cancer cases. Results Modestly reduced risks for ovarian cancer were observed in some categories of physical activity, but there were no consistent patterns of greater reductions in risk with higher activity levels. Physical activity prior to diagnosis was not significantly related to ovarian cancer survival overall, but survival was better for women who reported >2 hours of activity/week as compared to those reporting <1 hour/week among women who were non-obese (multivariable hazard ratio=0.69, 95% CI 0.47 – 1.00) Conclusions Our data provide weak evidence in support of beneficial effects of physical activity on ovarian cancer risk and survival, but results should be interpreted cautiously because of the lack of a clear dose response relation with higher levels of exercise and the likely misclassification of self-reported activity. PMID:21296269

  7. A new ovarian response prediction index (ORPI): implications for individualised controlled ovarian stimulation

    PubMed Central

    2012-01-01

    Background The objective was to present a new ovarian response prediction index (ORPI), which was based on anti-Müllerian hormone (AMH) levels, antral follicle count (AFC) and age, and to verify whether it could be a reliable predictor of the ovarian stimulation response. Methods A total of 101 patients enrolled in the ICSI programme were included. The ORPI values were calculated by multiplying the AMH level (ng/ml) by the number of antral follicles (2–9 mm), and the result was divided by the age (years) of the patient (ORPI=(AMH x AFC)/Patient age). Results The regression analysis demonstrated significant (P<0.0001) positive correlations between the ORPI and the total number of oocytes and of MII oocytes collected. The logistic regression revealed that the ORPI values were significantly associated with the likelihood of pregnancy (odds ratio (OR): 1.86; P=0.006) and collecting greater than or equal to 4 oocytes (OR: 49.25; P<0.0001), greater than or equal to 4 MII oocytes (OR: 6.26; P<0.0001) and greater than or equal to 15 oocytes (OR: 6.10; P<0.0001). Regarding the probability of collecting greater than or equal to 4 oocytes according to the ORPI value, the ROC curve showed an area under the curve (AUC) of 0.91 and an efficacy of 88% at a cut-off of 0.2. In relation to the probability of collecting greater than or equal to 4 MII oocytes according to the ORPI value, the ROC curve had an AUC of 0.84 and an efficacy of 81% at a cut-off of 0.3. The ROC curve for the probability of collecting greater than or equal to 15 oocytes resulted in an AUC of 0.89 and an efficacy of 82% at a cut-off of 0.9. Finally, regarding the probability of pregnancy occurrence according to the ORPI value, the ROC curve showed an AUC of 0.74 and an efficacy of 62% at a cut-off of 0.3. Conclusions The ORPI exhibited an excellent ability to predict a low ovarian response and a good ability to predict a collection of greater than or equal to 4 MII oocytes, an excessive ovarian response and

  8. Optimized Prediction of Extreme Treatment Outcomes in Ovarian Cancer

    PubMed Central

    Misganaw, Burook; Ahsen, Eren; Singh, Nitin; Baggerly, Keith A.; Unruh, Anna; White, Michael A.; Vidyasagar, M.

    2015-01-01

    Ovarian cancer is the fifth leading cause of death among female cancers. Front-line therapy for ovarian cancer is platinum-based chemotherapy. However, the response of patients is highly nonuniform. The TCGA database of serous ovarian carcinomas shows that ~10% of patients respond poorly to platinum-based chemotherapy, with tumors relapsing in seven months or less. Another 10% or so enjoy disease-free survival of three years or more. The objective of the present research is to identify a small number of highly predictive biomarkers that can distinguish between the two extreme responders and then extrapolate to all patients. This is achieved using the lone star algorithm that is specifically developed for biological applications. Using this algorithm, we are able to identify biomarker panels of 25 genes (of 12,000 genes) that can be used to classify patients into one of the three groups: super responders, medium responders, and nonresponders. We are also able to determine a discriminant function that can divide the entire patient population into two classes, such that one group has a clear survival advantage over the other. These biomarkers are developed using the TCGA Agilent platform data and cross-validated on the TCGA Affymetrix platform data, as well as entirely independent data from Tothill et al. The P-values on the training data are extremely small, sometimes below machine zero, while the P-values on cross-validation are well below the widely accepted threshold of 0.05. PMID:27034613

  9. Sprouty 1 predicts prognosis in human epithelial ovarian cancer

    PubMed Central

    Masoumi-Moghaddam, Samar; Amini, Afshin; Wei, Ai-Qun; Robertson, Gregory; Morris, David L

    2015-01-01

    Sprouty proteins are evolutionary-conserved modulators of receptor tyrosine kinase (RTK) signaling. We have previously reported inverse correlation of the Sprouty 1 (Spry1) protein expression with ovarian cancer cell proliferation, migration, invasion and survival. In the present study, the expression status of Spry1 protein and its clinical relevance in patients with epithelial ovarian cancer were explored. Matched tumor and normal tissue samples from 100 patients with epithelial ovarian cancer were immunohistochemically stained for Spry1. Expression of ERK, p-ERK, Ki67, FGF-2, VEGF and IL-6 and their correlation with Spry1 were also evaluated. In addition, correlation between Spry1 and clinicopathological characteristics and predictive significance of Spry1 for overall survival (OS) and disease-free survival (DFS) were analysed. Our data indicated that Spry1 was significantly downregulated in tumor tissues (p=0.004). Spry1 showed significant inverse correlation with p-ERK/ERK (p=0.045), Ki67 (p=0.010), disease stage (p=0.029), tumor grade (p=0.037), recurrence (p=0.001) and lymphovascular invasion (p=0.042). It was revealed that Spry1 low-expressing patients had significantly poorer OS (p=0.010) and DFS (p=0.012) than those with high expression of Spry1. Multivariate analysis showed that high Spry1 (p=0.030), low stage (p=0.048) and no residual tumor (p=0.007) were independent prognostic factors for a better OS, among which high Spry1 (p=0.035) and low stage (p=0.035) remained as independent predictors of DFS, too. We also found that the expression of Spry1 significantly correlates with the expression of Spry2 (p<0.001), but not that of Spry4. In conclusion, we report for the first time to our knowledge that Spry1 protein is downregulated in human epithelial ovarian cancer. Spry1 expression significantly impacts tumor behavior and shows predictive value as an independent prognostic factor for survival and recurrence. PMID:26101716

  10. Telomerase Activity in Human Ovarian Carcinoma

    NASA Astrophysics Data System (ADS)

    Counter, Christopher M.; Hirte, Hal W.; Bacchetti, Silvia; Harley, Calvin B.

    1994-04-01

    Telomeres fulfill the dual function of protecting eukaryotic chromosomes from illegitimate recombination and degradation and may aid in chromosome attachment to the nuclear membrane. We have previously shown that telomerase, the enzyme which synthesizes telomeric DNA, is not detected in normal somatic cells and that telomeres shorten with replicative age. In cells immortalized in vitro, activation of telomerase apparently stabilizes telomere length, preventing a critical destabilization of chromosomes, and cell proliferation continues even when telomeres are short. In vivo, telomeres of most tumors are shorter than telomeres of control tissues, suggesting an analogous role for the enzyme. To assess the relevance of telomerase and telomere stability in the development and progression of tumors, we have measured enzyme activity and telomere length in metastatic cells of epithelial ovarian carcinoma. We report that extremely short telomeres are maintained in these cells and that tumor cells, but not isogenic nonmalignant cells, express telomerase. Our findings suggest that progression of malignancy is ultimately dependent upon activation of telomerase and that telomerase inhibitors may be effective antitumor drugs.

  11. A VEGF-dependent gene signature enriched in mesenchymal ovarian cancer predicts patient prognosis.

    PubMed

    Yin, Xia; Wang, Xiaojie; Shen, Boqiang; Jing, Ying; Li, Qing; Cai, Mei-Chun; Gu, Zhuowei; Yang, Qi; Zhang, Zhenfeng; Liu, Jin; Li, Hongxia; Di, Wen; Zhuang, Guanglei

    2016-01-01

    We have previously reported surrogate biomarkers of VEGF pathway activities with the potential to provide predictive information for anti-VEGF therapies. The aim of this study was to systematically evaluate a new VEGF-dependent gene signature (VDGs) in relation to molecular subtypes of ovarian cancer and patient prognosis. Using microarray profiling and cross-species analysis, we identified 140-gene mouse VDGs and corresponding 139-gene human VDGs, which displayed enrichment of vasculature and basement membrane genes. In patients who received bevacizumab therapy and showed partial response, the expressions of VDGs (summarized to yield VDGs scores) were markedly decreased in post-treatment biopsies compared with pre-treatment baselines. In contrast, VDGs scores were not significantly altered following bevacizumab treatment in patients with stable or progressive disease. Analysis of VDGs in ovarian cancer showed that VDGs as a prognostic signature was able to predict patient outcome. Correlation estimation of VDGs scores and molecular features revealed that VDGs was overrepresented in mesenchymal subtype and BRCA mutation carriers. These findings highlighted the prognostic role of VEGF-mediated angiogenesis in ovarian cancer, and proposed a VEGF-dependent gene signature as a molecular basis for developing novel diagnostic strategies to aid patient selection for VEGF-targeted agents. PMID:27498762

  12. A VEGF-dependent gene signature enriched in mesenchymal ovarian cancer predicts patient prognosis

    PubMed Central

    Yin, Xia; Wang, Xiaojie; Shen, Boqiang; Jing, Ying; Li, Qing; Cai, Mei-Chun; Gu, Zhuowei; Yang, Qi; Zhang, Zhenfeng; Liu, Jin; Li, Hongxia; Di, Wen; Zhuang, Guanglei

    2016-01-01

    We have previously reported surrogate biomarkers of VEGF pathway activities with the potential to provide predictive information for anti-VEGF therapies. The aim of this study was to systematically evaluate a new VEGF-dependent gene signature (VDGs) in relation to molecular subtypes of ovarian cancer and patient prognosis. Using microarray profiling and cross-species analysis, we identified 140-gene mouse VDGs and corresponding 139-gene human VDGs, which displayed enrichment of vasculature and basement membrane genes. In patients who received bevacizumab therapy and showed partial response, the expressions of VDGs (summarized to yield VDGs scores) were markedly decreased in post-treatment biopsies compared with pre-treatment baselines. In contrast, VDGs scores were not significantly altered following bevacizumab treatment in patients with stable or progressive disease. Analysis of VDGs in ovarian cancer showed that VDGs as a prognostic signature was able to predict patient outcome. Correlation estimation of VDGs scores and molecular features revealed that VDGs was overrepresented in mesenchymal subtype and BRCA mutation carriers. These findings highlighted the prognostic role of VEGF-mediated angiogenesis in ovarian cancer, and proposed a VEGF-dependent gene signature as a molecular basis for developing novel diagnostic strategies to aid patient selection for VEGF-targeted agents. PMID:27498762

  13. A Computational Model to Predict Rat Ovarian Steroid Secretion from In Vitro Experiments with Endocrine Disruptors

    PubMed Central

    Quignot, Nadia; Bois, Frédéric Y.

    2013-01-01

    A finely tuned balance between estrogens and androgens controls reproductive functions, and the last step of steroidogenesis plays a key role in maintaining that balance. Environmental toxicants are a serious health concern, and numerous studies have been devoted to studying the effects of endocrine disrupting chemicals (EDCs). The effects of EDCs on steroidogenic enzymes may influence steroid secretion and thus lead to reproductive toxicity. To predict hormonal balance disruption on the basis of data on aromatase activity and mRNA level modulation obtained in vitro on granulosa cells, we developed a mathematical model for the last gonadal steps of the sex steroid synthesis pathway. The model can simulate the ovarian synthesis and secretion of estrone, estradiol, androstenedione, and testosterone, and their response to endocrine disruption. The model is able to predict ovarian sex steroid concentrations under normal estrous cycle in female rat, and ovarian estradiol concentrations in adult female rats exposed to atrazine, bisphenol A, metabolites of methoxychlor or vinclozolin, and letrozole. PMID:23326527

  14. [Prognostic and predictive factors in epithelial ovarian cancer].

    PubMed

    Boudou-Rouquette, P; Pautier, P; Morice, P; Lhommé, C

    2009-04-01

    Even if prognosis of epithelial ovarian cancer remains very bad, survival and response to treatment are variable according to the patients. Determination of new prognostic markers helps us to adapt therapeutics for each patient and is necessary for the elaboration and the interpretation of clinical research studies. Many prognostic factors related to the tumor, the patient or the treatment, have been evaluated. The goal of this work is to review these parameters. So far, the most powerful variables are volume of residual disease after cytoreductive surgery, FIGO tumor stage, histologic type and grade of differentiation. The progress and accessibility to novel technologies applied to biology will make possible in the future the assessment of new prognostic profiles-based on genetic and/or proteomic tumor characteristics. The future also relies on the identification of predictive factors of response to treatment, but force is to note that on the last hundred publications testing predictive factors (p53, HER2, Topo-2-alpha, BRCA...), none have modified today our clinical practices. PMID:19357017

  15. Predicting Ovarian Cancer Patients' Clinical Response to Platinum-Based Chemotherapy by Their Tumor Proteomic Signatures.

    PubMed

    Yu, Kun-Hsing; Levine, Douglas A; Zhang, Hui; Chan, Daniel W; Zhang, Zhen; Snyder, Michael

    2016-08-01

    Ovarian cancer is the deadliest gynecologic malignancy in the United States with most patients diagnosed in the advanced stage of the disease. Platinum-based antineoplastic therapeutics is indispensable to treating advanced ovarian serous carcinoma. However, patients have heterogeneous responses to platinum drugs, and it is difficult to predict these interindividual differences before administering medication. In this study, we investigated the tumor proteomic profiles and clinical characteristics of 130 ovarian serous carcinoma patients analyzed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC), predicted the platinum drug response using supervised machine learning methods, and evaluated our prediction models through leave-one-out cross-validation. Our data-driven feature selection approach indicated that tumor proteomics profiles contain information for predicting binarized platinum response (P < 0.0001). We further built a least absolute shrinkage and selection operator (LASSO)-Cox proportional hazards model that stratified patients into early relapse and late relapse groups (P = 0.00013). The top proteomic features indicative of platinum response were involved in ATP synthesis pathways and Ran GTPase binding. Overall, we demonstrated that proteomic profiles of ovarian serous carcinoma patients predicted platinum drug responses as well as provided insights into the biological processes influencing the efficacy of platinum-based therapeutics. Our analytical approach is also extensible to predicting response to other antineoplastic agents or treatment modalities for both ovarian and other cancers. PMID:27312948

  16. Ovarian function and gastrointestinal motor activity.

    PubMed

    Palomba, S; Di Cello, A; Riccio, E; Manguso, F; La Sala, G B

    2011-12-01

    Gastrointestinal disorders are strictly related to the ovary function. In fact, it is noted that the prevalence of visceral pain disorders such as irritable bowel syndrome, gastroesophageal reflux disease, gallbladder and biliary tract diseases are significantly higher in women. Furthermore, symptom such as nausea, vomiting, abdominal pain, distension, satiety, bloating, diarrhoa or constipation, frequently appears in relation with pregnancy, luteal phase of the menstrual cycle or perimenopausal and menopausal states. Further support for the contribution of ovarian steroids to functional gastrointestinal disorders comes from studies demonstrating that pharmacological ovariectomy reduces abdominal pain symptoms. Therefore, addressing the influence of sex and sex hormones in the modulation of visceral pain appears critical to develop new strategies of diagnosis and therapy sex-directed for gastro-intestinal disorders. PMID:22322653

  17. Cystic ovarian follicles and thyroid activity in the dairy cow.

    PubMed

    Mutinati, M; Rizzo, A; Sciorsci, R L

    2013-05-01

    Thyroid activity affects the functionality of the reproductive axis and thyroid dysfunction has been associated with ovarian hyperstimulation syndrome and polycystic ovarian syndrome, in human medicine. This study investigates serum17- estradiol, progesterone, thyrotropic and thyroid hormone levels, in cyclic dairy cows on heat (Group H) and in dairy cows with ovarian follicular cysts (Group FC). Both 17- estradiol and progesterone serum concentrations were statistically higher in cystic than in cyclic cows (estradiol: 8.51±1.91 vs 6.32±1pg/mL) (progesterone: 0.49±0.17 vs 0.13±0.03ng/mL), whereas TSH and fT4 serum concentrations were statistically lower in cows with cystic ovarian follicles (COF), compared to cyclic ones (TSH: 2.48±1.31 vs 3.56±1.03ng/mL) (fT4: 5.86±1.69 vs 8.63±1.08). fT3 serum levels were similar, in both cystic and cyclic subjects (2.94±0.65 vs 3.02±0.9, respectively). Based on these results it was decided to examine the function of the thyrothropic axis of dairy cows in a similar manner to that conducted on humans. If severe hypothyroidism should be found, a hormone replacement therapy could be attempted in cystic cows refractory to "ordinary" therapies. PMID:23567219

  18. Sprouty2 protein in prediction of post-treatment ascites in epithelial ovarian cancer treated with adjuvant carbotaxol chemotherapy

    PubMed Central

    Masoumi-Moghaddam, Samar; Amini, Afshin; Wei, Ai-Qun; Robertson, Gregory; Morris, David L

    2015-01-01

    Ascites development and resistance to chemotherapy with carbotaxol are common clinical problems in epithelial ovarian cancer, partly due to the activation of MAPK/ERK signaling. Sprouty proteins are negative modulators of MAPK/ERK pathway, but their role in predicting resistance to carbotaxol chemotherapy and ascites development is unknown. In this study, we evaluated the expression of Sprouty protein isoforms by immunohistochemistry. The associations between the Sprouty expression and the clinicopathological features, including chemoresistance and the presence of ascites, were then explored. We found that the decreased expression of Spry2 was correlated with the post-treatment development of ascites and represented an independent predictor of this condition in carbotaxol-treated patients. However, no association was observed between the Sprouty expression and chemoresistance. In conclusion, our results suggest that Spry2 may be useful for patient follow-up and monitoring as it predicts the development of ascites in epithelial ovarian cancer cases treated with carbotaxol. PMID:26396926

  19. Seasonal changes in ovarian activity: lessons learnt from the horse.

    PubMed

    Donadeu, F X; Watson, E D

    2007-08-01

    The annual reproductive cycle in the horse involves a reduction in ovarian activity during short days. The absence of ovulatory activity during winter has important consequences for an equine industry eager to breed mares early during the year. The anovulatory season results from a reduction in the secretion of pituitary gonadotropin that is in turn triggered by the inhibitory effects of short photoperiod on the hypothalamus-pituitary axis. Recent studies have provided evidence that the response of the ovaries to endocrine stimuli during the anovulatory season is affected not only by circulating concentrations of trophic hormones but also by locally produced growth factors that are putative modulators of follicular responses to gonadotropins. The present review summarises current knowledge on ovarian dynamics during the equine anovulatory season and the regulatory mechanisms involved at both systemic and local levels. PMID:17207590

  20. An epidemiologic risk prediction model for ovarian cancer in Europe: the EPIC study

    PubMed Central

    Li, K; Hüsing, A; Fortner, R T; Tjønneland, A; Hansen, L; Dossus, L; Chang-Claude, J; Bergmann, M; Steffen, A; Bamia, C; Trichopoulos, D; Trichopoulou, A; Palli, D; Mattiello, A; Agnoli, C; Tumino, R; Onland-Moret, N C; Peeters, P H; Bueno-de-Mesquita, H B(as); Gram, I T; Weiderpass, E; Sánchez-Cantalejo, E; Chirlaque, M-D; Duell, E J; Ardanaz, E; Idahl, A; Lundin, E; Khaw, K-T; Travis, R C; Merritt, M A; Gunter, M J; Riboli, E; Ferrari, P; Terry, K; Cramer, D; Kaaks, R

    2015-01-01

    Background: Ovarian cancer has a high case-fatality ratio, largely due to late diagnosis. Epidemiologic risk prediction models could help identify women at increased risk who may benefit from targeted prevention measures, such as screening or chemopreventive agents. Methods: We built an ovarian cancer risk prediction model with epidemiologic risk factors from 202 206 women in the European Prospective Investigation into Cancer and Nutrition study. Results: Older age at menopause, longer duration of hormone replacement therapy, and higher body mass index were included as increasing ovarian cancer risk, whereas unilateral ovariectomy, longer duration of oral contraceptive use, and higher number of full-term pregnancies were decreasing risk. The discriminatory power (overall concordance index) of this model, as examined with five-fold cross-validation, was 0.64 (95% confidence interval (CI): 0.57, 0.70). The ratio of the expected to observed number of ovarian cancer cases occurring in the first 5 years of follow-up was 0.90 (293 out of 324, 95% CI: 0.81–1.01), in general there was no evidence for miscalibration. Conclusion: Our ovarian cancer risk model containing only epidemiological data showed modest discriminatory power for a Western European population. Future studies should consider adding informative biomarkers to possibly improve the predictive ability of the model. PMID:25742479

  1. Predicting age of ovarian failure after radiation to a field that includes the ovaries

    SciTech Connect

    Wallace, W. Hamish B. . E-mail: Hamish.Wallace@ed.ac.uk; Thomson, Angela B.; Saran, Frank; Kelsey, Tom W.

    2005-07-01

    Purpose: To predict the age at which ovarian failure is likely to develop after radiation to a field that includes the ovary in women treated for cancer. Methods and Materials: Modern computed tomography radiotherapy planning allows determination of the effective dose of radiation received by the ovaries. Together with our recent assessment of the radiosensitivity of the human oocyte, the effective surviving fraction of primordial oocytes can be determined and the age of ovarian failure, with 95% confidence limits, predicted for any given dose of radiotherapy. Results: The effective sterilizing dose (ESD: dose of fractionated radiotherapy [Gy] at which premature ovarian failure occurs immediately after treatment in 97.5% of patients) decreases with increasing age at treatment. ESD at birth is 20.3 Gy; at 10 years 18.4 Gy, at 20 years 16.5 Gy, and at 30 years 14.3 Gy. We have calculated 95% confidence limits for age at premature ovarian failure for estimated radiation doses to the ovary from 1 Gy to the ESD from birth to 50 years. Conclusions: We report the first model to reliably predict the age of ovarian failure after treatment with a known dose of radiotherapy. Clinical application of this model will enable physicians to counsel women on their reproductive potential following successful treatment.

  2. Estradiol treatment, physical activity, and muscle function in ovarian-senescent mice.

    PubMed

    Greising, Sarah M; Carey, Ryan S; Blackford, Jennifer E; Dalton, Laurin E; Kosir, Allison M; Lowe, Dawn A

    2011-08-01

    Estradiol (E(2)) treatment in young adult, ovariectomized mice increases physical activity and reverses deleterious effects on skeletal muscle. Here we test the hypothesis that E(2) treatment improves muscle function and physical activity in aged, ovarian-senescent mice. Plasma E(2) levels and vaginal cytology confirmed ovarian senescence in 20-month-old C57BL/6 mice. Mice were then randomly divided into activity groups, having access to a running wheel or not, and further into those receiving E(2) or placebo. Placebo-treated mice wheel ran more than E(2)-treated mice (P=0.03), with no difference between treatment groups in cage activities such as time spent being active and ambulation distance (P≥0.55). Soleus muscles from aged mice that wheel ran adapted by getting larger and stronger, irrespective of E(2) status (P≤0.02). Soleus muscle fatigue resistance was greater in mice treated with E(2) (P=0.02), but maximal isometric tetanic force was not affected (P≥0.79). Because E(2) treatment did not improve physical activity or overall muscle function in the aged, ovarian-senescent mice as predicted, a second study was initiated to examine E(2) treatment of young adult mice prematurely ovarian senescent from exposure to the chemical, 4-vinylcyclohexene diepoxide (VCD). Four-month-old C57BL/6 female mice were dosed with oil (control) or VCD. Vaginal cytology confirmed ovarian senescence in all mice treated with VCD 63 days after the onset of dosing, and then a subset of the VCD mice received E(2) (VCD+E(2)). Wheel running distance did not differ among control, VCD, and VCD+E(2) mice (P≥0.34). Soleus muscle concentric, isometric, and eccentric in vitro forces were greater in VCD+E(2) than in VCD mice (P<0.04), indicating beneficial estrogenic effects on muscle function. In general, aged and young mice with senescent ovaries were less responsive to E(2) treatment, in terms of physical activities and muscle function, than what has previously been shown for young

  3. Estradiol treatment, physical activity, and muscle function in ovarian-senescent mice

    PubMed Central

    Greising, Sarah M.; Carey, Ryan S.; Blackford, Jennifer E.; Dalton, Laurin E.; Kosir, Allison M.; Lowe, Dawn A.

    2011-01-01

    Estradiol (E2) treatment in young adult, ovariectomized mice increases physical activity and reverses deleterious effects on skeletal muscle. Here we test the hypothesis that E2 treatment improves muscle function and physical activity in aged, ovarian-senescent mice. Plasma E2 levels and vaginal cytology confirmed ovarian senescence in 20-month-old C57BL/6 mice. Mice were then randomly divided into activity groups, having access to a running wheel or not, and further into those receiving E2 or placebo. Placebo-treated mice wheel ran more than E2-treated mice (P=0.03), with no difference between treatment groups in cage activities such as time spent being active and ambulation distance (P≥0.55). Soleus muscles from aged mice that wheel ran adapted by getting larger and stronger, irrespective of E2 status (P≤0.02). Soleus muscle fatigue resistance was greater in mice treated with E2 (P=0.02), but maximal isometric tetanic force was not affected (P≥0.79). Because E2 treatment did not improve physical activity or overall muscle function in the aged, ovarian-senescent mice as predicted, a second study was initiated to examine E2 treatment of young adult mice prematurely ovarian senescent from exposure to the chemical, 4-vinylcyclohexene diepoxide (VCD). 4-month-old C57BL/6 female mice were dosed with oil (control) or VCD. Vaginal cytology confirmed ovarian senescence in all mice treated with VCD 63 days after the onset of dosing, and then a subset of the VCD mice received E2 (VCD+E2). Wheel running distance did not differ among control, VCD, and VCD+E2 mice (P≥0.34). Soleus muscle concentric, isometric, and eccentric in vitro forces were greater in VCD+E2 than VCD mice (P<0.04), indicating beneficial estrogenic effects on muscle function. In general, aged and young mice with senescent ovaries were less responsive to E2 treatment, in terms of physical activities and muscle function, than what has previously been shown for young, ovariectomized mice. These results

  4. Restoration of ovarian activity and pregnancy after transplantation of cryopreserved ovarian tissue: a review of 60 cases of reimplantation.

    PubMed

    Donnez, Jacques; Dolmans, Marie-Madeleine; Pellicer, Antonio; Diaz-Garcia, Cesar; Sanchez Serrano, Maria; Schmidt, Kristen Tryde; Ernst, Erik; Luyckx, Valérie; Andersen, Claus Yding

    2013-05-01

    Aggressive chemotherapy/radiotherapy and bone marrow transplantation can cure >90% of girls and young women affected by disorders requiring such treatment. However, the ovaries are very sensitive to cytotoxic drugs, especially to alkylating agents. Several options are currently available to preserve fertility in cancer patients. The present review reports the results of 60 orthotopic reimplantations of cryopreserved ovarian tissue performed by three teams, as well as 24 live births reported in the literature to date. Restoration of ovarian activity occurred in almost all cases in the three series. Among the 60 patients, eleven conceived and six of those had already delivered twelve healthy babies. In the future, we are looking to: 1) improve freezing techniques; and 2) enhance the "vascular bed" before reimplantation to increase pregnancy rates. On the other hand, cryopreservation of ovarian tissue may be combined with removal, via puncture, of small antral follicles, making it possible to freeze both ovarian tissue and isolated immature oocytes. PMID:23635349

  5. A Five-Gene Expression Signature Predicts Clinical Outcome of Ovarian Serous Cystadenocarcinoma

    PubMed Central

    Guo, Wenna

    2016-01-01

    Ovarian serous cystadenocarcinoma is a common malignant tumor of female genital organs. Treatment is generally less effective as patients are usually diagnosed in the late stage. Therefore, a well-designed prognostic marker provides valuable data for optimizing therapy. In this study, we analyzed 303 samples of ovarian serous cystadenocarcinoma and the corresponding RNA-seq data. We observed the correlation between gene expression and patients' survival and eventually established a risk assessment model of five factors using Cox proportional hazards regression analysis. We found that the survival time in high-risk patients was significantly shorter than in low-risk patients in both training and testing sets after Kaplan-Meier analysis. The AUROC value was 0.67 when predicting the survival time in testing set, which indicates a relatively high specificity and sensitivity. The results suggest diagnostic and therapeutic applications of our five-gene model for ovarian serous cystadenocarcinoma. PMID:27478834

  6. BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

    PubMed Central

    Stefansson, Olafur A.; Villanueva, Alberto; Vidal, August; Martí, Lola; Esteller, Manel

    2012-01-01

    Germline mutations in the BRCA1 or BRCA2 genes are associated with an increased risk of breast and ovarian cancer development. Both genes are involved in DNA repair, and tumors harboring genetic defects in them are thought to be more sensitive to DNA-damaging agents used in chemotherapy. However, as only a minority of breast and ovarian cancer patients carry BRCA1 or BRCA2 mutations, few patients are likely to benefit from these pharmacogenetic biomarkers. Herein, we show that, in cancer cell lines and xenografted tumors, BRCA1 CpG island promoter hypermethylation-associated silencing also predicts enhanced sensitivity to platinum-derived drugs to the same extent as BRCA1 mutations. Most importantly, BRCA1 hypermethylation proves to be a predictor of longer time to relapse and improved overall survival in ovarian cancer patients undergoing chemotherapy with cisplatin. PMID:23069641

  7. To predict or not to predict? The dilemma of predicting the risk of suboptimal cytoreduction in ovarian cancer.

    PubMed

    Kang, S; Park, S-Y

    2011-12-01

    Although maximal cytoreduction is the cornerstone of current treatment for patients with advanced ovarian cancer, optimal cytoreduction is not always achievable in the clinic. Therefore, using clinical characteristics, diagnostic imaging, serum biomarkers or laparoscopic findings, many studies have attempted to find models for predicting surgical resectability. However, most of these prediction models showed limited effectiveness and have not been properly validated. To establish a reliable prediction model, several requirements should be met. First, the goal of surgical cytoreduction should be adequately defined. Second, the desired accuracy for making the model clinically useful should be defined. Third, the model should test all relevant predictors, including clinical, radiological and biochemical predictors, and be developed using a large dataset that provides a sufficient number of events. Fourth, any prediction model should be validated with a relevant external dataset. Lastly, the prediction model should be able to aid decision making and, thereby, improve the outcome of patients. Therefore, randomized clinical trials with decision making based on prediction models are urgently required. PMID:22180395

  8. [Anti mullerian hormone (AMH)--is it a new reliable marker of the ovarian reserve? Its role in predicting the ovarian response in assisted reproductive technology (ART)].

    PubMed

    Alshiek, Jonia Amer; Lessing, Joseph B; Amit, Ami; Azem, Foad

    2012-07-01

    Anti-Müllerian hormone (AMH) is predominantly known for its important role in the differentiation of the male and female sexual system during the early embryonic period. Recently, many animal and human researches have been studying the role of the AMH in the postnatal ovarian function. In the female, AMH is produced by the granulosa cells of early developing follicles. It plays a major role in the folliculogenesis and seems to be able to inhibit the initiation of the growth of primordial follicles and FSH-induced follicles. As AMH is expressed throughout the folliculogenesis, from the primary follicular stage to the antral stage, the serum levels of AMH may represent both the quantity and the quality of ovarian follicles. Thus, the AMH levels may be useful as a new potential marker of the ovarian reserve. As compared to other ovarian reserve tests, the AMH has unique characteristics which make it a favorable marker. The measurement of AMH levels may be useful in the prediction of poor response and cycle cancellation as well as hyper-response and the ovarian hyperstimulation syndrome in assisted reproductive technology (ART). We assume that the measurement of AMH Levels may play a role in the individualization of treatment strategies among patients who are treated by ART. However, the AMH cannot predict the qualitative ovarian response in ART. In men, the AMH was not found to have satisfactory clinical utility as a single marker of spermatogenesis. PMID:23002694

  9. Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

    PubMed Central

    XIAO, JUAN; XU, MANMAN; HOU, TENG; HUANG, YONGWEN; YANG, CHENLU; LI, JUNDONG

    2015-01-01

    Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho-Src-Y416 (p-Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V-fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p-Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p-Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti-ovarian cancer properties, by downregulating p-Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25–0.93 and 0.31–0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti-ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian

  10. Blue light-activated hypocrellin B damages ovarian cancer cells

    NASA Astrophysics Data System (ADS)

    Jiang, Y.; Leung, A. W. N.; Xiang, J. Y.; Xu, C. S.

    2011-10-01

    In the present study, a novel blue light source from LED was used to activate hypocrellin B in ovarian cancer HO-8910 cells. Hyppcrellin B concentration was kept at 2.5 μM and light doses from 0.5-4.0 J/cm2. Photocytotoxicity was investigated using MTT reduction assay and light microscopy after light irradiation. Cellular morphology was observed using transmission electron microscopy (TEM). MTT assay showed that the cytotoxicity of blue light-activated hypocrellin B in HO-8910 cells increased along with light dose. The observations from light microscopy reinforced the above results. TEM showed that microvillin disappearance, vacuole formation, chromatin condensation, and topical apoptotic body were observed in the cells treated by both light and hypocrellin B. The findings demonstrated that blue light from LED source could effectively activate hypocrellin B to cause the destruction of HO-8910 cells, indicating that Blue light-activated hypocrellin B might be potential therapeutic strategy in the management of ovarian cancer.

  11. Usefulness of the Ultrasensitive Anti-Müllerian Hormone Assay for Predicting True Ovarian Reserve.

    PubMed

    Iwase, Akira; Osuka, Satoko; Nakamura, Tomoko; Kato, Nao; Takikawa, Sachiko; Goto, Maki; Kikkawa, Fumitaka

    2016-06-01

    Serum concentration of anti-Müllerian hormone (AMH) is a useful marker for ovarian reserve. Measurement of AMH in clinical practice has gained widespread use to predict parameters such as the ovarian response, menopause, and recovery after chemotherapy. However, undetectable AMH levels assayed by conventional enzyme-linked immunosorbent assay (ELISA) kits fail to predict depletion of follicles because of low sensitivity of the kits. We investigated whether a recently developed ultrasensitive ELISA kit, picoAMH, would be more effective at detecting very low AMH levels in association with menstrual status. We analyzed 68 women with undetectable serum AMH levels using an ELISA kit, AMH Gen II. The AMH concentration of the same samples was detected in 36 samples using picoAMH; 32 samples were within the standard range, and 4 samples were out of the standard range but still detectable. Thirty-two women whose AMH levels were undetectable using the picoAMH all showed amenorrhea. We also found a significant correlation between the classes of serum AMH levels (undetectable, detectable under the limit of quantification, and measurable within the assay range) and menstrual status. Five of the 6 amenorrheic women with detectable AMH eventually achieved follicle growth. The present study demonstrated that very low AMH levels detectable using picoAMH correspond well to current and future ovulation status. This suggests that serum AMH levels can be useful for the assessment of ovarian reserve and follow-up of women with a declined ovarian reserve. PMID:26614267

  12. Irregular menses predicts ovarian cancer: Prospective evidence from the Child Health and Development Studies.

    PubMed

    Cirillo, Piera M; Wang, Erica T; Cedars, Marcelle I; Chen, Lee-May; Cohn, Barbara A

    2016-09-01

    We tested the hypothesis that irregular menstruation predicts lower risk for ovarian cancer, possibly due to less frequent ovulation. We conducted a 50-year prospective study of 15,528 mothers in the Child Health and Development Studies cohort recruited from the Kaiser Foundation Health Plan from 1959 to 1966. Irregular menstruation was classified via medical record and self-report at age 26. We identified 116 cases and 84 deaths due to ovarian cancer through 2011 via linkage to the California Cancer Registry and Vital Statistics. Contrary to expectation, women with irregular menstrual cycles had a higher risk of ovarian cancer incidence and mortality over the 50-year follow-up. Associations increased with age (p <0.05). We observed a 2-fold increased incidence and mortality by age 70 (95% confidence interval [CI] = 1.1, 3.4) rising to a 3-fold increase by age 77 (95% CI = 1.5, 6.7 for incidence; 95% CI = 1.4, 5.9 for mortality). We also found a 3-fold higher risk of mortality for high-grade serous tumors (95% CI = 1.3, 7.6) that did not vary by age. This is the first prospective study to show an association between irregular menstruation and ovarian cancer-we unexpectedly found higher risk for women with irregular cycles. These women are easy to identify and many may have polycystic ovarian syndrome. Classifying high-risk phenotypes such as irregular menstruation creates opportunities to find novel early biomarkers, refine clinical screening protocols and potentially develop new risk reduction strategies. These efforts can lead to earlier detection and better survival for ovarian cancer. PMID:27082375

  13. Serum estradiol level during withdrawal bleeding as a predictive factor for intermittent ovarian function in women with primary ovarian insufficiency.

    PubMed

    Miyazaki, Kaoru; Miki, Fumie; Uchida, Sayaka; Masuda, Hirotaka; Uchida, Hiroshi; Maruyama, Tetsuo

    2015-01-01

    The objective of this study was to assess the potential predictive factors for follicle growth, ovulation, and pregnancy rate in patients with primary ovarian insufficiency/premature ovarian failure (POI/POF). We enrolled 25 POI patients with desired fertility who were treated and monitored for a minimum of 7 months between the years of 2000-2009 into this retrospective study. The clinical, endocrinologic, chromosomal, and autoimmunologic parameters of these patients were collected. Furthermore, hormonal backgrounds on each of 620 treatment cycles were investigated. The main outcome measures were follicle growth, ovulation, and pregnancy rate. Four of 25 patients (16%) conceived while being monitored and undergoing treatment. Follicle growth, ovulation, and pregnancy rate were not significantly different as a function of parity, iatrogenic history (e.g., chemotherapy), age of disease onset, serum estradiol (E(2))/follicle stimulating hormone (FSH) level at the time of diagnosis, chromosomal abnormality, and positive autoantibody titer. The serum E2 levels on days 1-5 of withdrawal bleeding (Day 1-5 E(2)) were significantly higher in the cycles with successful follicle growth and ovulation than unsuccessful cycles (P<0.05). Receiver-operator characteristic curve analysis revealed the cut-off value of the Day 1-5 E(2) to be 15.5 pg/mL, and an area under the curve (AUC) value of 0.674 for follicle growth and 0.752 for ovulation. The results suggest that cycles with a Day 1-5 E(2)≥15.5 pg/mL have a higher rate of follicle growth and ovulation in patients with POI. PMID:25312800

  14. Nomogram to predict the number of oocytes retrieved in controlled ovarian stimulation

    PubMed Central

    Moon, Kyoung Yong; Kim, Hoon; Lee, Joong Yeup; Lee, Jung Ryeol; Jee, Byung Chul; Suh, Chang Suk; Kim, Ki Chul; Lee, Won Don; Lim, Jin Ho

    2016-01-01

    Objective Ovarian reserve tests are commonly used to predict ovarian response in infertile patients undergoing ovarian stimulation. Although serum markers such as basal follicle-stimulating hormone (FSH) or random anti-Müllerian hormone (AMH) level and ultrasonographic markers (antral follicle count, AFC) are good predictors, no single test has proven to be the best predictor. In this study, we developed appropriate equations and novel nomograms to predict the number of oocytes that will be retrieved using patients' age, serum levels of basal FSH and AMH, and AFC. Methods We analyzed a database containing clinical and laboratory information of 141 stimulated in vitro fertilization (IVF) cycles performed at a university-based hospital between September 2009 and December 2013. We used generalized linear models for prediction of the number of oocytes. Results Age, basal serum FSH level, serum AMH level, and AFC were significantly related to the number of oocytes retrieved according to the univariate and multivariate analyses. The equations that predicted the number of oocytes retrieved (log scale) were as follows: model (1) 3.21–0.036×(age)+0.089×(AMH), model (2) 3.422–0.03×(age)–0.049×(FSH)+0.08×(AMH), model (3) 2.32–0.017×(age)+0.039×(AMH)+0. 03×(AFC), model (4) 2.584–0.015×(age)–0.035×(FSH)+0.038×(AMH)+0.026×(AFC). model 4 showed the best performance. On the basis of these variables, we developed nomograms to predict the number of oocytes that can be retrieved. Conclusion Our nomograms helped predict the number of oocytes retrieved in stimulated IVF cycles. PMID:27358830

  15. YAP/TEAD Co-Activator Regulated Pluripotency and Chemoresistance in Ovarian Cancer Initiated Cells

    PubMed Central

    Yu, Chao; Chang, Ting; Fan, Heng-Yu

    2014-01-01

    Recent evidence suggests that some solid tumors, including ovarian cancer, contain distinct populations of stem cells that are responsible for tumor initiation, growth, chemo-resistance, and recurrence. The Hippo pathway has attracted considerable attention and some investigators have focused on YAP functions for maintaining stemness and cell differentiation. In this study, we successfully isolated the ovarian cancer initiating cells (OCICs) and demonstrated YAP promoted self-renewal of ovarian cancer initiated cell (OCIC) through its downstream co-activator TEAD. YAP and TEAD families were required for maintaining the expression of specific genes that may be involved in OCICs' stemness and chemoresistance. Taken together, our data first indicate that YAP/TEAD co-activator regulated ovarian cancer initiated cell pluripotency and chemo-resistance. It proposed a new mechanism on the drug resistance in cancer stem cell that Hippo-YAP signal pathway might serve as therapeutic targets for ovarian cancer treatment in clinical. PMID:25369529

  16. Prospective study of physical activity and the risk of ovarian cancer

    PubMed Central

    Koebnick, Corinna; Moore, Steven C.; Danforth, Kim N.; Brinton, Louise A.; Hollenbeck, Albert R.; Schatzkin, Arthur; Lacey, James V.

    2012-01-01

    Background Available studies on physical activity and ovarian cancer have produced inconsistent findings, with some previous studies reporting a positive association between vigorous physical activity and ovarian cancer risk. Methods We prospectively investigated the relations of self-reported moderate and vigorous physical activity to ovarian cancer in a cohort of 96,216 US women aged 51–72 years at baseline, followed from 1996–1997 to 31 December 2003. Results During seven years of follow-up, we documented 309 cases of epithelial ovarian carcinoma. In analyses adjusted for age, the relative risks (RRs) of ovarian cancer for individual and joint combinations of moderate and vigorous physical activity such as entirely inactive, neither moderate nor vigorous physical activity, moderate physical activity only, vigorous physical activity only, and both moderate and vigorous physical activity were 0.88, 1.0 (reference), 0.89, 1.05, and 1.08 (95% confidence interval (CI) = 0.81–1.43, respectively. After multivariate adjustment, the relation was essentially unchanged (RR comparing women with both moderate and vigorous physical activity to those with neither moderate nor vigorous physical activity = 1.10; 95% CI = 0.82–1.48). The null association between physical activity and ovarian cancer persisted in subgroups of women as defined by body mass index, parity, oral contraceptive use, menopausal hormone therapy, family history of ovarian cancer, and other variables (all p values for interaction >0.05). Conclusions Neither moderate nor vigorous physical activity showed a statistically significant association with ovarian cancer in this large cohort of women. PMID:19116765

  17. Predicting intrinsic brain activity.

    PubMed

    Craddock, R Cameron; Milham, Michael P; LaConte, Stephen M

    2013-11-15

    Multivariate supervised learning methods exhibit a remarkable ability to decode externally driven sensory, behavioral, and cognitive states from functional neuroimaging data. Although they are typically applied to task-based analyses, supervised learning methods are equally applicable to intrinsic effective and functional connectivity analyses. The obtained models of connectivity incorporate the multivariate interactions between all brain regions simultaneously, which will result in a more accurate representation of the connectome than the ones available with standard bivariate methods. Additionally the models can be applied to decode or predict the time series of intrinsic brain activity of a region from an independent dataset. The obtained prediction accuracy provides a measure of the integration between a brain region and other regions in its network, as well as a method for evaluating acquisition and preprocessing pipelines for resting state fMRI data. This article describes a method for learning multivariate models of connectivity. The method is applied in the non-parametric prediction accuracy, influence, and reproducibility-resampling (NPAIRS) framework, to study the regional variation of prediction accuracy and reproducibility (Strother et al., 2002). The resulting spatial distribution of these metrics is consistent with the functional hierarchy proposed by Mesulam (1998). Additionally we illustrate the utility of the multivariate regression connectivity modeling method for optimizing experimental parameters and assessing the quality of functional neuroimaging data. PMID:23707580

  18. LED-activated pheophorbide a in ovarian cancer cells: Cytotoxicity and apoptosis induction

    NASA Astrophysics Data System (ADS)

    Liu, L.; Xu, C. S.; Xia, X. S.; Leung, A. W. N.

    2011-02-01

    Pheophorbide a (Pa) from Chinese herbal medicine Scutellaria Barbata and Silkworm excreta has been proved to be potential photosensitizer. The present study investigated the cytotoxicity of ovarian cancer cells induced by LED-activated Pa using light microscopy with the SRB staining. We further investigated the apoptosis of the cells 6 h after LED-activated Pa using of the flow cytometer with PI staining and nuclear staining. The results showed that LED-activated Pa remarkably caused cell death of ovarian cancer cells. The condensation of chromatin, nuclear fragmentations, and 12.3% of cells containing subdiploid levels of DNA were found in the ovarian cancer cells after the treatment of LED-activated Pa. These data demonstrated that LED-activated Pa could cause significant cytotoxicity and apoptosis of ovarian cancer cells.

  19. Quality of life and sexuality comparison between sexually active ovarian cancer survivors and healthy women

    PubMed Central

    Kim, Se Ik; Lee, Yumi; Joo, Jungnam; Park, KiByung; Lee, Dong Ock; Park, Sang-Yoon

    2015-01-01

    Objective compare quality of life (QoL) and sexual functioning between sexually active ovarian cancer survivors and healthy women. Methods A cross-sectional study was performed in 103 successfully treated ovarian cancer survivors and 220 healthy women. All women had engaged in sexual activity within the previous 3 months, and ovarian cancer survivors were under surveillance after primary treatment without evidence of disease. QoL and sexual functioning were assessed using three questionnaires; the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), Ovarian Cancer Module (EORTC QLQ-OV28), and the Female Sexual Function Index (FSFI). Propensity score matching was used to adjust covariates between the ovarian cancer survivor and healthy women groups. In total, 73 ovarian cancer survivors and 73 healthy women were compared. Results Poorer social functioning (mean, 82.4 vs. 90.9; p=0.010) and more financial difficulties (mean, 16.4 vs. 7.8; p=0.019) were observed among ovarian cancer survivors than among healthy women. Sexuality, both in terms of desire, arousal, lubrication, orgasm, satisfaction, and pain and in terms of interest in sex, sexual activity, and enjoyment of sex (EORTC QLQ-OV28) were similar between the groups. However, vaginal dryness was more problematic in ovarian cancer survivors, with borderline statistical significance (p=0.081). Conclusion Sexuality was not impaired in ovarian cancer survivors who were without evidence of disease after primary treatment and having sexual activities, compared with healthy women, whereas social functioning and financial status did deteriorate. Prospective cohort studies are needed. PMID:25686396

  20. Modulatory role of the ovarian function in neuroimmunoendocrine axis activity.

    PubMed

    Perelló, Mario; Giovambattista, Andrés; Castrogiovanni, Daniel; Gaillard, Rolf C; Spinedi, Eduardo

    2011-01-01

    The aim of this study was to evaluate the effect of ovariectomy on the acute-phase response of inflammatory stress. Ex vivo adrenocortical, peripheral mononuclear cell (PMNC) and adipocyte activities were studied in intact and ovariectomized mice. Endotoxemia was mimicked by intraperitoneal administration of bacterial lipopolysaccharide (LPS; 25 mg per mouse) to sham-operated and 21-day ovariectomized mice. Circulating corticosterone, tumor necrosis factor-α (TNFα) and leptin concentrations were monitored before and 30-120 min after the administration of LPS. Additionally, in vitro experiments were performed with isolated corticoadrenal cells, PMNCs and omental adipocytes from sham-operated and ovariectomized mice incubated with specific secretagogues. The results indicate that while ovariectomy enhanced TNFα secretion after in vivo administration of LPS, it reduced corticoadrenal response and abrogated LPS-elicited leptin secretion into the circulation. While the corticoadrenal sensitivity to ACTH stimulation was reduced by ovariectomy, the LPS-induced PMNC response was not affected. Exogenous leptin enhanced baseline PMNC function regardless of surgery. Finally, ovariectomy drastically reduced in vitro adipocyte functionality. Our data support the notion that ovariectomy modified neuroendocrine-immune-adipocyte axis function and strongly suggest that ovarian activity could play a pivotal role in the development of an adequate immune defense mechanism after injury. PMID:20606490

  1. Loss of Secreted Frizzled-Related Protein 4 Correlates with an Aggressive Phenotype and Predicts Poor Outcome in Ovarian Cancer Patients

    PubMed Central

    Nixdorf, Sheri; Ford, Caroline E.; Olivier, Jake; Caduff, Rosmarie; Scurry, James P.; Guertler, Rea; Hornung, Daniela; Mueller, Renato; Fink, Daniel A.; Hacker, Neville F.; Heinzelmann-Schwarz, Viola A.

    2012-01-01

    Background Activation of the Wnt signaling pathway is implicated in aberrant cellular proliferation in various cancers. In 40% of endometrioid ovarian cancers, constitutive activation of the pathway is due to oncogenic mutations in β-catenin or other inactivating mutations in key negative regulators. Secreted frizzled-related protein 4 (SFRP4) has been proposed to have inhibitory activity through binding and sequestering Wnt ligands. Methodology/Principal Findings We performed RT-qPCR and Western-blotting in primary cultures and ovarian cell lines for SFRP4 and its key downstream regulators activated β-catenin, β-catenin and GSK3β. SFRP4 was then examined by immunohistochemistry in a cohort of 721 patients and due to its proposed secretory function, in plasma, presenting the first ELISA for SFRP4. SFRP4 was most highly expressed in tubal epithelium and decreased with malignant transformation, both on RNA and on protein level, where it was even more profound in the membrane fraction (p<0.0001). SFRP4 was expressed on the protein level in all histotypes of ovarian cancer but was decreased from borderline tumors to cancers and with loss of cellular differentiation. Loss of membrane expression was an independent predictor of poor survival in ovarian cancer patients (p = 0.02 unadjusted; p = 0.089 adjusted), which increased the risk of a patient to die from this disease by the factor 1.8. Conclusions/Significance Our results support a role for SFRP4 as a tumor suppressor gene in ovarian cancers via inhibition of the Wnt signaling pathway. This has not only predictive implications but could also facilitate a therapeutic role using epigenetic targets. PMID:22363760

  2. LY2109761 enhances cisplatin antitumor activity in ovarian cancer cells

    PubMed Central

    Gao, Yuxiu; Shan, Ning; Zhao, Cheng; Wang, Yunhai; Xu, Fuliang; Li, Jiacun; Yu, Xiaoqian; Gao, Lifeng; Yi, Zhengjun

    2015-01-01

    Background and Objective: Ovarian cancer is among the most lethal of all malignancies in women. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. Because transforming growth factor-beta (TGF-β) could increase survival of ovarian cancer cells in the presence of cisplatin, we conducted a preclinical study of the antitumor effects of the TGF-β type I (TβRI) and type II (TβRII) kinase inhibitor LY2109761 in combination with cisplatin. Methods: SKOV3, OV-90 and SKOV3DDP cells were treated with LY2109761, and/or cisplatin, and cell viability, apoptosis mRNA and protein expression levels were then evaluated. Furthermore, the efficacy of LY2109761 combined with cisplatin was further examined in established xenograft models. Results: LY2109761 was sufficient to induce spontaneous apoptosis of ovarian cancer cells. Combination with LY2109761 significantly augmented the cytotoxicity of cisplatin in both parental and cisplatin resistant ovarian cancer cells. LY2109761 significantly increased apoptotic cell death in cisplatin-resistant cells. Combination treatment of LY2109761 and cisplatin showed antiproliferative effects and induced a greater rate of apoptosis than the sum of the single-treatment rates and promoted tumor regression in established parental and cisplatin resistant ovarian cancer xenograft models. Conclusions: Chemotherapeutic approaches using LY2109761 might enhance the treatment benefit of the cisplatin in the treatment of ovarian cancer patients. PMID:26191185

  3. Overexpression of centromere protein K (CENPK) in ovarian cancer is correlated with poor patient survival and associated with predictive and prognostic relevance.

    PubMed

    Lee, Yi-Chao; Huang, Chi-Chen; Lin, Ding-Yen; Chang, Wen-Chang; Lee, Kuen-Haur

    2015-01-01

    Ovarian cancer has a poor prognosis. Most patients are diagnosed with ovarian cancer when the disease has reached an advanced stage and cure rates are generally under 30%. Hence, early diagnosis of ovarian cancer is the best means to control the disease in the long term and abate mortality. So far, cancer antigen 125 (CA125) and human epididymis protein 4 (HE4) are the gold-standard tumor markers for ovarian cancer; however, these two markers can be elevated in a number of conditions unrelated to ovarian cancer, resulting in decreased specifically and positive predictive value. Therefore, it is urgent to identify novel biomarkers with high reliability and sensitivity for ovarian cancer. In this study for the first time, we identified a member of the centromere protein (CENP) family, CENPK, which was specifically upregulated in ovarian cancer tissues and cell lines and the overexpression of which was associated with poor prognoses in patients with ovarian cancer. In addition, the presence of CENPK significantly improved the sensitivity of CA125 or HE4 for predicting clinical outcomes of ovarian cancer patients. In conclusion, we identified that CENPK was specifically upregulated in ovarian cancer cells and can be used as a novel tumor marker of ovarian cancer. PMID:26587348

  4. Evidence of Differential Effects of Vitamin D Receptor Variants on Epithelial Ovarian Cancer Risk by Predicted Vitamin D Status

    PubMed Central

    Prescott, Jennifer; Bertrand, Kimberly A.; Reid, Brett M.; Permuth-Wey, Jennifer; De Vivo, Immaculata; Cramer, Daniel W.; Terry, Kathryn L.; Tworoger, Shelley S.

    2014-01-01

    Introduction: Experimental studies suggest vitamin D inhibits ovarian carcinogenesis. Yet, epidemiologic studies of ovarian cancer risk and lifestyle correlates of vitamin D status, plasma 25-hydroxyvitamin D [25(OH)D], or vitamin D receptor (VDR) variants have been inconsistent. Objective: To evaluate VDR genetic associations by high vs. low predicted 25(OH)D, scores derived from known determinants of plasma 25(OH)D. To assess ovarian cancer associations with variants identified in genome-wide association studies (GWAS) of plasma 25(OH)D. Methods: We genotyped up to seven VDR and eight 25(OH)D GWAS variants in the Nurses’ Health Studies (562 cases, 1,553 controls) and New England Case–Control study (1,821 cases, 1,870 controls). We estimated haplotype scores using expectation-maximization-based algorithms. We used unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CI). We combined study results using DerSimonian and Laird meta-analysis. Results: Ovarian cancer risk increased per A allele of rs7975232 (VDR; OR = 1.12, 95% CI = 1.01–1.25) among all women. When stratified by predicted 25(OH)D, ovarian cancer was associated with rs731236 (VDR; per C allele OR = 1.31) and rs7975232 (OR = 1.38) among women with high predicted 25(OH)D, but not among women with low levels (P ≤ 0.009). We also observed heterogeneity by predicted 25(OH)D for the ovarian cancer association with VDR 3′ end haplotypes (P = 0.009). Of 25(OH)D-associated GWAS loci, rs7041 was associated with reduced ovarian cancer risk (per T allele OR = 0.92, 95% CI = 0.85-0.99), which did not differ by predicted 25(OH)D status. Conclusion: Our study suggests an influence of VDR 3′ end variants on ovarian cancer risk may be observed in women with high predicted 25(OH)D, which remained even after taking multiple comparisons into consideration. Future studies are needed to confirm our results and explore further the relation

  5. MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas

    PubMed Central

    Gruosso, Tina; Garnier, Camille; Abelanet, Sophie; Kieffer, Yann; Lemesre, Vincent; Bellanger, Dorine; Bieche, Ivan; Marangoni, Elisabetta; Sastre-Garau, Xavier; Mieulet, Virginie; Mechta-Grigoriou, Fatima

    2015-01-01

    Ovarian cancer is a silent disease with a poor prognosis that urgently requires new therapeutic strategies. In low-grade ovarian tumours, mutations in the MAP3K BRAF gene constitutively activate the downstream kinase MEK. Here we demonstrate that an additional MAP3K, MAP3K8 (TPL-2/COT), accumulates in high-grade serous ovarian carcinomas (HGSCs) and is a potential prognostic marker for these tumours. By combining analyses on HGSC patient cohorts, ovarian cancer cells and patient-derived xenografts, we demonstrate that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. In addition, we show that the MEK pathway is the main pathway involved in mediating MAP3K8 function, and that MAP3K8 exhibits a reliable predictive value for the effectiveness of MEK inhibitor treatment. Our data highlight key roles for MAP3K8 in HGSC and indicate that MEK inhibitors could be a useful treatment strategy, in combination with conventional chemotherapy, for this disease. PMID:26456302

  6. Identification of therapeutic targets in ovarian cancer through active tyrosine kinase profiling

    PubMed Central

    Ocaña, Alberto; Pandiella, Atanasio

    2015-01-01

    The activation status of a set of pro-oncogenic tyrosine kinases in ovarian cancer patient samples was analyzed to define potential therapeutic targets. Frequent activation of HER family receptor tyrosine kinases, especially HER2, was observed. Studies in ovarian cancer cell lines confirmed the activation of HER2. Moreover, knockdown of HER2 caused a strong inhibition of their proliferation. Analyses of the action of agents that target HER2 indicated that the antibody drug conjugate trastuzumab-emtansine (T-DM1) caused a substantial antitumoral effect in vivo and in vitro, and potentiated the action of drugs used in the therapy of ovarian cancer. T-DM1 provoked cell cycle arrest in mitosis, and caused the appearance of aberrant mitotic spindles in cells treated with the drug. Biochemical experiments confirmed accumulation of the mitotic markers phospho-Histone H3 and phospho-BUBR1 in cells treated with the drug. Prolonged treatment of ovarian cancer cells with T-DM1 provoked the appearance of multinucleated cells which later led to cell death. Together, these data indicate that HER2 represents an important oncogene in ovarian cancer, and suggest that targeting this tyrosine kinase with T-DM1 may be therapeutically effective, especially in ovarian tumors with high content of HER2. PMID:26336133

  7. IL17a and IL21 combined with surgical status predict the outcome of ovarian cancer patients.

    PubMed

    Chen, Yu-Li; Chou, Cheng-Yang; Chang, Ming-Cheng; Lin, Han-Wei; Huang, Ching-Ting; Hsieh, Shu-Feng; Chen, Chi-An; Cheng, Wen-Fang

    2015-10-01

    Aside from tumor cells, ovarian cancer-related ascites contains the immune components. The aim of this study was to evaluate whether a combination of clinical and immunological parameters can predict survival in patients with ovarian cancer. Ascites specimens and medical records from 144 ovarian cancer patients at our hospital were used as the derivation group to select target clinical and immunological factors to generate a risk-scoring system to predict patient survival. Eighty-two cases from another hospital were used as the validation group to evaluate this system. The surgical status and expression levels of interleukin 17a (IL17a) and IL21 in ascites were selected for the risk-scoring system in the derivation group. The areas under the receiver operating characteristic (AUROC) curves of the overall score for disease-free survival (DFS) of the ovarian cancer patients were 0.84 in the derivation group, 0.85 in the validation group, and 0.84 for all the patients. The AUROC curves of the overall score for overall survival (OS) of cases were 0.78 in the derivation group, 0.76 in the validation group, and 0.76 for all the studied patients. Good correlations between overall risk score and survival of the ovarian cancer patients were demonstrated by sub-grouping all participants into four groups (P for trend <0.001 for DFS and OS). Therefore, acombination of clinical and immunological parameters can provide a practical scoring system to predict the survival of patients with ovarian carcinoma. IL17a and IL21 can potentially be used as prognostic and therapeutic biomarkers. PMID:26150382

  8. Everolimus exhibits anti-tumorigenic activity in obesity-induced ovarian cancer

    PubMed Central

    Guo, Hui; Zhong, Yan; Jackson, Amanda L.; Clark, Leslie H.; Kilgore, Josh; Zhang, Lu; Han, Jianjun; Sheng, Xiugui; Gilliam, Timothy P.; Gehrig, Paola A.; Zhou, Chunxiao; Bae, Victoria L.

    2016-01-01

    Everolimus inhibits mTOR kinase activity and its downstream targets by acting on mTORC1 and has anti-tumorigenic activity in ovarian cancer. Clinical and epidemiologic data find that obesity is associated with worse outcomes in ovarian cancer. In addition, obesity leads to hyperactivation of the mTOR pathway in epithelial tissues, suggesting that mTOR inhibitors may be a logical choice for treatment in obesity-driven cancers. However, it remains unclear if obesity impacts the effect of everolimus on tumor growth in ovarian cancer. The present study was aimed at evaluating the effects of everolimus on cytotoxicity, cell metabolism, apoptosis, cell cycle, cell stress and invasion in human ovarian cancer cells. A genetically engineered mouse model of serous ovarian cancer fed a high fat diet or low fat diet allowed further investigation into the inter-relationship between everolimus and obesity in vivo. Everolimus significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, reduced invasion and caused cellular stress via inhibition of mTOR pathways in vitro. Hypoglycemic conditions enhanced the sensitivity of cells to everolimus through the disruption of glycolysis. Moreover, everolimus was found to inhibit ovarian tumor growth in both obese and lean mice. This reduction coincided with a decrease in expression of Ki-67 and phosphorylated-S6, as well as an increase in cleaved caspase 3 and phosphorylated-AKT. Metabolite profiling revealed that everolimus was able to alter tumor metabolism through different metabolic pathways in the obese and lean mice. Our findings support that everolimus may be a promising therapeutic agent for obesity-driven ovarian cancers. PMID:26959121

  9. Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis

    PubMed Central

    Emmanuel, Catherine; Gava, Natalie; Kennedy, Catherine; Balleine, Rosemary L.; Sharma, Raghwa; Wain, Gerard; Brand, Alison; Hogg, Russell; Etemadmoghadam, Dariush; George, Joshy; Birrer, Michael J.; Clarke, Christine L.; Chenevix-Trench, Georgia; Bowtell, David D. L.; Harnett, Paul R.; deFazio, Anna

    2011-01-01

    Molecular events leading to epithelial ovarian cancer are poorly understood but ovulatory hormones and a high number of life-time ovulations with concomitant proliferation, apoptosis, and inflammation, increases risk. We identified genes that are regulated during the estrous cycle in murine ovarian surface epithelium and analysed these profiles to identify genes dysregulated in human ovarian cancer, using publically available datasets. We identified 338 genes that are regulated in murine ovarian surface epithelium during the estrous cycle and dysregulated in ovarian cancer. Six of seven candidates selected for immunohistochemical validation were expressed in serous ovarian cancer, inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium. Most were overexpressed in ovarian cancer compared with ovarian surface epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2 were expressed as highly in fallopian tube epithelium as in ovarian cancer. We prioritised the 338 genes for those likely to be important for ovarian cancer development by in silico analyses of copy number aberration and mutation using publically available datasets and identified genes with established roles in ovarian cancer as well as novel genes for which we have evidence for involvement in ovarian cancer. Chromosome segregation emerged as an important process in which genes from our list of 338 were over-represented including two (BUB1, NCAPD2) for which there is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface epithelium in proestrus and predicted to have a driver mutation in ovarian cancer, was examined in a larger cohort of serous ovarian cancer where patients with lower NUAK2 expression had shorter overall survival. In conclusion, defining genes that are activated in normal epithelium in the course of ovulation that are also dysregulated in cancer has identified a number of pathways and novel candidate genes that may contribute

  10. The predicted relative risk of premature ovarian failure for three radiotherapy modalities in a girl receiving craniospinal irradiation

    NASA Astrophysics Data System (ADS)

    Pérez-Andújar, A.; Newhauser, W. D.; Taddei, P. J.; Mahajan, A.; Howell, R. M.

    2013-05-01

    In girls and young women, irradiation of the ovaries can reduce the number of viable ovarian primordial follicles, which may lead to premature ovarian failure (POF) and subsequently to sterility. One strategy to minimize this late effect is to reduce the radiation dose to the ovaries. A primary means of reducing dose is to choose a radiotherapy technique that avoids irradiating nearby normal tissue; however, the relative risk of POF (RRPOF) due to the various therapeutic options has not been assessed. This study compared the predicted RRPOF after craniospinal proton radiotherapy, conventional photon radiotherapy (CRT) and intensity-modulated photon radiotherapy (IMRT). We calculated the equivalent dose delivered to the ovaries of an 11-year-old girl from therapeutic and stray radiation. We then predicted the percentage of ovarian primordial follicles killed by radiation and used this as a measure of the RRPOF; we also calculated the ratio of the relative risk of POF (RRRPOF) among the three radiotherapies. Proton radiotherapy had a lower RRPOF than either of the other two types. We also tested the sensitivity of the RRRPOF between photon and proton therapies to the anatomic position of the ovaries, i.e., proximity to the treatment field (2 ≤ RRRPOF ≤ 10). We found that CRT and IMRT have higher risks of POF than passive-scattering proton radiotherapy (PRT) does, regardless of uncertainties in the ovarian location. Overall, PRT represents a lower RRPOF over the two other modalities.

  11. Multidrug Resistance-Linked Gene Signature Predicts Overall Survival of Patients With Primary Ovarian Serous Carcinoma

    PubMed Central

    Gillet, Jean-Pierre; Calcagno, Anna Maria; Varma, Sudhir; Davidson, Ben; Bunkholt Elstrand, Mari; Ganapathi, Ram; Kamat, Aparna A.; Sood, Anil K.; Ambudkar, Suresh V.; Seiden, Michael V.; Rueda, Bo R.; Gottesman, Michael M.

    2012-01-01

    Purpose This study assesses the ability of multidrug resistance (MDR)-associated gene expression patterns to predict survival in patients with newly diagnosed carcinoma of the ovary. The scope of this research differs substantially from that of previous reports, as a very large set of genes was evaluated whose expression has been shown to affect response to chemotherapy. Experimental Design We applied a customized TaqMan Low Density Array, a highly sensitive and specific assay, to study the expression profiles of 380 MDR-linked genes in 80 tumor specimens collected at initial surgery to debulk primary serous carcinoma. The RNA expression profiles of these drug resistance genes were correlated with clinical outcomes. Results Leave-one-out cross-validation was used to estimate the ability of MDR gene expression to predict survival. Although gene expression alone does not predict overall survival (P=0.06), four covariates (age, stage, CA125 level and surgical debulking) do (P=0.03). When gene expression was added to the covariates, we found an 11-gene signature that provides a major improvement in overall survival prediction (log-rank statistic P<0.003). The predictive power of this 11-gene signature was confirmed by dividing high and low risk patient groups, as defined by their clinical covariates, into four specific risk groups based on expression levels. Conclusion This study reveals an 11-gene signature that allows a more precise prognosis for patients with serous cancer of the ovary treated with carboplatin- and paclitaxel-based therapy. These 11 new targets offer opportunities for new therapies to improve clinical outcome in ovarian cancer. PMID:22492981

  12. Relationship between metabolism and ovarian activity in dairy cows with different dry period lengths.

    PubMed

    Chen, J; Soede, N M; van Dorland, H A; Remmelink, G J; Bruckmaier, R M; Kemp, B; van Knegsel, A T M

    2015-11-01

    The objectives of the present study were to evaluate the effects of dry period length on ovarian activity in cows fed a lipogenic or a glucogenic diet within 100 days in milk (DIM) and to determine relationships between ovarian activity and energy balance and metabolic status in early lactation. Holstein-Friesian dairy cows (n = 167) were randomly assigned to one of three dry period lengths (0, 30, or 60 days) and one of two diets in early lactation (glucogenic or lipogenic diet) resulting in a 3 × 2 factorial design. Cows were monitored for body condition score, milk yield, dry matter intake, and energy balance from calving to week 8 postpartum, and blood was sampled weekly from 95 cows from calving to week 8 postpartum. Milk samples were collected three times a week until 100 DIM postpartum for determination of progesterone concentration. At least two succeeding milk samples with progesterone concentration of 2 ng/mL or greater were used to indicate the occurrence of luteal activity. Normal resumption of ovarian cyclicity was defined as the onset of luteal activity (OLA) occurring at 45 DIM or less, followed by regular ovarian cycles of 18 to 24 days in length. Within 100 DIM postpartum, cows with a 0-day dry period had greater incidence of normal resumption of ovarian cyclicity (53.2%; 25 out of 47 cows) compared with cows with a 60-day dry period (26.0%; 13 out of 50 cows, P = 0.02). Independent of dry period length or diet, cows with OLA at less than 21 DIM had a greater body condition score during weeks 1 and 2 (P = 0.01) and weeks 1 through 8 (P = 0.01) postpartum compared with cows with OLA at greater than 30 DIM. Cows with the first ovarian cycle of medium length (18-24 days) had greater energy balance (P = 0.03), plasma concentrations of insulin (P = 0.03), glucose (P = 0.04), and insulin-like growth factor I (P = 0.04) than cows with long ovarian cycle lengths (>24 days) but had lower plasma β-hydroxybutyrate (P < 0.01) and

  13. Troglitazone regulates peroxisome proliferator-activated receptors and inducible nitric oxide synthase in murine ovarian macrophages.

    PubMed

    Minge, Cadence E; Ryan, Natalie K; Van Der Hoek, Kylie H; Robker, Rebecca L; Norman, Robert J

    2006-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARG) and PPAR-alpha (PPARA) control metabolic processes in many cell types and act as anti-inflammatory regulators in macrophages. PPAR-activating ligands include thiazolidinediones (TZDs), such as troglitazone, once frequently used to treat insulin resistance as well as symptoms of polycystic ovary syndrome (PCOS). Since macrophages within the ovary mediate optimal follicle development, TZD actions to improve PCOS symptoms are likely to be partly mediated through these specifically localized immune cells. In mouse ovary, PPARG protein was expressed in granulosa cells and in isolated cells localized to theca, stroma, and corpora lutea, consistent with EMR1+ macrophages. Isolation of immune cells (EMR1+ or H2+) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages. Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in EMR1+ ovarian macrophages, but no hormonal responsiveness was observed in H2+ cells. Downstream anti-inflammatory effects of PPARG activation were analyzed by in vitro treatment of isolated macrophages with troglitazone. Interleukin-1 beta (Il1b) expression was not altered, and tumor necrosis factor-alpha (Tnf) expression was affected in peritoneal macrophages only. In ovarian macrophages, inducible nitric oxide synthase (Nos2), an important proinflammatory enzyme that regulates ovulation, was significantly reduced by troglitazone treatment, an effect that was restricted to cells from the preovulatory ovary. Thus, expression of PPARs within ovarian macrophages is hormonally regulated, reflecting the changing roles of these cells during the ovulatory cycle. Additionally, ovarian macrophages respond directly to troglitazone to downregulate expression of proinflammatory Nos2, providing mechanistic information about ovarian effects of TZD treatment. PMID:16192401

  14. Preoperative Evaluation of Risk of Ovarian Malignancy Algorithm Index in Prediction of Malignancy of Adnexal Masses

    PubMed Central

    Farzaneh, Farah; Honarvar, Zahra; Yaraghi, Mansoore; Yaseri, Mehdi; Arab, Maliheh; Hosseini, Maryamsadat; Ashrafgangoi, Tahereh

    2014-01-01

    Background: Differentiation between benign and malignant ovarian neoplasms is essential to create a system for patient referrals. Objectives: The aim of the present prospective trial was to analyze the value of the risk of ovarian malignancy algorithm (ROMA) in prediction of adnexal masses malignancy in pre- and post-menopause women before operation. Materials and Methods: Preoperative serum samples were tested for CA125 and HE4 using fully automated methods (Abbott architect) and gained best cutoff. The ROMA index was analyzed in 99 patients (including 68 pre-menopause and 31 menopause) with adnexal masses referred to Imam Hossein Hospital/Tehran/Iran and had been scheduled for operation. The pathological results showed 43 cases (22 menopause) with malignant adnexal masses and 56 cases (9 menopauses) with benign adnexal masses. Demographical data, clinical symptoms and the ROMA index were separately analyzed and contrasted in benign and malignant in both menopause and pre-menopause patients. Results: The only significant difference was the older age of the malignant group vs. benign group (P = 0.001) regarding demographic findings. As concerns the clinical symptoms, presence of abdominal discomfort in pre-diagnosis period was the only significant parameter in malignant group (P = 0.001). Additionally, data analysis of patients as a total group showed that specificity (96.4%), positive predictive value (PPV) (94.1%), area under the curve (AUC) (0.907), and diagnostic accuracy (DA) (86.9%) of the ROMA were higher than HE4 (91.1%, 85.7%, 0.857 and 81.8%. respectively) and CA125 (87.9%, 67.3%, 0.828 and 75.8%, respectively) alone. Besides, negative predictive value (NPV) (86.4%) and sensitivity (86.1%) of CA125 were higher than HE4 (79.7% and 69.8%, respectively). In contrast, specificity of HE4 (91.1%) was higher than CA125 (67.9%). Data analysis of patients as two groups (pre and post menopause groups) showed the same results. Conclusions: Specificity, DA and AUC of

  15. Ovarian volume and antral follicle count for the prediction of low and hyper responders with in vitro fertilization

    PubMed Central

    Kwee, Janet; Elting, Mariet E; Schats, Roel; McDonnell, Joseph; Lambalk, Cornelis B

    2007-01-01

    Background The current study was designed to compare antral follicle count (AFC) and basal ovarian volume (BOV), the exogenous FSH ovarian reserve test (EFORT) and the clomiphene citrate challenge test (CCCT), with respect to their ability to predict poor and hyper responders. Methods One hundred and ten regularly menstruating patients, aged 18–39 years, participated in this prospective study, randomized, by a computer designed 4-blocks system study into two groups. Fifty six patients underwent a CCCT, and 54 patients underwent an EFORT. All patients underwent a transvaginal sonography to measure the basal ovarian volume and count of basal antral follicle. In all patients, the test was followed by a standard IVF treatment. The result of ovarian hyperstimulation during IVF treatment, expressed by the total number of follicles, was used as gold standard. Results The best prediction of ovarian reserve (Y) was seen in a multiple regression prediction model that included, AFC, Inhibin B-increment in the EFORT and BOV simultaneously (Y = -3.161 + 0.805 × AFC (0.258-1.352) + 0.034 × Inh. B-incr. (0.007-0.601) + 0.511 BOV (0.480-0.974) (r = 0.848, p < 0.001). Univariate logistic regression showed that the best predictors for poor response were the CCCT (ROC-AUC = 0.87), the bFSH (ROC-AUC = 0.83) and the AFC (ROC-AUC = 0.83). Multiple logistic regression analysis did not produce a better model in terms of improving the prediction of poor response. For hyper response, univariate logistic regression showed that the best predictors were AFC (ROC-AUC = 0.92) and the inhibin B-increment in the EFORT (ROC-AUC = 0.92), but AFC had better test characteristics, namely a sensitivity of 82% and a specificity 89%. Multiple logistic regression analysis did not produce a better model in terms of predicting hyper response. Conclusion In conclusion AFC performs well as a test for ovarian response being superior or at least similar to complex expensive and time consuming endocrine tests

  16. The NER-related gene GTF2H5 predicts survival in high-grade serous ovarian cancer patients

    PubMed Central

    Kamieniak, Marta M.; Muñoz-Repeto, Ivan; Borrego, Salud; Hernando, Susana; Hernández-Agudo, Elena; Heredia Soto, Victoria; Márquez-Rodas, Ivan; Echarri, María José; Lacambra-Calvet, Carmen; Sáez, Raquel; Redondo, Andrés; Benítez, Javier

    2016-01-01

    Objective We aimed to evaluate the prognostic and predictive value of the nucleotide excision repair-related gene GTF2H5, which is localized at the 6q24.2-26 deletion previously reported by our group to predict longer survival of high-grade serous ovarian cancer patients. Methods In order to test if protein levels of GTF2H5 are associated with patients' outcome, we performed GTF2H5 immunohistochemical staining in 139 high-grade serous ovarian carcinomas included in tissue microarrays. Upon stratification of cases into high- and low-GTF2H5 staining categories (> and ≤ median staining, respectively) Kaplan-Meier and log-rank test were used to estimate patients’ survival and assess statistical differences. We also evaluated the association of GTF2H5 with survival at the transcriptional level by using the on-line Kaplan-Meier plotter tool, which includes gene expression and survival data of 855 high-grade serous ovarian cancer patients from 13 different datasets. Finally, we determined whether stable short hairpin RNA-mediated GTF2H5 downregulation modulates cisplatin sensitivity in the SKOV3 and COV504 cell lines by using cytotoxicity assays. Results Low expression of GTF2H5 was associated with longer 5-year survival of patients at the protein (hazard ratio [HR], 0.52; 95% CI, 0.29 to 0.93; p=0.024) and transcriptional level (HR, 0.80; 95% CI, 0.65 to 0.97; p=0.023) in high-grade serous ovarian cancer patients. We confirmed the association with 5-year overall survival (HR, 0.55; 95% CI, 0.38 to 0.78; p=0.0007) and also found an association with progression-free survival (HR, 0.72; 95% CI, 0.54 to 0.96; p=0.026) in a homogenous group of 388 high-stage (stages III-IV using the International Federation of Gynecology and Obstetrics staging system), optimally debulked high-grade serous ovarian cancer patients. GTF2H5-silencing induced a decrease of the half maximal inhibitory concentration upon cisplatin treatment in GTF2H5-silenced ovarian cancer cells. Conclusion Low

  17. Curcumin induces apoptosis by inhibiting sarco/endoplasmic reticulum Ca2+ ATPase activity in ovarian cancer cells.

    PubMed

    Seo, Jeong-Ah; Kim, Boyun; Dhanasekaran, Danny N; Tsang, Benjamin K; Song, Yong Sang

    2016-02-01

    Aberrant increase in the expression levels of sarco/endoplasmic reticulum calcium ATPase (SERCA), which regulates Ca(2+) homeostasis, has been observed in ovarian cancers. In this study, we demonstrated that curcumin increases cytosolic Ca(2+) concentration through inhibition of SERCA activity, causing apoptosis in ovarian cancer cells but not in normal cells, including peripheral blood mononuclear cells (PBMCs) and ovarian surface epithelial cells (OSE). Curcumin induced apoptosis in ovarian cancer cells in a concentration- and time-dependent manner. Cytosolic Ca(2+) flux was evident after the curcumin treatment (15 µM). Treatment with Ca(2+) chelator reduced curcumin-induced apoptosis, confirming the possible involvement of increased cytosolic Ca(2+) concentration in this response. Basal mRNA and protein levels of SERCA2 were significantly higher in ovarian cancer cells than in OSE. SERCA activity was suppressed by curcumin, with no effect on protein expression. Forced expression of the SERCA2b gene in ovarian cancer cells prevented curcumin-induced cytosolic Ca(2+) elevation and subsequent apoptosis, supporting an important role of SERCA in curcumin-induced apoptosis of ovarian cancer cells. Taken together, inhibition of SERCA activity by curcumin disrupts the Ca(2+) homeostasis and thereby promotes apoptosis in ovarian cancer cells. PMID:26607901

  18. Effects of p21-activated kinase 1 inhibition on 11q13-amplified ovarian cancer cells.

    PubMed

    Prudnikova, T Y; Villamar-Cruz, O; Rawat, S J; Cai, K Q; Chernoff, J

    2016-04-28

    p21-activated kinases (Paks) are Cdc42/Rac-activated serine-threonine protein kinases that regulate several key cancer-relevant signaling pathways, such as the Mek/Erk, PI3K/Akt and Wnt/b-catenin signaling pathways. Pak1 is frequently overexpressed and/or hyperactivated in different human cancers, including human breast, ovary, prostate and brain cancer, due to amplification of the PAK1 gene in an 11q13 amplicon. Genetic or pharmacological inactivation of Pak1 has been shown to reduce proliferation of different cancer cells in vitro and reduce tumor progression in vivo. In this work, we examined the roles of Pak1 in cellular and animal models of PAK1-amplified ovarian cancer. We found that inhibition of Pak1 leads to decreased proliferation and migration in PAK1-amplified/overexpressed ovarian cancer cells, and has no effect in cell that lack such amplification/overexpression. Further, we observed that loss of Pak1 function causes 11q13-amplified ovarian cancer cells to arrest in the G2/M phase of the cell cycle. This arrest correlates with activation of p53 and p21(Cip) and decreased expression of cyclin B1. These findings suggest that small-molecule inhibitors of Pak1 may have a therapeutic role in the ~25% of ovarian cancers characterized by PAK1 gene amplification. PMID:26257058

  19. Targeting constitutively-activated STAT3 in hypoxic ovarian cancer, using a novel STAT3 inhibitor

    PubMed Central

    McCann, Georgia A.; Naidu, Shan; Rath, Kellie S.; Bid, Hemant K.; Tierney, Brent J.; Suarez, Adrian; Varadharaj, Saradhadevi; Zhang, Jianying; Hideg, Kálmán; Houghton, Peter; Kuppusamy, Periannan; Cohn, David E.; Selvendiran, Karuppaiyah

    2014-01-01

    Tumor hypoxia, a feature of many solid tumors including ovarian cancer, is associated with resistance to therapies. We previously demonstrated that hypoxic exposure results in increased expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT3). We hypothesized the activation of STAT3 could lead to chemotherapeutic resistance in ovarian cancer cells in hypoxic conditions. In this study, we demonstrate the level of pSTAT3 Tyr705 is increased in the hypoxic regions of human epithelial ovarian cancer (EOC) specimens, as determined by HIF-1α and CD-31 staining. In vitro mutagenesis studies proved that pSTAT3 Tyr705 is necessary for cell survival and proliferation under hypoxic conditions. In addition, we show that S1PR1, a regulator of STAT3 transcription via the JAK/STAT pathway, is highly expressed in hypoxic ovarian cancer cells (HOCCs). Knock down of S1PR1 in HOCCs reduced pSTAT3 Tyr705 levels and was associated with decreased cell survival. Treatment of HOCCs with the STAT3 inhibitor HO-3867 resulted in a rapid and dramatic decrease in pSTAT3 Tyr705 levels as a result of ubiquitin proteasome degradation. STAT3-target proteins Bcl-xL, cyclin D2 and VEGF showed similar decreases in HO-3867 treated cells. Taken together, these findings suggest that activation of STAT3 Tyr705 promotes cell survival and proliferation in HOCCs, and that S1PR1 is involved in the initiation of STAT3 activation. Targeting hypoxia-mediated STAT3 activation represents a therapeutic option for ovarian cancer and other solid tumors. PMID:25594014

  20. Gene Expression Profile for Predicting Survival in Advanced-Stage Serous Ovarian Cancer Across Two Independent Datasets

    PubMed Central

    Yoshihara, Kosuke; Tajima, Atsushi; Yahata, Tetsuro; Kodama, Shoji; Fujiwara, Hiroyuki; Suzuki, Mitsuaki; Onishi, Yoshitaka; Hatae, Masayuki; Sueyoshi, Kazunobu; Fujiwara, Hisaya; Kudo, Yoshiki; Kotera, Kohei; Masuzaki, Hideaki; Tashiro, Hironori; Katabuchi, Hidetaka; Inoue, Ituro; Tanaka, Kenichi

    2010-01-01

    Background Advanced-stage ovarian cancer patients are generally treated with platinum/taxane-based chemotherapy after primary debulking surgery. However, there is a wide range of outcomes for individual patients. Therefore, the clinicopathological factors alone are insufficient for predicting prognosis. Our aim is to identify a progression-free survival (PFS)-related molecular profile for predicting survival of patients with advanced-stage serous ovarian cancer. Methodology/Principal Findings Advanced-stage serous ovarian cancer tissues from 110 Japanese patients who underwent primary surgery and platinum/taxane-based chemotherapy were profiled using oligonucleotide microarrays. We selected 88 PFS-related genes by a univariate Cox model (p<0.01) and generated the prognostic index based on 88 PFS-related genes after adjustment of regression coefficients of the respective genes by ridge regression Cox model using 10-fold cross-validation. The prognostic index was independently associated with PFS time compared to other clinical factors in multivariate analysis [hazard ratio (HR), 3.72; 95% confidence interval (CI), 2.66–5.43; p<0.0001]. In an external dataset, multivariate analysis revealed that this prognostic index was significantly correlated with PFS time (HR, 1.54; 95% CI, 1.20–1.98; p = 0.0008). Furthermore, the correlation between the prognostic index and overall survival time was confirmed in the two independent external datasets (log rank test, p = 0.0010 and 0.0008). Conclusions/Significance The prognostic ability of our index based on the 88-gene expression profile in ridge regression Cox hazard model was shown to be independent of other clinical factors in predicting cancer prognosis across two distinct datasets. Further study will be necessary to improve predictive accuracy of the prognostic index toward clinical application for evaluation of the risk of recurrence in patients with advanced-stage serous ovarian cancer. PMID:20300634

  1. Ovarian Cysts

    MedlinePlus

    f AQ FREQUENTLY ASKED QUESTIONS FAQ075 GYNECOLOGIC PROBLEMS Ovarian Cysts • What is an ovarian cyst? • What are the symptoms of ovarian cysts? • How are ovarian cysts diagnosed? • How are ovarian ...

  2. Ovarian Function, Not Age, Predicts the Benefit from Ovarian Suppression or Ablation for Premenopausal Women with Breast Cancer

    PubMed Central

    Cao, Ye; Wang, Shusen; Shi, Yanxia; An, Xin; Xu, Fei; Yuan, Zhongyu

    2016-01-01

    The role of adjuvant ovarian suppression or ablation (OS/OA) in premenopausal women with hormone receptor-positive breast cancer remains controversial. The purpose of our study was to examine which patients might benefit from the addition of OS/OA to tamoxifen. We analyzed the data of 2065 premenopausal patients with hormone receptor-positive invasive ductal carcinomas who were treated at Sun Yat-Sen University Cancer Center from 2000 to 2008. The five-year disease-free survival rate (DFSR) and overall survival rate (OSR) were compared by menstrual status and treatment. Compared with patients older than forty years of age, patients younger than forty years old had significant lower DFSRs and OSRs. The addition of OS/OA to tamoxifen increased the DFSR and OSR of patients with normal menstrual cycles after chemotherapy, regardless of their age at diagnosis. Patients with normal menstrual cycles after chemotherapy are the main beneficiaries of an adjuvant OS/OA. PMID:26866810

  3. YAP induces cisplatin resistance through activation of autophagy in human ovarian carcinoma cells

    PubMed Central

    Xiao, Lan; Shi, Xiao-Yan; Zhang, Ying; Zhu, Ying; Zhu, Lin; Tian, Wang; Zhu, Bing-Kun; Wei, Zhao-Lian

    2016-01-01

    Objective To identify the role of YAP in cisplatin resistance in human ovarian cancer cells and in the regulation of autophagy in these cancer cells. Materials and methods The cisplatin-sensitive OV2008 parental cell line and its cisplatin-resistant variant C13K were cultured. RNA interference was used to knock down the YAP gene. Accumulation of GFP-LC3 puncta was performed by fluorescence microscopy. The formation of autophagosomes was observed by transmission electron microscopy. Drug sensitivity was examined using CCK-8 assay, while apoptosis, the level of intracellular rhodamine 123 and lysosomal acidification were analyzed by fluorescence-activated cell sorting. Acid phosphatase activity was measured using an acid phosphatase-assay kit. Real-time polymerase chain reaction, Western blotting, and immunofluorescence detection were used to detect the protein and messenger RNA expression of YAP, YAP target genes, CCND1, cleaved PARP, and caspase 3, Atg-3 and -5, and the LC3B protein. Results YAP signaling may regulate cisplatin resistance in ovarian cancer cells by augmenting cellular autophagic flux. After knockdown of YAP-sensitized C13K cells to cisplatin by inducing a decrease in autophagy, YAP led to an increase in autophagy via enhancement of autolysosome degradation. Conclusion YAP-mediated autophagy may play a protective role in cisplatin-resistant human ovarian cancer cells. Therefore, YAP-mediated autophagy should be explored as a new target for enhancing the efficacy of cisplatin against ovarian cancer and other types of malignancies. PMID:27073322

  4. Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer

    PubMed Central

    Daudi, Sayeema; Eng, Kevin H.; Mhawech-Fauceglia, Paulette; Morrison, Carl; Miliotto, Anthony; Beck, Amy; Matsuzaki, Junko; Tsuji, Takemasa; Groman, Adrienne; Gnjatic, Sacha; Spagnoli, Guillo; Lele, Shashikant; Odunsi, Kunle

    2014-01-01

    The MAGE cancer-testis antigens (CTA) are attractive candidates for immunotherapy. The aim of this study was to determine the frequency of expression, humoral immunity and prognostic significance of MAGE CTA in human epithelial ovarian cancer (EOC). mRNA or protein expression frequencies were determined for MAGE-A1, -A3, -A4, -A10 and -C1 (CT7) in tissue samples obtained from 400 patients with EOC. The presence of autologous antibodies against the MAGE antigens was determined from 285 serum samples. The relationships between MAGE expression, humoral immunity to MAGE antigens, and clinico-pathologic characteristics were studied. The individual frequencies of expression were as follows: A1: 15% (42/281), A3: 36% (131/390), A4: 47% (186/399), A10: 52% (204/395), C1: 16% (42/267). Strong concordant expression was noted with MAGE-A1:–A4, MAGE-A1:–C1 and MAGE-A4:–A10 (p<0.0005). Expression of MAGE-A1 or -A10 antigens resulted in poor progression free survival (PFS) (OR 1.44, CI 1.01–2.04, p = 0.044 and OR 1.3, CI 1.03–1.64, p = 0.03, respectively); whereas, MAGE-C1 expression was associated with improved PFS (OR 0.62, CI 0.42–0.92, p = 0.016). The improved PFS observed for MAGE-C1 expression, was diminished by co-expression of MAGE-A1 or -A10. Spontaneous humoral immunity to the MAGE antigens was present in 9% (27/285) of patients, and this predicted poor overall survival (log-rank test p = 0.0137). These findings indicate that MAGE-A1, MAGE-A4, MAGE-A3, and MAGE-A10 are priority attractive targets for polyvalent immunotherapy in ovarian cancer patients. PMID:25101620

  5. Expression Proteomics Predicts Loss of RXR-γ during Progression of Epithelial Ovarian Cancer

    PubMed Central

    Kalra, Rajkumar S.; Bapat, Sharmila A.

    2013-01-01

    The process of cellular transformation involves cascades of molecular changes that are modulated through altered epigenetic, transcription, post-translational and protein regulatory networks. Thus, identification of transformation-associated protein alterations can provide an insight into major regulatory pathways activated during disease progression. In the present protein expression profiling approach, we identified differential sets of proteins in a two-dimensional gel electrophoresis screen of a serous ovarian adenocarcinoma progression model. Function-based categorization of the proteins exclusively associated with pre-transformed cells identified four cellular processes of which RXR-γ is known to modulate cellular differentiation and apoptosis. We thus probed the functional relevance of RXR-γ expression and signaling in these two pathways during tumor progression. RXR-γ expression was observed to modulate cellular differentiation and apoptosis in steady-state pre-transformed cells. Interestingly, retinoid treatment was found to enhance RXR-γ expression in transformed cells and sensitize them towards apoptosis in vitro, and also reduce growth of xenografts derived from transformed cells. Our findings emphasize that loss of RXR-γ levels appears to provide mechanistic benefits to transformed cells towards the acquisition of resistance to apoptosis hallmark of cancer, while effective retinoid treatment may present a viable approach towards sensitization of tumor cells to apoptosis through induction of RXR-γ expression. PMID:23936423

  6. The Lymphocyte-Monocyte Ratio Predicts Patient Survival and Aggressiveness of Ovarian Cancer

    PubMed Central

    Eo, Wan Kyu; Chang, Hye Jung; Kwon, Sang Hoon; Koh, Suk Bong; Kim, Young Ok; Ji, Yong Il; Kim, Hong-Bae; Lee, Ji Young; Suh, Dong Soo; Kim, Ki Hyung; Chang, Ik Jin; Kim, Heung Yeol; Chang, Suk Choo

    2016-01-01

    Objective: To measure the prognostic value of the lymphocyte-monocyte ratio (LMR) in patients with epithelial ovarian cancer (EOC). Methods: We retrospectively examined the LMR as a prognosticator in a cohort of 234 patients with EOC who underwent surgical resection. Patients were categorized into two different groups based on the LMR (LMR-low and LMR-high) using cut-off values determined by receiver operating characteristic (ROC) curve analysis. The objective of the study was to assess the effect of the LMR on progression-free survival (PFS) and overall survival (OS), and to validate the LMR as an independent predictor of survival. Results: Using the data collected from the whole cohort, the optimized LMR cut-off value selected on the ROC curve was 2.07 for both PFS and OS. The LMR-low and LMR-high groups included 48 (20.5%) and 186 patients (79.5%), respectively. The 5-year PFS rates in the LMR-low and LMR-high groups were 40.0 and 62.5% (P < 0.0001), respectively, and the 5-year OS rates in these two groups were 42.2 and 67.2% (P < 0.0001), respectively. On multivariate analysis, we identified age, International Federation of Gynecology and Obstetrics (FIGO) stage, and cancer antigen 125 levels to be the strongest valuable prognostic factors affecting PFS (P = 0.0421, P = 0.0012, and P = 0.0313, respectively) and age, FIGO stage, and the LMR as the most valuable prognostic factors predicting OS (P = 0.0064, P = 0.0029, and P = 0.0293, respectively). Conclusion: The LMR is an independent prognostic factor affecting the survival of patients with EOC. PMID:26918042

  7. Optimizing outcomes from ovarian tissue cryopreservation and transplantation; activation versus preservation.

    PubMed

    Meirow, Dror; Roness, Hadassa; Kristensen, Stine Gry; Andersen, Claus Yding

    2015-11-01

    Ovarian tissue cryopreservation and transplantation (OTCP) is gaining increasing traction in the field of fertility preservation as a result of accumulated successes. We now have a decade of experience with the technique, with tens of live births and greater than 90% return of ovarian function in graft recipients. Recently, a novel method of OTCP has been described, termed in vitro activated OTCP which proposes significant changes to the standard protocol. This method aims to stimulate activation of dormant follicles within the grafts prior to transplantation and ensure that mature oocytes can be generated in the immediate short term after transplantation. By contrast, conventional OTCP seeks to maintain dormancy and thus preserve the follicle reserve in the graft with the aim of maximizing graft lifespan. This opinion paper will compare the two methods of OTCP, highlighting their respective advantages and disadvantages, and provide suggestions as to when to apply either one of these methods in a clinical setting. PMID:26345687

  8. Anticancer activity of NOB1-targeted shRNA combination with TRAIL in epithelial ovarian cancer cells

    PubMed Central

    Lin, Yang; Xu, Tianmin; Teng, Hong; Cui, Manhua

    2015-01-01

    Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of ovarian cancer. However, the effectiveness of the treatment remains limited due to the inherent or acquired resistance of tumor cells to TRAIL. Our previously study demonstrated that downregulation of NOB1 (NIN1/RPN12 binding protein 1 homolog) expression by a lentiviral short hairpin RNA (shRNA) delivery system (Lv/sh-NOB1) suppressed ovarian cancer growth. Here, Lv/sh-NOB1 and TRAIL were combined and tested the effects of this combination on ovarian cancer cells to identify more effective therapeutics against ovarian cancer by several in vitro experiments. Tumor growth ability in SKVO3 xenograft nude mice was also determined to define this combination treatment effect in tumorigenesis in vivo. In vitro assay showed that Lv/sh-NOB1 in combination with TRAIL treatment in ovarian cancer cell synergistically suppressed the proliferation and colony formation, as well as induced cell apoptosis and increased the activity of caspase-3, -8 and -9. In vivo assay showed that Lv/sh-NOB1 combination with TRAIL synergistically suppressed tumor growth of nude mice model. Importantly, we found that downregulation of NOB1 could upregulate DR5 expression and active MAPK pathway, which might contribute to increase sensitivity TRAIL to ovarian cancer cells. These findings suggested that Lv/sh-NOB1 combination with TRAIL treatment may be a potential treatment approach for ovarian cancer. PMID:26617713

  9. Prognostic factors in ovarian carcinoma stage III patients. Can biomarkers improve the prediction of short- and long-term survivors?

    PubMed

    Kaern, J; Aghmesheh, M; Nesland, J M; Danielsen, H E; Sandstad, B; Friedlander, M; Tropé, C

    2005-01-01

    The aim of the study was to determine if biomarker expression could help discriminate between short-term and long-term survivors in women with advanced ovarian cancer. Fifty-one patients with stage III ovarian cancer were selected for the study, which included 28 short-term survivors (death from ovarian cancer within 18 months) and 23 long-term survivors (alive for more than 5 years). There was no difference between the two groups with respect to FIGO substage, age, World Health Organization score, and first-line platinum therapy. Classic clinical pathologic parameters were examined together with p53, Bcl-2, Ki-67, PDGFRalpha, P-glycoprotein, BRCA1, and DNA ploidy. Immunohistochemistry was used for scoring biomarker expression and image cytometry for DNA ploidy. All patients had primary debulking surgery followed by first-line platinum therapy. On multivariate analysis, the presence of ascites, debulking surgery and repeat laparotomy, clear-cell histology, elevated CA125, and high Ki-67 score were all found to be of prognostic importance. The long-term survivors were characterized by primary optimal cytoreduction surgery (<1 cm residual disease), attempt at maximal tumor debulking by experienced gynecological oncologic surgeons, and the absence of ascites. Normal CA125 level before platinum therapy and negative Ki-67 expression also predicted a more favorable prognosis. PMID:16343177

  10. Influence of dominance status on adrenal activity and ovarian cyclicity status in captive African elephants.

    PubMed

    Proctor, Christine M; Freeman, Elizabeth W; Brown, Janine L

    2010-01-01

    The North American African (Loxodonta africana) elephant population is not self-sustaining, in part because of a high rate of abnormal ovarian activity. About 12% of adult females exhibit irregular cycles and 31% do not cycle at all. Our earlier work revealed a relationship between dominance status and ovarian acyclicity, with dominant females being more likely to not cycle normally. One theory is that dominant females may be expending more energy to maintaining peace within the captive herd than for supporting reproduction. The goal of this study was to determine if there was a relationship among dominance status, serum cortisol concentrations, and ovarian acyclicity. We hypothesized that adrenal glucocorticoid activity would be increased in dominant, noncycling elephants as compared with subdominant individuals. Blood samples were collected weekly over a 2-year period in 81 females of known dominance and cyclicity status, and analyzed for cortisol. Based on a path analysis model (Reticular Action Model Or Near Approximation [RAMONA]), noncycling, dominant African elephant females did not have higher mean serum cortisol concentrations, or exhibit more variability (i.e., coefficient of variation, standard deviation) in cortisol secretion. This study suggests that alterations in adrenal activity are not related to dominance status nor contribute directly to acyclicity in captive African elephants. PMID:20033989

  11. Prognostic nomogram to predict progression-free survival in patients with platinum-sensitive recurrent ovarian cancer

    PubMed Central

    Lee, C K; Simes, R J; Brown, C; Lord, S; Wagner, U; Plante, M; Vergote, I; Pisano, C; Parma, G; Burges, A; Bourgeois, H; Högberg, T; Bentley, J; Angleitner-Boubenizek, L; Ferrero, A; Richter, B; Hirte, H; Gebski, V; Pfisterer, J; Pujade-Lauraine, E; Friedlander, M

    2011-01-01

    Background: Patients with platinum-sensitive recurrent ovarian cancer are a heterogeneous group, and it is not possible to accurately predict the progression-free survival (PFS) in these patients. We developed and validated a nomogram to help improve prediction of PFS in patients treated with platinum-based chemotherapy. Methods: The nomogram was developed in a training cohort (n=955) from the CALYPSO trial and validated in the AGO-OVAR 2.5 Study (n=340). The proportional-hazards model (nomogram) was based on pre-treatment characteristics. Results: The nomogram had a concordance index (C-index) of 0.645. Significant predictors were tumour size platinum-chemotherapy-free interval, CA-125, number of organ metastatic sites and white blood count. When the nomogram was applied without CA-125 (CA-125 was not available in validation cohort), the C-indices were 0.624 (training) and 0.594 (validation). When classification was based only on the platinum-chemotherapy-free interval, the indices were 0.571 (training) and 0.560 (validation). The calibration plot in the validation cohort based on four predictors (without CA-125) suggested good agreement between actual and nomogram-predicted 12-month PFS probabilities. Conclusion: This nomogram, using five pre-treatment characteristics, improves prediction of PFS in patients with platinum-sensitive ovarian cancer having platinum-based chemotherapy. It will be useful for the design and stratification of patients in clinical trials and also for counselling patients. PMID:21915127

  12. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium

    PubMed Central

    UTSUMI, FUMI; KAJIYAMA, HIROAKI; NAKAMURA, KAE; TANAKA, HIROMASA; MIZUNO, MASAAKI; TOYOKUNI, SHINNYA; HORI, MASARU; KIKKAWA, FUMITAKA

    2016-01-01

    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma-activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related PMID:27035127

  13. Variable susceptibility of ovarian cancer cells to non-thermal plasma-activated medium.

    PubMed

    Utsumi, Fumi; Kajiyama, Hiroaki; Nakamura, Kae; Tanaka, Hiromasa; Mizuno, Masaaki; Toyokuni, Shinnya; Hori, Masaru; Kikkawa, Fumitaka

    2016-06-01

    Non-thermal atmospheric pressure plasma has been widely studied in recent years in many fields, including cancer treatment. However, its efficiency for inducing apoptosis sometimes varies depending on the cell species and experimental conditions. The aim of this study was to elucidate what causes these differences in responses to plasma treatment. Using four ovarian cancer cell lines, the cell density had a markedly negative impact on the proliferation inhibition rate (PIR) and it was more obvious in OVCAR-3 and NOS2 cells. Furthermore, TOV21G and ES-2 cells were drastically sensitive to plasma‑activated medium (PAM) compared with the other two cell lines. We demonstrated that the proportion of reactive oxygen species and cell number had a marked impact on the effect of PAM against ovarian cancer cells. Additionally it was suggested that the morphological features of cells were also closely related to the sensitivity of cancer cells to the plasma treatment. PMID:27035127

  14. Locally constrained active contour: a region-based level set for ovarian cancer metastasis segmentation

    NASA Astrophysics Data System (ADS)

    Liu, Jianfei; Yao, Jianhua; Wang, Shijun; Linguraru, Marius George; Summers, Ronald M.

    2014-03-01

    Accurate segmentation of ovarian cancer metastases is clinically useful to evaluate tumor growth and determine follow-up treatment. We present a region-based level set algorithm with localization constraints to segment ovarian cancer metastases. Our approach is established on a representative region-based level set, Chan-Vese model, in which an active contour is driven by region competition. To reduce over-segmentation, we constrain the level set propagation within a narrow image band by embedding a dynamic localization function. The metastasis intensity prior is also estimated from image regions within the level set initialization. The localization function and intensity prior force the level set to stop at the desired metastasis boundaries. Our approach was validated on 19 ovarian cancer metastases with radiologist-labeled ground-truth on contrast-enhanced CT scans from 15 patients. The comparison between our algorithm and geodesic active contour indicated that the volume overlap was 75+/-10% vs. 56+/-6%, the Dice coefficient was 83+/-8% vs. 63+/-8%, and the average surface distance was 2.2+/-0.6mm vs. 4.4+/-0.9mm. Experimental results demonstrated that our algorithm outperformed traditional level set algorithms.

  15. Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes)

    PubMed Central

    Zhou, Linyan; Charkraborty, Tapas; Zhou, Qian; Mohapatra, Sipra; Nagahama, Yoshitaka; Zhang, Yueguang

    2016-01-01

    In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (Rspo1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of Rspo1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the Rspo1 gene was performed in XY medaka (Oryzias latipes). The results obtained demonstrated that the gain of Rspo1 function induced femininity in XY fish. The overexpression of Rspo1 enhanced Wnt4b and β-catenin transcription, and completely suppressed the expression of male-biased genes (Dmy, Gsdf, Sox9a2 and Dmrt1) as well as testicular differentiation. Gonadal reprograming of Rspo1-over-expressed-XY (Rspo1-OV-XY) fish, induced the production of female-biased genes (Cyp19a1a and Foxl2), estradiol-17β production and further female type secondary sexuality. Moreover, Rspo1-OV-XY females were fertile and produced successive generations. Promoter analyses showed that Rspo1 transcription was directly regulated by DM domain genes (Dmy, the sex-determining gene, and Dmrt1) and remained unresponsive to Foxl2. Taken together, our results strongly suggest that Rspo1 is sufficient to activate ovarian development and plays a decisive role in the ovarian differentiation in medaka. PMID:26782368

  16. Rspo1-activated signalling molecules are sufficient to induce ovarian differentiation in XY medaka (Oryzias latipes).

    PubMed

    Zhou, Linyan; Charkraborty, Tapas; Zhou, Qian; Mohapatra, Sipra; Nagahama, Yoshitaka; Zhang, Yueguang

    2016-01-01

    In contrast to our understanding of testicular differentiation, ovarian differentiation is less well understood in vertebrates. In mammals, R-spondin1 (Rspo1), an activator of Wnt/β-catenin signaling pathway, is located upstream of the female sex determination pathway. However, the functions of Rspo1 in ovarian differentiation remain unclear in non-mammalian species. In order to elucidate the detailed functions of Rspo/Wnt signaling pathway in fish sex determination/differentiation, the ectopic expression of the Rspo1 gene was performed in XY medaka (Oryzias latipes). The results obtained demonstrated that the gain of Rspo1 function induced femininity in XY fish. The overexpression of Rspo1 enhanced Wnt4b and β-catenin transcription, and completely suppressed the expression of male-biased genes (Dmy, Gsdf, Sox9a2 and Dmrt1) as well as testicular differentiation. Gonadal reprograming of Rspo1-over-expressed-XY (Rspo1-OV-XY) fish, induced the production of female-biased genes (Cyp19a1a and Foxl2), estradiol-17β production and further female type secondary sexuality. Moreover, Rspo1-OV-XY females were fertile and produced successive generations. Promoter analyses showed that Rspo1 transcription was directly regulated by DM domain genes (Dmy, the sex-determining gene, and Dmrt1) and remained unresponsive to Foxl2. Taken together, our results strongly suggest that Rspo1 is sufficient to activate ovarian development and plays a decisive role in the ovarian differentiation in medaka. PMID:26782368

  17. Regulation of gene expression in ovarian cancer cells by luteinizing hormone receptor expression and activation

    PubMed Central

    2011-01-01

    Background Since a substantial percentage of ovarian cancers express gonadotropin receptors and are responsive to the relatively high concentrations of pituitary gonadotropins during the postmenopausal years, it has been suggested that receptor activation may contribute to the etiology and/or progression of the neoplasm. The goal of the present study was to develop a cell model to determine the impact of luteinizing hormone (LH) receptor (LHR) expression and LH-mediated LHR activation on gene expression and thus obtain insights into the mechanism of gonadotropin action on ovarian surface epithelial (OSE) carcinoma cells. Methods The human ovarian cancer cell line, SKOV-3, was stably transfected to express functional LHR and incubated with LH for various periods of time (0-20 hours). Transcriptomic profiling was performed on these cells to identify LHR expression/activation-dependent changes in gene expression levels and pathways by microarray and qRT-PCR analyses. Results Through comparative analysis on the LHR-transfected SKOV-3 cells exposed to LH, we observed the differential expression of 1,783 genes in response to LH treatment, among which five significant families were enriched, including those of growth factors, translation regulators, transporters, G-protein coupled receptors, and ligand-dependent nuclear receptors. The most highly induced early and intermediate responses were found to occupy a network impacting transcriptional regulation, cell growth, apoptosis, and multiple signaling transductions, giving indications of LH-induced apoptosis and cell growth inhibition through the significant changes in, for example, tumor necrosis factor, Jun and many others, supportive of the observed cell growth reduction in in vitro assays. However, other observations, e.g. the substantial up-regulation of the genes encoding the endothelin-1 subtype A receptor, stromal cell-derived factor 1, and insulin-like growth factor II, all of which are potential therapeutic

  18. Complement, complement activation and anaphylatoxins in human ovarian follicular fluid.

    PubMed Central

    Perricone, R; de Carolis, C; Moretti, C; Santuari, E; de Sanctis, G; Fontana, L

    1990-01-01

    Functionally active complement was sought and detected in human follicular fluids obtained during the pre-ovulatory period. All the functional complement activities tested, including total haemolytic complement, classical pathway activity and alternative pathway activity were present in nine fluids from four different donors with values within the normal serum range. The immunochemical analysis demonstrated the presence of complement factors from C1 to C9, of B and of C1 INH, H, I. Complement anaphylatoxins were found employing RIA techniques in amounts significantly higher than in human plasma, thus demonstrating that follicular fluid complement, at least during the pre-ovulatory period, is partially activated. A possible role for urokinase-like substances in such an activation was indicated by further in vitro experiments. The presence of active complement in follicular fluid can be relevant for the function of the enzymatic multi-factorial mechanism of ovulation. PMID:2242616

  19. Ovarian activity in the scimitar-horned oryx (Oryx dammah) determined by faecal steroid analysis.

    PubMed

    Morrow, C J; Monfort, S L

    1998-10-01

    Ultrasonography and radioimmunoassay (RIA) of serum oestradiol-17beta, luteinizing hormone (LH) and progesterone, and faecal oestrogen and progestin was used to assess ovarian activity in the scimitar-horned oryx (Oryx dammah). Ovarian examination using ultrasonography revealed maximal follicle and corpus luteum (CL) diameters of 15 and 32 mm, respectively. Steroid hormone metabolite distribution among individual faecal pellets within the same defaecation was relatively homogeneous with coefficients of variation averaging 10.2+/-1.8% and 16.2+/-4.6% for oestrogens and progestins, respectively. Elevated faecal oestrogen concentrations were associated with large (> 10 mm) antral follicles detected by ultrasonography. Periovulatory peaks in faecal oestrogen excretion, coincident with nadirs in progestin excretion, were detected in three females. Faecal progestin excretion exhibited a similar temporal pattern to serum progesterone concentrations, with a time lag of approximately 16 h. Faecal progestin concentrations corresponded with the presence of functional CL and proved useful for monitoring luteal function, spontaneous and prostaglandin-F2alpha analogue-induced luteolysis and anovulation. In summary, faecal steroid monitoring is a practical, noninvasive method for characterising ovarian steroid excretion and has potential for facilitating the application of assisted reproductive technologies in scimitar-horned oryx. PMID:9835376

  20. RAD51 and BRCA2 enhance oncolytic adenovirus type 5 activity in ovarian cancer

    PubMed Central

    Tookman, Laura A.; Browne, Ashley K.; Connell, Claire M.; Bridge, Gemma; Ingemarsdotter, Carin K.; Dowson, Suzanne; Shibata, Atsushi; Lockley, Michelle; Martin, Sarah A.; McNeish, Iain A.

    2015-01-01

    Homologous Recombination (HR) function is critically important in High Grade Serous Ovarian Cancer (HGSOC). HGSOC with intact HR has a worse prognosis and is less likely to respond to platinum chemotherapy and PARP inhibitors. Oncolytic adenovirus, a novel therapy for human malignancies, stimulates a potent DNA damage response that influences overall anti-tumor activity. Here, the importance of HR was investigated by determining the efficacy of adenovirus type 5 (Ad5) vectors in ovarian cancer. Using matched BRCA2 mutant and wild-type HGSOC cells, it was demonstrated that intact HR function promotes viral DNA replication and augments overall efficacy, without influencing viral DNA processing. These data were confirmed in a wider panel of HR competent and defective ovarian cancer lines. Mechanistically, both BRCA2 and RAD51 localize to viral replication centers within the infected cell nucleus and that RAD51 localization occurs independently of BRCA2. In addition, a direct interaction was identified between RAD51 and adenovirus E2 DNA binding protein. Finally, using functional assays of HR competence, despite inducing degradation of MRE11, Ad5 infection does not alter cellular ability to repair DNA double strand break damage via HR. These data reveal that Ad5 redistributes critical HR components to viral replication centers and enhances cytotoxicity. Implications Oncolytic adenoviral therapy may be most clinically relevant in tumors with intact HR function. PMID:26452665

  1. Ovarian cancer.

    PubMed

    Matulonis, Ursula A; Sood, Anil K; Fallowfield, Lesley; Howitt, Brooke E; Sehouli, Jalid; Karlan, Beth Y

    2016-01-01

    Ovarian cancer is not a single disease and can be subdivided into at least five different histological subtypes that have different identifiable risk factors, cells of origin, molecular compositions, clinical features and treatments. Ovarian cancer is a global problem, is typically diagnosed at a late stage and has no effective screening strategy. Standard treatments for newly diagnosed cancer consist of cytoreductive surgery and platinum-based chemotherapy. In recurrent cancer, chemotherapy, anti-angiogenic agents and poly(ADP-ribose) polymerase inhibitors are used, and immunological therapies are currently being tested. High-grade serous carcinoma (HGSC) is the most commonly diagnosed form of ovarian cancer and at diagnosis is typically very responsive to platinum-based chemotherapy. However, in addition to the other histologies, HGSCs frequently relapse and become increasingly resistant to chemotherapy. Consequently, understanding the mechanisms underlying platinum resistance and finding ways to overcome them are active areas of study in ovarian cancer. Substantial progress has been made in identifying genes that are associated with a high risk of ovarian cancer (such as BRCA1 and BRCA2), as well as a precursor lesion of HGSC called serous tubal intraepithelial carcinoma, which holds promise for identifying individuals at high risk of developing the disease and for developing prevention strategies. PMID:27558151

  2. Recreational physical activity and ovarian cancer risk in African American women.

    PubMed

    Abbott, Sarah E; Bandera, Elisa V; Qin, Bo; Peres, Lauren C; Moorman, Patricia G; Barnholtz-Sloan, Jill; Schwartz, Ann G; Funkhouser, Ellen; Peters, Edward S; Cote, Michele L; Alberg, Anthony J; Terry, Paul; Bondy, Melissa; Paddock, Lisa E; Crankshaw, Sydnee; Wang, Frances; Camacho, Fabian; Schildkraut, Joellen M

    2016-06-01

    The literature on recreational physical activity (RPA) and ovarian cancer risk is inconclusive and most studies of RPA and ovarian cancer have been conducted in white populations. This study is the first to investigate the association between RPA and ovarian cancer in an exclusively African American (AA) population. We analyzed data from an ongoing U.S. population-based, case-control study of AA women, which included 393 women recently diagnosed with invasive epithelial ovarian cancer (IEOC) and 611 controls. A baseline interview assessed RPA frequency, intensity, and duration. Each RPA intensity was assigned a metabolic equivalent of task (MET) value and MET-min/week were calculated. Unconditional multivariable logistic regression was performed to investigate associations between RPA and IEOC risk. Compared with sedentary women, predominantly mild intensity RPA was significantly inversely associated with IEOC risk for women reporting above median (>297) MET-min/week (odds ratio [OR] = 0.52; 95% confidence interval [CI]: 0.34, 0.78) and nonsignificantly for <297 MET-min/week (OR = 0.71; 95% CI: 0.44, 1.12). Predominantly moderate intensity RPA was associated with significantly increased risk for women reporting above median (>540) MET-min/week (OR = 1.51; 95% CI: 1.03, 2.23). Predominantly strenuous intensity RPA was nonsignificantly associated with lower IEOC risk for women reporting above median (>1800) MET-min/week (OR = 0.72; 95% CI: 0.33, 1.57). The inverse associations for mild and strenuous intensity RPA were most pronounced in obese women (body mass index >30 kg/m(2) ). The findings that mild and strenuous RPA may reduce the risk of IEOC particularly among obese women are difficult to reconcile with the increased risk observed for moderate RPA. Further research is warranted to determine whether these findings are genuine and, if so, their mechanistic basis. PMID:26923432

  3. AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells.

    PubMed

    Lorenzato, Annalisa; Biolatti, Marta; Delogu, Giuseppe; Capobianco, Giampiero; Farace, Cristiano; Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco; Madeddu, Roberto; Olivero, Martina; Di Renzo, Maria Flavia

    2013-10-15

    The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. PMID:23948303

  4. Risk Prediction for Breast, Endometrial, and Ovarian Cancer in White Women Aged 50 y or Older: Derivation and Validation from Population-Based Cohort Studies

    PubMed Central

    Pfeiffer, Ruth M.; Park, Yikyung; Kreimer, Aimée R.; Lacey, James V.; Pee, David; Greenlee, Robert T.; Buys, Saundra S.; Hollenbeck, Albert; Rosner, Bernard; Gail, Mitchell H.; Hartge, Patricia

    2013-01-01

    Background Breast, endometrial, and ovarian cancers share some hormonal and epidemiologic risk factors. While several models predict absolute risk of breast cancer, there are few models for ovarian cancer in the general population, and none for endometrial cancer. Methods and Findings Using data on white, non-Hispanic women aged 50+ y from two large population-based cohorts (the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [PLCO] and the National Institutes of Health–AARP Diet and Health Study [NIH-AARP]), we estimated relative and attributable risks and combined them with age-specific US-population incidence and competing mortality rates. All models included parity. The breast cancer model additionally included estrogen and progestin menopausal hormone therapy (MHT) use, other MHT use, age at first live birth, menopausal status, age at menopause, family history of breast or ovarian cancer, benign breast disease/biopsies, alcohol consumption, and body mass index (BMI); the endometrial model included menopausal status, age at menopause, BMI, smoking, oral contraceptive use, MHT use, and an interaction term between BMI and MHT use; the ovarian model included oral contraceptive use, MHT use, and family history or breast or ovarian cancer. In independent validation data (Nurses' Health Study cohort) the breast and ovarian cancer models were well calibrated; expected to observed cancer ratios were 1.00 (95% confidence interval [CI]: 0.96–1.04) for breast cancer and 1.08 (95% CI: 0.97–1.19) for ovarian cancer. The number of endometrial cancers was significantly overestimated, expected/observed = 1.20 (95% CI: 1.11–1.29). The areas under the receiver operating characteristic curves (AUCs; discriminatory power) were 0.58 (95% CI: 0.57–0.59), 0.59 (95% CI: 0.56–0.63), and 0.68 (95% CI: 0.66–0.70) for the breast, ovarian, and endometrial models, respectively. Conclusions These models predict absolute risks for breast, endometrial, and

  5. Temsirolimus and pegylated liposomal doxorubicin (PLD) combination therapy in breast, endometrial, and ovarian cancer: phase Ib results and prediction of clinical outcome with FDG-PET/CT.

    PubMed

    Boers-Sonderen, Marye J; de Geus-Oei, Lioe-Fee; Desar, Ingrid M E; van der Graaf, Winette T A; Oyen, Wim J G; Ottevanger, Petronella B; van Herpen, Carla M L

    2014-12-01

    Pegylated liposomal doxorubicin (PLD) is active in breast, endometrial, and ovarian cancer. Preclinical data suggest that the combination of PLD with a mammalian target of rapamycin (mTOR) inhibitor has an additive effect. The safety and recommended phase two dose (RPTD) of temsirolimus in combination with PLD were assessed. (18) F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT was performed for early response monitoring. Nineteen patients with advanced breast, endometrial, and ovarian cancer were treated with increasing doses of temsirolimus (10, 15, or 20 mg once weekly) and PLD (30 or 40 mg/m(2) once every 4 weeks). PLD was initiated 2 weeks after start of temsirolimus. FDG-PET/CT was performed at baseline, after 2 and 6 weeks. Standardized uptake values (SUV), metabolic volume, and total lesion glycolysis (TLG, SUV × metabolic volume) were calculated. The RPTD was 15 mg temsirolimus and 40 mg/m(2) PLD. Dose-limiting toxicities (DLT) were thrombocytopenia grade 3 with nose bleeding and skin toxicity grade 3. Most frequent treatment-related toxicities were nausea, fatigue, mucositis, and skin toxicity. Changes in TLG after 2 weeks predicted partial response (PR) after 10 weeks (p = 0.037). A rise in SUV between the second and sixth week predicted progression (PD) (p = 0.034) and was associated with worse progression free survival (PFS) (HR 1.068; p = 0.013). The RPTD was established at 15 mg temsirolimus weekly and PLD 40 mg/m(2) once every 4 weeks and the combination was safe. Early response evaluation with FDG-PET/CT may predict subsequent radiological PR and PD. This trial is registered under number NCT0098263. PMID:24577626

  6. MEK1-independent activation of MAPK and MEK1-dependent activation of p70 S6 kinase by stem cell factor (SCF) in ovarian cancer cells

    SciTech Connect

    Liu, Lian; Zhang, Xin; Du, Chao; Zhang, Xiaoning; Hou, Nan; Zhao, Di; Sun, Jianzhi; Li, Li; Wang, Xiuwen; Ma, Chunhong

    2009-05-01

    We discovered a stem cell factor (SCF)-triggered, MEK1-independent, and PI3K-dependent MAPK activation pathway in the Kit-expressing ovarian cancer cell line HEY. When we knocked down MEK1 with RNA interference (RNAi) to study the function of MEK1 on the proliferation and survival of ovarian cancer cells, we found that impaired cell growth still occurred after MEK1 expression had been suppressed, although MAPK activation remained intact. This suggests that there is MEK1-independent activation of MAPK in the SCF-induced ovarian cancer cell growth process, and that MEK1 still plays a crucial role in maintaining the malignant properties of ovarian cancer cells even when it fails to activate MAPK as expected.

  7. The Role of Ect2 Nuclear RhoGEF Activity in Ovarian Cancer Cell Transformation

    PubMed Central

    Huff, Lauren P.; DeCristo, Molly J.; Trembath, Dimitri; Kuan, Pei Fen; Yim, Margaret; Liu, Jinsong; Cook, Danielle R.; Miller, C. Ryan; Der, Channing J.

    2013-01-01

    Ect2, a Rho guanine nucleotide exchange factor (RhoGEF), is atypical among RhoGEFs in its predominantly nuclear localization in interphase cells. One current model suggests that Ect2 mislocalization drives cellular transformation by promoting aberrant activation of cytoplasmic Rho family GTPase substrates. However, in ovarian cancers, where Ect2 is both amplified and overexpressed at the mRNA level, we observed that the protein is highly expressed and predominantly nuclear and that nuclear but not cytoplasmic Ect2 increases with advanced disease. Knockdown of Ect2 in ovarian cancer cell lines impaired their anchorage-independent growth without affecting their growth on plastic. Restoration of Ect2 expression rescued the anchorage-independent growth defect, but not if either the DH catalytic domain or the nuclear localization sequences of Ect2 were mutated. These results suggested a novel mechanism whereby Ect2 could drive transformation in ovarian cancer cells by acting as a RhoGEF specifically within the nucleus. Interestingly, Ect2 had an intrinsically distinct GTPase specificity profile in the nucleus versus the cytoplasm. Nuclear Ect2 bound preferentially to Rac1, while cytoplasmic Ect2 bound to RhoA but not Rac. Consistent with nuclear activation of endogenous Rac, Ect2 overexpression was sufficient to recruit Rac effectors to the nucleus, a process that required a functional Ect2 catalytic domain. Furthermore, expression of active nuclearly targeted Rac1 rescued the defect in transformed growth caused by Ect2 knockdown. Our work suggests a novel mechanism of Ect2-driven transformation, identifies subcellular localization as a regulator of GEF specificity, and implicates activation of nuclear Rac1 in cellular transformation. PMID:24386507

  8. Oral progestin induces rapid, reversible suppression of ovarian activity in the cat.

    PubMed

    Stewart, R A; Pelican, K M; Brown, J L; Wildt, D E; Ottinger, M A; Howard, J G

    2010-04-01

    The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: (1) 0mg/kg (control; n=5 cats); (2) 0.044 mg/kg (LOW; n=5); (3) 0.088 mg/kg (MID; n=6); or (4) 0.352 mg/kg (HIGH; n=6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n=6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin re-initiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P<0.05) after treatment in HIGH, but not in LOW or MID cats compared to pre-treatment values. The results demonstrate that: (1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and (2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding. PMID:20051246

  9. Oral progestin induces rapid, reversible suppression of ovarian activity in the cat

    PubMed Central

    Stewart, R.A.; Pelican, K.M.; Brown, J.L.; Wildt, D.E.; Ottinger, M.A.; Howard, J.G.

    2010-01-01

    The influence of oral progestin (altrenogest; ALT) on cat ovarian activity was studied using non-invasive fecal steroid monitoring. Queens were assigned to various ALT dosages: 1) 0 mg/kg (control; n = 5 cats); 2) 0.044 mg/kg (LOW; n = 5); 3) 0.088 mg/kg (MID; n = 6); or 4) 0.352 mg/kg (HIGH; n = 6). Fecal estrogen and progestagen concentrations were quantified using enzyme immunoassays for 60 days before, 38 days during and 60 days after ALT treatment. Initiation of follicular activity was suppressed in all cats during progestin treatment, whereas controls continued to cycle normally. Females (n = 6) with elevated fecal estrogens at treatment onset completed a normal follicular phase before returning to baseline and remained suppressed until treatment withdrawal. All cats receiving oral progestin reinitiated follicular activity after treatment, although MID cats experienced the most synchronized return (within 10-16 days). Mean baseline fecal estrogens and progestagens were higher (P < 0.05) after treatment in HIGH, but not LOW or MID cats compared to pre-treatment values. Results demonstrate that: 1) oral progestin rapidly suppresses initiation of follicular activity in the cat, but does not influence a follicular phase that exists before treatment initiation; and 2) queens return to normal follicular activity after progestin withdrawal. This study provides foundational information for research aimed at using progestin priming to improve ovarian response in felids scheduled for ovulation induction and assisted breeding. PMID:20051246

  10. Effects of seasonal adiposity on ovarian activity of Vespertilionid bat, Scotophilus heathi: Proteomics analysis

    PubMed Central

    Singh, Ajit; Powell, Michael D.; Sridaran, Rajagopala; Krishna, Amitabh

    2014-01-01

    In present study comparative proteomics was utilized to identify ovarian protein profiles and correlate the expression of these proteins with adiposity induced changes in ovarian activity leading to suppression of ovulation (delayed ovulation) in the bat, S. heathi. To achieve this, two-dimension gel electrophoresis combined with protein identification by tandem mass spectrometry (LC–MS/MS) was applied. Protein profiles were obtained from intact ovaries of bats collected during recrudescence (basal body weight) and delayed ovulation (increased body weight) phases of reproductive cycle. Out of 42 differentially expressed protein spots, 15 protein spots were identified by LC–MS/MS. A majority of the 15 protein spots identified belonged to a group of enzymes within the glycolytic and citrate cycles. Greater concentrations of these enzymes were found during the period of delayed ovulation, which may be responsible for an increase in the production of ATP within the ovary. The increased metabolic activity and energy production observed within the ovary during winter dormancy may be required for increased steroidogenic activity during this period. The protein 14-3-3 identified by LC–MS/MS was verified by immunoblotting, which confirmed its increased expression during the period of delayed ovulation and may be associated with development of insulin resistance. Treatment with adipokines (adiponectin, resistin) is responsible for increased expression of 14-3-3 protein in the ovary of S. heathi. Adiposity-associated rise in adipokines are thus responsible for increased expression of 14-3-3 protein in the ovary of S. heathi, which may be responsible for prolonged survival of antral follicles and suppression of ovulation. The 14-3-3 protein may represent a new marker for adiposity associated ovarian anovulation (disorders). PMID:25305638

  11. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment

    PubMed Central

    Xu, Shili; Butkevich, Alexey N.; Yamada, Roppei; Zhou, Yu; Debnath, Bikash; Duncan, Roger; Zandi, Ebrahim; Petasis, Nicos A.; Neamati, Nouri

    2012-01-01

    Protein disulfide isomerase (PDI), an endoplasmic reticulum chaperone protein, catalyzes disulfide bond breakage, formation, and rearrangement. The effect of PDI inhibition on ovarian cancer progression is not yet clear, and there is a need for potent, selective, and safe small-molecule inhibitors of PDI. Here, we report a class of propynoic acid carbamoyl methyl amides (PACMAs) that are active against a panel of human ovarian cancer cell lines. Using fluorescent derivatives, 2D gel electrophoresis, and MS, we established that PACMA 31, one of the most active analogs, acts as an irreversible small-molecule inhibitor of PDI, forming a covalent bond with the active site cysteines of PDI. We also showed that PDI activity is essential for the survival and proliferation of human ovarian cancer cells. In vivo, PACMA 31 showed tumor targeting ability and significantly suppressed ovarian tumor growth without causing toxicity to normal tissues. These irreversible small-molecule PDI inhibitors represent an important approach for the development of targeted anticancer agents for ovarian cancer therapy, and they can also serve as useful probes for investigating the biology of PDI-implicated pathways. PMID:22988091

  12. Expression and activity analysis of a new fusion protein targeting ovarian cancer cells.

    PubMed

    Su, Manman; Chang, Weiqin; Wang, Dingding; Cui, Manhua; Lin, Yang; Wu, Shuying; Xu, Tianmin

    2015-09-01

    The aim of the present study was to develop a new therapeutic drug to improve the prognosis of ovarian cancer patients. Human urokinase-type plasminogen activator (uPA)17-34-kunitz-type protease inhibitor (KPI) eukaryotic expression vector was constructed and recombinant human uPA17-34-KPI (rhuPA17-34-KPI) in P. pastoris was expressed. In the present study, the DNA sequences that encode uPA 17-34 amino acids were created according to the native amino acids sequence and inserted into the KPI-pPICZαC vector, which was constructed. Then, uPA17‑34-KPI-pPICZαC was transformed into P. pastoris X-33, and rhuPA17-34-KPI was expressed by induction of methanol. The bioactivities of a recombinant fusion protein were detected with trypsin inhibition analysis, and the inhibitory effects on the growth of ovarian cancer cells were identified using the TUNEL assay, in vitro wound‑healing assay and Matrigel model analysis. The results of the DNA sequence analysis of the recombinant vector uPA17-34-KPI‑pPICZα demonstrated that the DNA‑encoding human uPA 17-34 amino acids, 285-288 amino acids of amyloid precursor protein (APP) and 1-57 amino acids of KPI were correctly inserted into the pPICZαC vector. Following induction by methonal, the fusion protein with a molecular weight of 8.8 kDa was observed using SDS-PAGE and western blot analysis. RhuPA17-34-KPI was expressed in P. pastoris with a yield of 50 mg/l in a 50-ml tube. The recombinant fusion protein was able to inhibit the activity of trypsin, inhibit growth and induce apoptosis of SKOV3 cells, and inhibit the invasion and metastasis of ovarian cancer cells. By considering uPA17-34 amino acid specific binding uPAR as the targeted part of fusion protein and utilizing the serine protease inhibitor activity of KPI, it was found that the recombinant fusion protein uPA17-34-KPI inhibited the invasion and metastasis of ovarian tumors, and may therefore be regarded as effective in targeted treatment. PMID

  13. Casticin induces ovarian cancer cell apoptosis by repressing FoxM1 through the activation of FOXO3a

    PubMed Central

    JIANG, LING; CAO, XIAO-CHENG; CAO, JIAN-GUO; LIU, FEI; QUAN, MEI-FANG; SHENG, XI-FENG; REN, KAI-QUN

    2013-01-01

    Casticin, a polymethoxyflavone, is reported to have anticancer activities. The aim of the present study was to examine the molecular mechanisms by which casticin induces apoptosis in ovarian cancer cells. The human ovarian cancer cell lines SKOV3 and A2780 were cultured in vitro. Various molecular techniques, including histone/DNA enzyme-linked immunosorbent assay (ELISA), reverse transcription polymerase chain reaction (RT-PCR), western blot analysis and gene transfection, were used to assess the expression of FOXO3a and forkhead box protein M1 (FoxM1) in casticin-treated ovarian cancer cell lines. Casticin-induced apoptotic cell death was accompanied by the activation of transcription factor FOXO3a, with a concomitant decrease in the expression levels of FoxM1 and its downstream target factors, namely survivin and polo-like kinase 1 (PLK1), and an increase in p27KIP1. A small inhibitory RNA (siRNA) knockout of FoxM1 potentiated casticin-induced apoptosis in ovarian cancer cells. Silencing FOXO3a expression using siRNA increased FoxM1 expression levels and clearly attenuated the induction of apoptosis by casticin treatment. These results show that casticin-induced apoptosis in ovarian cancer may be caused by the activation of FOXO3a, leading to FoxM1 inhibition. PMID:23761826

  14. Aromatase activity in ovarian follicles of the golden hamster.

    PubMed

    Matson, P L; Collins, W P

    1984-09-01

    The aromatizing ability of recombined granulosa and thecal cells in culture, isolated from hamsters 72-78 h and 96-102 h after PMSG-stimulation, was assessed by the addition to the culture medium of androstenedione, testosterone, dehydroepiandrosterone (DHEA) or 5 alpha-dihydrotestosterone (DHT), and measuring the output of oestradiol 4 h later. The cells from all follicles taken after 96-102 h had a reduced oestradiol output compared to those isolated after 72-78 h (P less than 0.02). Recombined cells from the unluteinized follicles at 96-102 h (Group I) showed similar oestradiol output in the presence of androstenedione, testosterone and DHEA to the cells from follicles taken at 72-78 h. However, the recombined cells from the luteinized follicles (Group II) showed a reduced output of oestradiol in the presence of androstenedione, testosterone and DHEA when compared to the recombined cells from the previous period cultured with the corresponding C19 steroid. The results show that a reduced oestradiol output can be caused by (1) the reduced availability of aromatizable substrate and (2) a reduced potential aromatase activity. PMID:6471042

  15. High preoperative blood levels of HE4 predicts poor prognosis in patients with ovarian cancer

    PubMed Central

    2012-01-01

    Abstract The aim of this study was to assess the clinical value of preoperative blood levels of HE4 as a predictor of overall survival in patients with ovarian cancer and to validate previous data of HE4 and the ROMA algorithm including HE4 and CA125 in discriminating benign and malignant ovarian tumors. Experimental design The preoperative plasma levels of HE4 and CA125 were analyzed with ELISA in 312 patients with adnexal lesions. Tumors were classified as benign (n= 206), borderline (i.e. low malignant potential tumors) (n= 25), and well (n= 14), moderately (n= 15), and poorly (n= 51) differentiated malignant. Results In univariate Cox regression analyses high levels (dichotomized at the median) of HE4, CA125, increased age (continuous variable), advanced-stage of disease 2–4, histological grade 3 and non-optimal tumor debulking at primary surgery were all significantly associated with shorter overall survival. A multivariate Cox regression model including pre-operative available covariates HE4 and CA125 both dichotomized at median in addition to age as continuous variable showed that high levels of HE4 was an independent prognostic marker for worse prognosis HR 2.02 (95% CI 1.1-3.8). In postmenopausal women the ROMA algorithm gave the highest AUC of 0.94 (95% CI, 0.90-0.97) which was higher than the separate markers HE4 AUC 0.91 (95% CI 0.86-0.95) and CA125 AUC 0.91(95% CI 0.87-0.96). Conclusions High concentration of plasma HE4 is an independent preoperative marker of poor prognosis in patients with ovarian cancer. The algorithm ROMA discriminates in postmenopausal women between malignant and benign tumors with an AUC of 0.94. PMID:22909379

  16. Prediction of tumour response induced by chemotherapy using modelling of CA-125 kinetics in recurrent ovarian cancer patients

    PubMed Central

    Wilbaux, M; Hénin, E; Oza, A; Colomban, O; Pujade-Lauraine, E; Freyer, G; Tod, M; You, B

    2014-01-01

    Background: The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment. Methods: The data from the CALYPSO-randomised phase III trial, comparing two platinum-based regimens in recurrent ovarian cancer (ROC) patients, was randomly split into a ‘learning data set' to estimate model parameters and a ‘validation data set' to validate model performances. A kinetic–pharmacodynamic semi-mechanistic model was built to describe tumour size and CA-125 kinetics during chemotherapy. The ability of the model to predict tumour response induced by chemotherapy, based on CA-125 values, was assessed. Results: Data from 535 ROC patients were used to model CA-125 kinetics and tumour size changes during the first 513 days after treatment initiation. Using the validated model, we could predict with accuracy the tumour size changes induced by chemotherapy based on the baseline imaging assessment and longitudinal CA-125 values (mean prediction error: 0.3%, mean absolute prediction error: 10.6%). Conclusions: Using a semi-mechanistic model, the dynamic relationships between tumour size changes and CA-125 kinetics induced by chemotherapy were established in ROC patients. A modelling approach allowed CA-125 to be assessed as a biomarker for tumour size dynamics, to predict treatment efficacy for research and clinical purposes. PMID:24556626

  17. Transitory activation of the central and ovarian norepinephrine systems during cold stress-induced polycystic ovary in rats.

    PubMed

    Bernuci, M P; Leite, C M; Barros, P; Kalil, B; Leoni, G B; Del Bianco-Borges, B; Franci, C R; Szawka, R E; Lara, H E; Anselmo-Franci, J A

    2013-01-01

    Cold stress-induced ovarian sympathetic activation is associated with the development of ovarian cysts in rats. Although we have hypothesised that polycystic ovary (PCO) features induced by cold stress, as prevented by lesion of the noradrenergic nucleus locus coeruleus (LC), were a result of the increased activity of the ovarian norepinephrine (NE) system, this was not evident after 8 weeks of stress. In the present study, we investigated the temporal changes in LC and ovarian NE activities and steroid secretion in rats exposed to single (SS) or repeated (RS) cold stress. SS and 4 week (4W)-RS but not 8 week (8W)-RS increased c-Fos expression in the LC and ovarian NE release. Plasma oestradiol, testosterone and progesterone levels tended to increase in 4W-RS and were elevated in 8W-RS rats, which displayed PCO morphology. β-adrenergic receptor agonist increased steroid hormone release from the ovary of unstressed (US) but not from 8W-RS rats. To determine whether increased activity of noradrenergic system during the initial 4 weeks of RS would be sufficient to promote PCO, rats were exposed to 4 weeks of cold stress and kept in ambient temperature for the next 4 weeks (4W-RS/4W-US). Accordingly, PCO morphology, increased steroid secretion and decreased ovulation rate were found in 4W-RS/4W-US rats, strengthening the hypothesis that the initial increase in NE release triggers the development of PCO. The correlated activity of LC neurones and ovarian noradrenergic terminals and the induction of PCO in 4W-RS/4W-US rats provide functional evidence for a major role of NE in disrupting follicular development and causing the long-lasting endocrine abnormalities found in stress-induced PCO. PMID:22882492

  18. HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer.

    PubMed

    Stronach, Euan A; Alfraidi, Albandri; Rama, Nona; Datler, Christoph; Studd, James B; Agarwal, Roshan; Guney, Tankut G; Gourley, Charlie; Hennessy, Bryan T; Mills, Gordon B; Mai, Antonello; Brown, Robert; Dina, Roberto; Gabra, Hani

    2011-07-01

    Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests that resistant clones exist within a larger drug-sensitive cell population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically derived, intrapatient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 downregulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of histone deacetylase (HDAC) 4, FOLR2, PIK3R1, or STAT1 (P < 0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum-sensitive cells but not in HDAC4 overexpressing platinum-resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum-induced STAT1 activation, and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors [n = 7 of 16 (44%); P = 0.04]. Therefore, clinical selection of HDAC4-overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum

  19. HDAC4-regulated STAT1 activation mediates platinum resistance in ovarian cancer

    PubMed Central

    Stronach, Euan A; Alfraidi, Albandri; Rama, Nona; Datler, Christoph; Studd, Jamie; Agarwal, Roshan; Guney, Tankut G; Gourley, Charlie; Hennessy, Bryan T; Mills, Gordon B; Mai, Antonello; Brown, Robert; Dina, Roberto; Gabra, Hani

    2011-01-01

    Ovarian cancer frequently acquires resistance to platinum chemotherapy, representing a major challenge for improving patient survival. Recent work suggests resistant clones exist within a larger drug sensitive cell-population prior to chemotherapy, implying that resistance is selected for rather than generated by treatment. We sought to compare clinically-derived, intra-patient paired models of initial platinum response and subsequent resistant relapse to define molecular determinants of evolved resistance. Transcriptional analysis of a matched cell-line series from three patients with high-grade serous ovarian cancer before and after development of clinical platinum resistance (PEO1/PEO4/PEO6, PEA1/PEA2, PEO14/PEO23) identified 91 up- and 126 down-regulated genes common to acquired resistance. Significantly enhanced apoptotic response to platinum treatment in resistant cells was observed following knockdown of HDAC4, FOLR2, PIK3R1 or STAT1 (p<0.05). Interestingly, HDAC4 and STAT1 were found to physically interact. Acetyl-STAT1 was detected in platinum sensitive but not HDAC4 over-expressing platinum resistant cells from the same patient. In resistant cells, STAT1 phosphorylation/nuclear translocation was seen following platinum exposure, whereas silencing of HDAC4 increased acetyl-STAT1 levels, prevented platinum induced STAT1 activation and restored cisplatin sensitivity. Conversely, matched sensitive cells were refractory to STAT1 phosphorylation on platinum treatment. Analysis of 16 paired tumor biopsies taken before and after development of clinical platinum resistance showed significantly increased HDAC4 expression in resistant tumors (n=7/16[44%]; p=0.04). Therefore, clinical selection of HDAC4 overexpressing tumor cells upon exposure to chemotherapy promotes STAT1 deacetylation and cancer cell survival. Together, our findings identify HDAC4 as a novel, therapeutically tractable target to counter platinum resistance in ovarian cancer. PMID:21571862

  20. Effects of Sheng Hua Tang on Uterine Involution and Ovarian Activity in Postpartum Dairy Cows

    PubMed Central

    Lee, K. H.; Lee, Y. T.; Chen, T. C.; Yeh, C. C.; Chen, J. Y.; Liu, L. Y.; Chi, C. H.

    2013-01-01

    The effects of Sheng Hua Tang (SHT) on uterine involution and ovarian activity were investigated in postpartum dairy cows. SHT (70 g) was given to dairy cows (n = 10) to evaluate its effects for five days from the first postpartum day. Postpartum cows fed with a basal diet without SHT were used as the control group (n = 10). Ultrasounds and blood tests were recorded for four weeks from postpartum day seven with a 3-d interval. The results showed that the areas and diameters of endometria were significantly (p<0.01) reduced in the group that received SHT compared to the control group on the seventh postpartum day. The group that received SHT had an intrauterine fluid volume mean of 1.2±0.6 cm3, which was significantly lower than that of the control group, 2.3±0.8 cm3 (p<0.01) on the 13th postpartum day. In addition, the uterine tension score was a mean of 1.0±0.0 in the group that received SHT, which was also significantly lower than that of the control group, 1.5±0.5 (p<0.01) on the 19th postpartum day. Taken together, the Chinese herbal medicine remedy, SHT, promoted uterine involution and ovarian activity in postpartum dairy cows. PMID:25049906

  1. Glucocorticoids impair oocyte developmental potential by triggering apoptosis of ovarian cells via activating the Fas system

    PubMed Central

    Yuan, Hong-Jie; Han, Xiao; He, Nan; Wang, Guo-Liang; Gong, Shuai; Lin, Juan; Gao, Min; Tan, Jing-He

    2016-01-01

    Previous studies indicate that stress damages oocytes with increased secretion of glucorticoids. However, although injection of female mice with cortisol decreased oocyte competence, exposure of mouse oocytes directly to physiological or stress-induced concentrations of glucorticoids did not affect oocyte maturation and embryo development. This study has explored the mechanisms by which glucocorticoids impair oocyte competence. Female mice were injected with cortisol and the effects of cortisol-injection on oocyte competence, ovarian cell apoptosis and Fas/FasL activation were observed. The results showed that cortisol-injection decreased (a) oocyte developmental potential, (b) the E2/P4 ratio in serum and ovaries, and (c) expression of insulin-like growth factor 1, brain-derived neurotrophic factor and glucocorticoid receptor in mural granulosa cells (MGCs), while increasing levels of (a) cortisol in serum and ovaries, (b) apoptosis in MGCs and cumulus cells (CCs), (c) FasL secretion in ovaries and during oocyte maturation in vitro, and (d) Fas in MGCs, CCs and oocytes. The detrimental effects of cortisol-injection on oocyte competence and apoptosis of MGCs and CCs were significantly relieved when the gld (generalized lymphoproliferative disorder) mice harboring FasL mutations were observed. Together, the results suggested that glucocorticoids impair oocyte competence by triggering apoptosis of ovarian cells via activating the Fas system. PMID:27040909

  2. Glucocorticoids impair oocyte developmental potential by triggering apoptosis of ovarian cells via activating the Fas system.

    PubMed

    Yuan, Hong-Jie; Han, Xiao; He, Nan; Wang, Guo-Liang; Gong, Shuai; Lin, Juan; Gao, Min; Tan, Jing-He

    2016-01-01

    Previous studies indicate that stress damages oocytes with increased secretion of glucorticoids. However, although injection of female mice with cortisol decreased oocyte competence, exposure of mouse oocytes directly to physiological or stress-induced concentrations of glucorticoids did not affect oocyte maturation and embryo development. This study has explored the mechanisms by which glucocorticoids impair oocyte competence. Female mice were injected with cortisol and the effects of cortisol-injection on oocyte competence, ovarian cell apoptosis and Fas/FasL activation were observed. The results showed that cortisol-injection decreased (a) oocyte developmental potential, (b) the E2/P4 ratio in serum and ovaries, and (c) expression of insulin-like growth factor 1, brain-derived neurotrophic factor and glucocorticoid receptor in mural granulosa cells (MGCs), while increasing levels of (a) cortisol in serum and ovaries, (b) apoptosis in MGCs and cumulus cells (CCs), (c) FasL secretion in ovaries and during oocyte maturation in vitro, and (d) Fas in MGCs, CCs and oocytes. The detrimental effects of cortisol-injection on oocyte competence and apoptosis of MGCs and CCs were significantly relieved when the gld (generalized lymphoproliferative disorder) mice harboring FasL mutations were observed. Together, the results suggested that glucocorticoids impair oocyte competence by triggering apoptosis of ovarian cells via activating the Fas system. PMID:27040909

  3. Postmigratory body condition and ovarian steroid production predict breeding decisions by female gray-headed albatrosses.

    PubMed

    Crossin, Glenn T; Phillips, Richard A; Wynne-Edwards, Katherine E; Williams, Tony D

    2013-01-01

    Carryover effects have been documented in many migratory bird species, but we know little about the physiological mechanisms that mediate those effects. Here we show that the energetic, endocrine, and aerobic characteristics of postmigratory female gray-headed albatrosses (Thalassarche chrysostoma) can affect their decision to breed. All females in this study, whether breeding or not, were secreting ovarian steroids when they arrived at the breeding colony at Bird Island, South Georgia, which suggests that all were responding to seasonal cues. However, deferring, nonbreeding birds were characterized by a steroid profile of high progesterone (P4) and low testosterone (T), whereas breeding birds showed the opposite pattern. Deferring birds also had low body mass, hematocrit, and hemoglobin. These results suggest that postmigratory condition can influence patterns of ovarian steroidogenesis and that the maintenance of high P4 without subsequent conversion to T favors breeding deferral. Whereas breeding females normally convert P4 to T, which is a key deterministic step toward 17β-estradiol synthesis, vitellogenesis, and follicle development, deferring females did not make this conversion and instead maintained high levels of P4, perhaps due to inhibition of the hydroxylase-lyase enzyme complex, thus rendering them infertile for the current season. Results are discussed within the context of the biennial breeding system of this species, and comparisons with other biennially and annually breeding albatrosses are made. PMID:24241072

  4. ERCC1 and RRM1 as a predictive parameter for non-small cell lung, ovarian or pancreas cancer treated with cisplatin and/or gemcitabine

    PubMed Central

    Ulker, Mehmet; Sahin, Berksoy; Gumurdulu, Derya

    2015-01-01

    Background We aimed to investigate the impact of RRM1 and ERCC1 expression on response to cisplatin and/or gemcitabine chemotherapy in patients with lung, ovarian or pancreatic cancer. Material and methods Patients with lung, ovarian or pancreatic cancer, who used cisplatin and/or gemcitabine therapy were included; hospital files were examined and RRM1 and ERCC1 expression were evaluated with an immunohistochemical method on tissue cross sections from paraffin blocks of the tumour. Results Out of 89 patients, 51%, 30% and 19% had lung, ovarian and pancreatic cancer, respectively. The response rates to the therapy in patients with lung and ovarian cancer having low ERCC1 expression were 62% and 90%, respectively (p = 0.028 and p = 0.044, respectively). No significant association was found between ERCC1 expression and response to therapy in patients with pancreatic cancer (p = 0.354). Therapeutic response rates in patients with lung and pancreatic cancer with low RRM1 expression were 60% and 82%, respectively. Survival rates were higher in patients with lung cancer in which ERCC1 and RRM1 expressions were low. Median survival duration in patients with ovarian cancer showing low ERCC1 and RRM1 expressions was longer than that seen in patients with high expressions. Although no significant correlation was found between ERCC1 and the survival in ovarian cancer (p = 0.183), there was a significant correlation between RRM1 expression and survival in patients with pancreatic cancer (p = 0.005). Conclusions Our results suggest a predictive value of ERCC1 in lung and ovarian cancers, and also RRM1 in lung and pancreatic cancers. PMID:26557761

  5. Ovarian Cancer

    MedlinePlus

    ... deaths than other female reproductive cancers. The sooner ovarian cancer is found and treated, the better your chance for recovery. But ovarian cancer is hard to detect early. Women with ovarian ...

  6. Ovarian Cancer

    MedlinePlus

    Ovarian Cancer There are five main types of cancer that affect a woman’s reproductive organs: cervical, ovarian, uterine, ... rare fallopian tube cancer.) This fact sheet about ovarian cancer is part of the Centers for Disease Control ...

  7. Ovarian cysts

    MedlinePlus

    Physiologic ovarian cysts; Functional ovarian cysts; Corpus luteum cysts; Follicular cysts ... cyst often contains a small amount of blood. Ovarian cysts are more common in the childbearing years between ...

  8. A prospective study of leisure-time physical activity and risk of incident epithelial ovarian cancer: Impact by menopausal status.

    PubMed

    Huang, Tianyi; Eliassen, A Heather; Hankinson, Susan E; Okereke, Olivia I; Kubzansky, Laura D; Wang, Molin; Poole, Elizabeth M; Chavarro, Jorge E; Tworoger, Shelley S

    2016-02-15

    Despite multiple hypotheses for a protective effect, epidemiologic findings are inconsistent regarding the association between physical activity and risk of ovarian cancer. Considering physical activity assessment at different times of life, including pre- and postmenopause, may be important for explaining these discrepancies. Therefore, we examined the risk of ovarian cancer according to total, premenopausal and postmenopausal physical activity among 85,462 women from the Nurses' Health Study and 112,679 women from the Nurses' Health Study II. Leisure-time physical activity was prospectively assessed about every 2-4 years using validated questionnaires, and characterized as metabolic equivalent task hours per week (MET-hr/week), which combines exercise duration and intensity. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for these associations. We identified 815 incident epithelial ovarian cancer cases during 24 years of follow-up. A modestly increased ovarian cancer risk was observed for high levels of total cumulative average physical activity and a suggestively increased risk for low activity. Compared to 3-9 MET-hr/week, HRs (95% CIs) were 1.26 (1.02, 1.55) for ≥ 27 MET-hr/week (equivalent to 1 hr/day of brisk walking) and 1.19 (0.94, 1.52) for <3 MET-hr/week. This association was limited to premenopausal physical activity [comparable HR (95% CI) of 1.50 (1.13, 1.97) and 1.29 (0.95, 1.75), respectively]. Postmenopausal physical activity was not associated with risk. Our data do not support a protective role of physical activity for ovarian cancer. The increased risk associated with physical activity during premenopausal years and the underlying etiology require further investigation. PMID:26335147

  9. A photobleaching-based PDT dose metric predicts PDT efficacy over certain BPD concentration ranges in a three-dimensional model of ovarian cancer

    NASA Astrophysics Data System (ADS)

    Anbil, S.; Rizvi, I.; Celli, J. P.; Alagic, N.; Hasan, T.

    2013-03-01

    Photodynamic therapy (PDT) dosimetry is an active area of study that is motivated by the need to reliably predict treatment outcomes. Implicit dosimetric parameters, such as photosensitizer (PS) photobleaching, may indicate PDT efficacy and could establish a framework to provide patient-customized PDT. Here, tumor destruction and benzoporphryin-derivative (BPD) photobleaching are characterized by systematically varying BPD-light combinations to achieve fixed PDT doses (M * J * cm-2) in a three-dimensional (3D) model of micrometastatic ovarian cancer (OvCa). It is observed that the BPD-light parameters used to construct a given PDT dose significantly impact nodule viability and BPD photobleaching. As a result, PDT dose, when measured by the product of BPD concentration and fluence, does not reliably predict overall efficacy. A PDT dose metric that incorporates a term for BPD photobleaching more robustly predicts PDT efficacy at low concentrations of BPD. These results suggest that PDT dose metrics that are informed by implicit approaches to dosimetry could improve the reliability of PDT-based regimens and provide opportunities for patient-specific treatment planning.

  10. The role of HE4 for prediction of recurrence in epithelial ovarian cancer patients-results from the OVCAD study.

    PubMed

    Nassir, Mani; Guan, Jun; Luketina, Hrvoje; Siepmann, Timo; Rohr, Irena; Richter, Rolf; Castillo-Tong, Dan Cacsire; Zeillinger, Robert; Vergote, Ignace; Van Nieuwenhuysen, Els; Concin, Nicole; Marth, Christian; Hall, Christina; Mahner, Sven; Woelber, Linn; Sehouli, Jalid; Braicu, Elena Ioana

    2016-03-01

    Patients with epithelial ovarian cancer (EOC) are at high risk of tumor recurrence. Human epididymis protein 4 (HE4) has been shown to be overexpressed in EOC. The primary aim of our study was to evaluate the role of HE4 in predicting recurrence in EOC patients. Furthermore, we assessed the role of HE4 in predicting recurrence after second-line chemotherapy. We retrospectively analyzed data of 92 out of 275 primary EOC patients of the multicenter project "Ovarian Cancer: Diagnosis of a silent killer" (OVCAD). The concentrations of HE4 and CA125 were determined preoperatively and 6 months after the end of platinum-based first-line chemotherapy (FU) using ELISA and Luminex technique, respectively. The role of HE4 and CA125 for prediction of recurrence was determined using receiver operating characteristics (ROC) curves. Out of 92 patients included, 70 (76 %) were responders and 22 (23 %) non-responders in terms of response to platinum-based first-line chemotherapy. Median HE4 concentrations at follow-up (FU) differed between responders and non-responders (60.5 vs. 237.25 pM, p = 0.0001), respectively. The combined use of HE4 and CA125 at FU with cut-off values of 49.5 pM and 25 U/ml for HE4 and CA125, respectively, for predicting recurrence within 12 months after first-line chemotherapy performed better than HE4 or CA125 alone (area under the curve (AUC) 0.928, 95 % confidence intervals (CI) 0.838-1, p < 0.001). HE4 at FU could predict recurrence within 6 months after second-line chemotherapy (AUC 0.719, 95 % CI 0.553-0.885, p = 0.024). The combination of both elevated biomarkers revealed significantly worse estimated median progression-free survival (PFS; hazard ratio (HR) 8.14, 95 % CI 3.75-17.68, p < 0.001) and slightly worse PFS in those in whom only one biomarker was elevated (HR 1.46, 95 % CI 0.72-2.96, p = 0.292) compared to those patients in whom no biomarker was elevated. For the estimated median overall survival (OS), our

  11. Aurora Kinase A expression predicts platinum-resistance and adverse outcome in high-grade serous ovarian carcinoma patients.

    PubMed

    Mignogna, Chiara; Staropoli, Nicoletta; Botta, Cirino; De Marco, Carmela; Rizzuto, Antonia; Morelli, Michele; Di Cello, Annalisa; Franco, Renato; Camastra, Caterina; Presta, Ivan; Malara, Natalia; Salvino, Angela; Tassone, Pierfrancesco; Tagliaferri, Pierosandro; Barni, Tullio; Donato, Giuseppe; Di Vito, Anna

    2016-01-01

    High-Grade Serous Ovarian Carcinoma (HGSOC) is the predominant histotype of epithelial ovarian cancer (EOC), characterized by advanced stage at diagnosis, frequent TP53 mutation, rapid progression, and high responsiveness to platinum-based-chemotherapy. To date, standard first-line-chemotherapy in advanced EOC includes platinum salts and paclitaxel with or without bevacizumab. The major prognostic factor is the response duration from the end of the platinum-based treatment (platinum-free interval) and about 10-0 % of EOC patients bear a platinum-refractory disease or develop early resistance (platinum-free interval shorter than 6 months). On these bases, a careful selection of patients who could benefit from chemotherapy is recommended to avoid unnecessary side effects and for a better disease outcome. In this retrospective study, an immunohistochemical evaluation of Aurora Kinase A (AURKA) was performed on 41 cases of HGSOC according to platinum-status. Taking into account the number and intensity of AURKA positive cells we built a predictive score able to discriminate with high accuracy platinum-sensitive patients from platinum-resistant patients (p < 0.001). Furthermore, we observed that AURKA overexpression correlates to worse overall survival (p = 0.001; HR 0.14). We here suggest AURKA as new effective tool to predict the biological behavior of HGSOC. Particularly, our results indicate that AURKA has a role both as predictor of platinum-resistance and as prognostic factor, that deserves further investigation in prospective clinical trials. Indeed, in the era of personalized medicine, AURKA could assist the clinicians in selecting the best treatment and represent, at the same time, a promising new therapeutic target in EOC treatment. PMID:27209210

  12. AKT activation drives the nuclear localization of CSE1L and a pro-oncogenic transcriptional activation in ovarian cancer cells

    SciTech Connect

    Lorenzato, Annalisa; Biolatti, Marta; Delogu, Giuseppe; Capobianco, Giampiero; Farace, Cristiano; Dessole, Salvatore; Cossu, Antonio; Tanda, Francesco; Madeddu, Roberto; Olivero, Martina; Di Renzo, Maria Flavia

    2013-10-15

    The human homolog of the yeast cse1 gene (CSE1L) is over-expressed in ovarian cancer. CSE1L forms complex with Ran and importin-α and has roles in nucleocytoplasmic traffic and gene expression. CSE1L accumulated in the nucleus of ovarian cancer cell lines, while it was localized also in the cytoplasm of other cancer cell lines. Nuclear localization depended on AKT, which was constitutively active in ovarian cancer cells, as the CSE1L protein translocated to the cytoplasm when AKT was inactivated. Moreover, the expression of a constitutively active AKT forced the translocation of CSE1L from the cytoplasm to the nucleus in other cancer cells. Nuclear accrual of CSE1L was associated to the nuclear accumulation of the phosphorylated Ran Binding protein 3 (RanBP3), which depended on AKT as well. Also in samples of human ovarian cancer, AKT activation was associated to nuclear accumulation of CSE1L and phosphorylation of RanBP3. Expression profiling of ovarian cancer cells after CSE1L silencing showed that CSE1L was required for the expression of genes promoting invasion and metastasis. In agreement, CSE1L silencing impaired motility and invasiveness of ovarian cancer cells. Altogether these data show that in ovarian cancer cells activated AKT by affecting RanBP3 phosphorylation determines the nuclear accumulation of CSE1L and likely the nuclear concentration of transcription factors conveying pro-oncogenic signals. - highlights: • CSE1L is a key player in nucleocytoplasmic traffic by forming complex with Ran. • AKT phosphorylates RanBP3 that regulates the nucleocytoplasmic gradient of Ran. • The activated oncogenic AKT drives the nuclear accumulation of CSE1L. • CSE1L in the nucleus up-regulates genes conveying pro-oncogenic signals. • CSE1L might contribute to tumor progression driven by the activated oncogenic AKT.

  13. Usefulness of human epididymis protein 4 in predicting cytoreductive surgical outcomes for advanced ovarian tubal and peritoneal carcinoma

    PubMed Central

    Tang, Zhijian; Chang, Xiaohong; Ye, Xue; Li, Yi; Cheng, Hongyan

    2015-01-01

    Objective Human epididymis protein 4 (HE4) is a promising biomarker of epithelial ovarian cancer (EOC). But its role in assessing the primary optimal debulking (OD) of EOC remains unknown. The purpose of this study is to elucidate the ability of preoperative HE4 in predicting the primary cytoreductive outcomes in advanced EOC, tubal or peritoneal carcinoma. Methods We reviewed the records of 90 patients with advanced ovarian, tubal or peritoneal carcinoma who underwent primary cytoreduction at the Department of Obstetrics and Gynecology of Peking University People’s Hospital between November 2005 and October 2010. Preoperative serum HE4 and CA125 levels were detected with EIA kit. A receiver operating characteristic (ROC) curve was used to determine the most useful HE4 cut-off value. Logistic regression analysis was performed to identify significant preoperative clinical characteristics to predict optimal primary cytoreduction. Results OD was achieved in 47.7% (43/48) of patients. The median preoperative HE4 level for patients with OD vs. suboptimal debulking was 423 and 820 pmol/L, respectively (P<0.001). The areas under the ROC curve for HE4 and CA125 were 0.716 and 0.599, respectively (P=0.080). The most useful HE4 cut-off value was 473 pmol/L. Suboptimal cytoreduction was obtained in 66.7% (38/57) of cases with HE4 ≥473 pmol/L compared with only 27.3% (9/33) of cases with HE4 <473 pmol/L. At this threshold, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for diagnosing suboptimal debulking were 81%, 56%, 67%, and 73%, respectively. Logistic regression analysis showed that the patients with HE4 ≥473 pmol/L were less likely to achieve OD (odds ratio =5.044, P=0.002). Conclusions Preoperative serum HE4 may be helpful to predict whether optimal cytoreductive surgery could be obtained or whether extended cytoreduction would be needed by an interdisciplinary team. PMID:26157328

  14. Immunohistochemical expression of MMP-14 and MMP-2, and MMP-2 activity during human ovarian follicular development

    PubMed Central

    2014-01-01

    Background The aim of this study was to investigate the presence of MMP-14 and MMP-2 during human ovarian follicular development using immunohistochemistry, and the activity of MMP-2 in follicular fluid using zymography. Methods Ovarian tissue collected from the archives of the Department of Pathology was examined and medical records and histopathology were reviewed. Follicular fluids were collected at the IVF-department and analyzed using zymography. Results MMP-14 and MMP-2 were increasingly found in the growing follicles and MMP-2 was highly expressed in the corpus luteum. Pro-MMP-2 was present in follicular fluid of IVF-patients. Conclusions The presence of MMP-14 and MMP-2 during human ovarian follicular development from the primordial follicle to the tertiary follicle and corpus luteum is confirmed, as was indicated by earlier animal studies following stimulation with gonadotrophins. PMID:24485069

  15. STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer

    PubMed Central

    Permuth-Wey, Jennifer; Fulp, William J.; Reid, Brett M.; Chen, Zhihua; Georgeades, Christina; Cheng, Jin Q.; Magliocco, Anthony; Chen, Dung-Tsa; Lancaster, Johnathan M.

    2016-01-01

    Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case–control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. “Cases” included 102 incomplete responders (IRs) and “controls” included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r2 > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32–3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML 5 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors. PMID:26264211

  16. STAT3 polymorphisms may predict an unfavorable response to first-line platinum-based therapy for women with advanced serous epithelial ovarian cancer.

    PubMed

    Permuth-Wey, Jennifer; Fulp, William J; Reid, Brett M; Chen, Zhihua; Georgeades, Christina; Cheng, Jin Q; Magliocco, Anthony; Chen, Dung-Tsa; Lancaster, Johnathan M

    2016-02-01

    Cancer stem cells (CSC) contribute to epithelial ovarian cancer (EOC) progression and therapeutic response. We hypothesized that germline single nucleotide polymorphisms (SNPs) in CSC-related genes may predict an initial therapeutic response for women newly diagnosed with EOC. A nested case-control design was used to study 361 women with advanced-stage serous EOC treated with surgery followed by first-line platinum-based combination therapy at Moffitt Cancer Center or as part of The Cancer Genome Atlas Study. "Cases" included 102 incomplete responders (IRs) and "controls" included 259 complete clinical responders (CRs) to therapy. Using Illumina genotyping arrays and imputation, DNA samples were evaluated for 5,509 SNPs in 24 ovarian CSC-related genes. We also evaluated the overall significance of each CSC gene using the admixture maximum likelihood (AML) test, and correlated genotype with EOC tumor tissue expression. The strongest SNP-level associations with an IR to therapy were identified for correlated (r(2) > 0.80) SNPs within signal transducer and activator of transcription 3 (STAT3) [odds ratio (OR), 2.24; 95% confidence interval (CI), 1.32-3.78; p = 0.0027], after adjustment for age, population stratification, grade and residual disease. At the gene level, STAT3 was significantly associated with an IR to therapy (pAML = 0.006). rs1053004, a STAT3 SNP in a putative miRNA-binding site, was associated with STAT3 expression (p = 0.057). This is the first study to identify germline STAT3 variants as independent predictors of an unfavorable therapeutic response for EOC patients. Findings suggest that STAT3 genotype may identify high-risk women likely to respond more favorably to novel therapeutic combinations that include STAT3 inhibitors. PMID:26264211

  17. Down-regulation of telomerase activity by anticancer drugs in human ovarian cancer cells.

    PubMed

    Kunifuji, Yasumasa; Gotoh, Sadao; Abe, Tetsuya; Miura, Masayoshi; Karasaki, Yuji

    2002-07-01

    Maintenance of telomere length is crucial for survival of cells. Telomerase, an enzyme that is responsible for elongation of shortened telomeres, is active in human germ cells as well as most tumor tissues and experimentally immortalized cells. In contrast, most mature somatic cells in human tissues express undetectable or low telomerase activity, implying the existence of a stringent and negative regulatory mechanism. In this study we report the effects of anticancer drugs on telomerase activity in human cancer cells. In assaying for telomerase activity, we basically followed the original TRAP assay system, but with some modifications. A down-regulation of telomerase activity was found when cells of a human ovarian cancer cell line, A2780, were treated with;cis-diamminedichloroplatinum(II) (CDDP; cisplatin). However, down-regulation of telomerase activity was not found in cells of a cisplatin-resistant cell line, A2780CP, treated with cisplatin. On the other hand, telomerase activity in both the cell lines A2780 and A2780CP was reduced when A2780 or A2780CP was treated with adriamycin, an anthracycline antibiotic having a broad spectrum of antineoplastic activity. The different effects on the telomerase activity of the two types of anticancer drugs may be due the distinct chemical functions of these drugs. The present results may indicate a positive relationship between anticancer effects and down-regulation of telomerase activity by anticancer drugs. PMID:12172504

  18. TLR4 activates NF-{kappa}B in human ovarian granulosa tumor cells

    SciTech Connect

    Woods, Dori C.; Johnson, A.L.

    2011-06-17

    Highlights: {yields} TLR4 is expressed in human ovarian granulosa tumor cells. {yields} Acting through TLR4, LPS and HSP60 induce a NF{kappa}B signaling cascade in human ovarian granulosa tumor cells. {yields} NF{kappa}B activation or inhibition did not alter chemosensitivity to TRAIL or cisplatin. -- Abstract: Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-{kappa}B) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to I{kappa}B degradation and activation of NF-{kappa}B. NF-{kappa}B activation was confirmed by nuclear localization of NF-{kappa}B p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-{kappa}B signaling attenuated LPS-induced TNF{alpha} plus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-{kappa}B signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-{kappa}B does not sensitize GCTs to TRAIL or cisplatin.

  19. Photodynamic action of LED-activated pyropheophorbide-α methyl ester in cisplatin-resistant human ovarian carcinoma cells

    NASA Astrophysics Data System (ADS)

    Tan, Y.; Xu, C. S.; Xia, X. S.; Yu, H. P.; Bai, D. Q.; He, Y.; Leung, A. W. N.

    2009-04-01

    Cisplatin-resistance is a major obstacle for the successful therapy to ovarian cancer, and exploring novel approach to deactivate cisplatin-resistant ovarian cells will improve the clinical outcomes. Our present study showed that there was no dark cytotoxicity of MPPa in the COC1/DDP cells at the dose of 0.25 - 4 μM, and LED-activated MPPa resulted in drug dose- and light-dependent cytotoxicity. Apoptotic rate 6 h after LED-activated MPPa (2 μM) increased to 16.71% under the light energy of 1 J/cm2. Confocal laser scanning microscopy showed that MPPa mainly localized in the intracellular membrane system, namely the endoplasmic reticulum, Golgi apparatus, lysosomes and mitochondria in the COC1/DDP cells. Mitochondrial membrane potential (ΔΨm) was collapsed when COC1/DDP cells were exposed to 2 μM MPPa for 20 h and then 1 J/cm2 irradiation of LED source. These data demonstrated that LED-activated MPPa significantly deactivated cisplatin-resistant ovarian cell line COC1/DDP cells and enhanced apoptosis and decreased ΔΨm, which suggests LED is an efficient light source for PDT and LED-activated MPPa can be developed as new modality for treating cisplatin-resistant ovarian.

  20. Solar activity predicted with artificial intelligence

    NASA Astrophysics Data System (ADS)

    Lundstedt, Henrik

    The variability of solar activity has been described as a non-linear chaotic dynamic system. AI methods are therefore especially suitable for modelling and predicting solar activity. Many indicators of the solar activity have been used, such as sunspot numbers, F 10.7 cm solar radio flux, X-ray flux, and magnetic field data. Artificial neural networks have also been used by many authors to predict solar cycle activity. Such predictions will be discussed. A new attempt to predict the solar activity using SOHO/MDI high-time resolution solar magnetic field data is discussed. The purpose of this new attempt is to be able to predict episodic events and to predict occurrence of coronal mass ejections. These predictions will be a part of the Lund Space Weather Model.

  1. Use of CA125 and HE4 serum markers to predict ovarian cancer in elevated-risk women

    PubMed Central

    Karlan, Beth Y.; Thorpe, Jason; Watabayashi, Kate; Drescher, Charles W.; Palomares, Melanie; Daly, Mary B.; Paley, Pam; Hillard, Paula; Andersen, M Robyn; Anderson, Garnet; Drapkin, Ronny; Urban, Nicole

    2014-01-01

    Background Serum markers are used prior to pelvic imaging to improve specificity and positive predictive value (PPV) of ovarian cancer multimodal screening strategies. Methods We conducted a randomized controlled pilot trial to estimate surgical PPV of a “2 of 3 tests positive” screening rule, and to compare use of HE4 as a 1st-line (Arm 1) vs. a 2nd-line (Arm 2) screen, in women at high and elevated risk for EOC at five study sites. Semi-annual screening was offered to 208 women aged 25-80 with deleterious BRCA germ-line mutations, and to 834 women aged 35-80 with pedigrees suggesting inherited susceptibility. Annual screening was offered to 130 women aged 45-80 (Risk Group 3) with epidemiologic and serum marker risk factors. Rising marker levels were identified using the parametric empirical Bayes algorithm. Results Both strategies yielded surgical PPV above 25%. Protocol-indicated surgery was performed in six women, identifying two ovarian malignancies and yielding a surgical PPV in both arms combined of 33% (95% CI: 4%-78%), 25% in Arm 1 and 50% in Arm 2. Surgical consultation was recommended for 37 women (26 in Arm 1, 11 in Arm 2). Based on 12 women with at least 2 of 3 tests positive (CA125, HE4 or imaging), an intent-to-treat analysis yielded PPV of 14% in Arm 1 and 20% in Arm 2. Conclusions Positive screens were more frequent when HE4 was included in the primary screen. Impact. HE4 may be useful as a confirmatory screen when rising CA125 is used alone as a primary screen. PMID:24789859

  2. Aberrant DNA Damage Response Pathways May Predict the Outcome of Platinum Chemotherapy in Ovarian Cancer

    PubMed Central

    Stefanou, Dimitra T.; Bamias, Aristotelis; Episkopou, Hara; Kyrtopoulos, Soterios A.; Likka, Maria; Kalampokas, Theodore; Photiou, Stylianos; Gavalas, Nikos; Sfikakis, Petros P.; Dimopoulos, Meletios A.; Souliotis, Vassilis L.

    2015-01-01

    Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Despite the advances in the treatment of OC with combinatorial regimens, including surgery and platinum-based chemotherapy, patients generally exhibit poor prognosis due to high chemotherapy resistance. Herein, we tested the hypothesis that DNA damage response (DDR) pathways are involved in resistance of OC patients to platinum chemotherapy. Selected DDR signals were evaluated in two human ovarian carcinoma cell lines, one sensitive (A2780) and one resistant (A2780/C30) to platinum treatment as well as in peripheral blood mononuclear cells (PBMCs) from OC patients, sensitive (n = 7) or resistant (n = 4) to subsequent chemotherapy. PBMCs from healthy volunteers (n = 9) were studied in parallel. DNA damage was evaluated by immunofluorescence γH2AX staining and comet assay. Higher levels of intrinsic DNA damage were found in A2780 than in A2780/C30 cells. Moreover, the intrinsic DNA damage levels were significantly higher in OC patients relative to healthy volunteers, as well as in platinum-sensitive patients relative to platinum-resistant ones (all P<0.05). Following carboplatin treatment, A2780 cells showed lower DNA repair efficiency than A2780/C30 cells. Also, following carboplatin treatment of PBMCs ex vivo, the DNA repair efficiency was significantly higher in healthy volunteers than in platinum-resistant patients and lowest in platinum-sensitive ones (t1/2 for loss of γH2AX foci: 2.7±0.5h, 8.8±1.9h and 15.4±3.2h, respectively; using comet assay, t1/2 of platinum-induced damage repair: 4.8±1.4h, 12.9±1.9h and 21.4±2.6h, respectively; all P<0.03). Additionally, the carboplatin-induced apoptosis rate was higher in A2780 than in A2780/C30 cells. In PBMCs, apoptosis rates were inversely correlated with DNA repair efficiencies of these cells, being significantly higher in platinum-sensitive than in platinum-resistant patients and lowest in healthy volunteers (all P<0.05). We conclude that

  3. Wnt ligands regulate Tkv expression to constrain Dpp activity in the Drosophila ovarian stem cell niche

    PubMed Central

    Luo, Lichao; Wang, Huashan; Fan, Chao; Liu, Sen

    2015-01-01

    Stem cell self-renewal versus differentiation is regulated by the niche, which provides localized molecules that favor self-renewal. In the Drosophila melanogaster female germline stem cell (GSC) niche, Decapentaplegic (Dpp), a fly transforming growth factor β molecule and well-established long-range morphogen, acts over one cell diameter to maintain the GSCs. Here, we show that Thickveins (Tkv; a type I receptor of Dpp) is highly expressed in stromal cells next to Dpp-producing cells and functions to remove excess Dpp outside the niche, thereby spatially restricting its activity. Interestingly, Tkv expression in these stromal cells is regulated by multiple Wnt ligands that are produced by the niche. Our data demonstrate a self-restraining mechanism by which the Drosophila ovarian GSC niche acts to define its own boundary. PMID:26008746

  4. Delivery of siRNA to ovarian cancer cells using laser-activated carbon nanoparticles

    PubMed Central

    Sengupta, Aritra; Mezencev, Roman; McDonald, John F; Prausnitz, Mark R

    2015-01-01

    Aim The RNAi-mediated knockdown of gene expression is an attractive tool for research and therapeutic purposes but its implementation is challenging. Here we report on a new method based on photoacoustic delivery of siRNA developed to address some of these challenges. Materials & methods Physical properties and photoacoustic emission of carbon black (CB) particles upon near-infrared laser irradiation were characterized. Next, ovarian cancer cells Hey A8-F8 were exposed to near-infrared nanosecond laser pulses in the presence of siRNA targeting EGFR gene and CB particles. The intracellular delivery of siRNA and silencing of the target gene were determined by specific qPCR assays. Results & conclusion Laser-activated CB nanoparticles generated photoacoustic emission and enabled intracellular delivery of siRNA and significant knockdown of its target EGFR mRNA. This physical method represents a new promising approach to targeted therapeutic delivery of siRNA. PMID:26080699

  5. Phenotypes of the ovarian follicular basal lamina predict developmental competence of oocytes

    PubMed Central

    Irving-Rodgers, Helen F.; Morris, Stephanie; Collett, Rachael A.; Peura, Teija T.; Davy, Margaret; Thompson, Jeremy G.; Mason, Helen D.; Rodgers, Raymond J.

    2009-01-01

    BACKGROUND The ovarian follicular basal lamina underlies the epithelial membrana granulosa and maintains the avascular intra-follicular compartment. Additional layers of basal lamina occur in a number of pathologies, including pili annulati and diabetes. We previously found additional layers of follicular basal lamina in a significant percentage of healthy bovine follicles. We wished to determine if this phenomenon existed in humans, and if it was related to oocyte function in the bovine. METHODS AND RESULTS We examined follicles from human ovaries (n = 18) by electron microscopy and found that many follicles had additional layers of basal lamina. Oocytes (n = 222) from bovine follicles with normal or unusual basal laminas were isolated and their ability to undergo in vitro maturation, fertilization and culture to blastocyst was compared. Healthy bovine follicles with a single layer of basal lamina had oocytes with significantly (P < 0.01) greater developmental competence than healthy follicles with additional layers of follicular basal lamina (65% versus 28%). CONCLUSIONS These findings provide direct evidence that the phenotype of the follicular basal lamina is related to oocyte competence. PMID:19095662

  6. Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma

    PubMed Central

    Bao, Ling-Jie; Jaramillo, Melba C; Zhang, Zhen-Bo; Zheng, Yun-Xi; Yao, Ming; Zhang, Donna D; Yi, Xiao-Fang

    2014-01-01

    Cisplatin resistance is a major problem affecting ovarian carcinoma treatment. NF-E2-related factor 2 (Nrf2), a nuclear transcription factor, plays an important role in chemotherapy resistance. However, the underlying mechanism by which Nrf2 mediates cisplatin chemoresistance is unclear. Methods: The human ovarian carcinoma cell line, A2780, and its cisplatin-resistant variant, A2780cp were cultivated. Cell viability was determined with WST-8 assay. Western blot was applied to detect the expression of Nrf2, Nrf2 target genes, and autophagy-related proteins. RNA interference was used to knock down target genes. Annexin V and propidium iodide (PI) staining was utilized to quantify apoptosis. The ultrastructural analysis of autophagosomes was performed by transmission electron microscopy (TEM). Results: Nrf2 and its targeting genes, NQO1 and HO-1, are overexpressed in A2780cp cells compared with A2780 cells. Knocking down Nrf2 sensitized A2780cp cells to cisplatin treatment and decreased autophagy-related genes, Atg3, Atg6, Atg12 and p62 in both mRNA and protein levels. Furthermore, we demonstrated that in both cell lines cisplatin could induce the formation of autophagosomes and upregulate the expression of autophagy-related genes Atg3, Atg6 and Atg12. Treatment with an autophagy inhibitor, 3-Methyladenine (3-MA), or beclin 1 siRNA enhanced cisplatin-induced cell death in A2780cp cells, suggesting that inhibition of autophagy renders resistant cells to be more sensitive to cisplatin. Taken together, Nrf2 signaling may regulate cisplatin resistance by activating autophagy. Conclusions: Nrf2-activated autophagy may function as a novel mechanism causing cisplatin-resistance. PMID:24817946

  7. Assessment of ovarian activity in captive goral (Naemorhedus griseus) using noninvasive fecal steroid monitoring.

    PubMed

    Khonmee, Jaruwan; Brown, Janine L; Taya, Kazuyoshi; Rojanasthien, Suvichai; Punyapornwithaya, Veerasak; Thumasanukul, Dissakul; Kongphoemphun, Adisorn; Siriaroonrat, Boripat; Tipkantha, Wanlaya; Pongpiachan, Petai; Thitaram, Chatchote

    2014-10-15

    To date, there is no information on gonadal steroidogenic activity of female goral (Naemorhedus griseus), a threatened species of Thailand. Captive goral populations have been established to produce animals for ex situ conservation and reintroduction, but as yet none are self-sustaining. The objectives of the present study were to (1) determine the influence of season on ovarian steriodogenic function; and (2) examine the relationship between gonadal hormone excretion and sexual behaviors throughout the year. Fecal samples were collected 5 to 7 days/wk for 15 months from 8 adult females housed at Omkoi Wildlife Breeding Center in Thailand and analyzed for ovarian steroid metabolites using validated enzyme immunoassays. Observations of sexual behaviors and mating were conducted each morning for 30 min/session. Based on fecal estrogen and progestagen metabolite concentrations, the overall estrous cycle length was about 21 days, with a 2- to 3-day follicular phase and an 18- to 20-day luteal phase. Sexual behaviors, most notably tail-up, increased for 2 to 3 days during the time estrogens were elevated during mating. Fecal progestagens were elevated during luteal phases and increased further during gestation, which lasted approximately 7 months. The lactation period was 5 months, and females were anestrus for 2 to 5 of those months, with the exception of one that cycled continuously throughout. Two females conceived around 2 months postpartum and so were pregnant during lactation. Birth records over the past 21 years indicated young are born throughout the year. This combined with the hormonal data suggests that female gorals are not strongly seasonal, at least in captivity, although there was considerable variation among females in estrogen and progestagen patterns. In conclusion, fecal steroid metabolite monitoring is an effective means of assessing ovarian function in this species and will be a useful tool for breeding management and planned development of

  8. Methylseleninic acid sensitizes Notch3-activated OVCA429 ovarian cancer cells to carboplatin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Ovarian cancer, the deadliest of gynecologic cancers, is usually diagnosed at advanced stage due to invalidated screening test and non-specific symptoms presented. Although carboplatin has been popular for treating ovarian cancer for decades, patients eventually develop resistance to this platinum-c...

  9. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression

    PubMed Central

    Ward, Kristy K.; Tancioni, Isabelle; Lawson, Christine; Miller, Nichol L.G.; Jean, Christine; Chen, Xiao Lei; Uryu, Sean; Kim, Josephine; Tarin, David; Stupack, Dwayne G.; Plaxe, Steven C.; Schlaepfer, David D.

    2013-01-01

    Recurrence and spread of ovarian cancer is the 5th leading cause of death for women in the United States. Focal adhesion kinase (FAK) is a cytoplasmic protein-tyrosine kinase located on chromosome 8q24.3 (gene is Ptk2), a site commonly amplified in serous ovarian cancer. Elevated FAK mRNA levels in serous ovarian carcinoma are associated with decreased (logrank P = 0.0007, hazard ratio 1.43) patient overall survival, but how FAK functions in tumor progression remains undefined. We have isolated aggressive ovarian carcinoma cells termed ID8-IP after intraperitoneal (IP) growth of murine ID8 cells in C57Bl6 mice. Upon orthotopic implantation within the periovarian bursa space, ID8-IP cells exhibit greater tumor growth, local and distant metastasis, and elevated numbers of ascites-associated cells compared to parental ID8 cells. ID8-IP cells exhibit enhanced growth under non-adherent conditions with elevated FAK and c-Src tyrosine kinase activation compared to parental ID8 cells. In vitro, the small molecule FAK inhibitor (Pfizer, PF562,271, PF-271) at 0.1 uM selectively prevented anchorage-independent ID8-IP cell growth with the inhibition of FAK tyrosine (Y)397 but not c-Src Y416 phosphorylation. Oral PF-271 administration (30 mg/kg, twice daily) blocked FAK but not c-Src tyrosine phosphorylation in ID8-IP tumors. This was associated with decreased tumor size, prevention of peritoneal metastasis, reduced tumor-associated endothelial cell number, and increased tumor cell-associated apoptosis. FAK knockdown and re-expression assays showed that FAK activity selectively promoted anchorage-independent ID8-IP cell survival. These results support the continued evaluation of FAK inhibitors as a promising clinical treatment for ovarian cancer. PMID:23275034

  10. Rosiglitazone stimulates peroxisome proliferator-activated receptor gamma expression and directly affects in vitro steroidogenesis in porcine ovarian follicles.

    PubMed

    Rak-Mardyła, Agnieszka; Karpeta, Anna

    2014-07-01

    Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) synthetic activator from the group of thiazolidinediones often used in the treatment of chronic diseases such as type 2 diabetes and other forms of insulin resistance. The present in vitro study assessed the direct effects of rosiglitazone at 25 and 50 μM doses on PPARγ gene expression, steroid secretion (progesterone [P4], androstenedione [A4], testosterone [T], and estradiol), and protein expression of PPARγ, 3βHSD, CYP17, 17βHSD, CYP19 by porcine ovarian follicles from prepubertal and cycling animals. We analyzed also steroid enzymatic activity by conversion of pregnen-3β-ol-20-one to P4, P4 to A4, and A4 to T. Our results indicated that rosiglitazone increased significantly PPARγ expression, P4 secretion, 3βHSD activity, and protein expression. Rosiglitazone decreased A4 and T secretion by reducing the expression and activity of CYP17 and 17βHSD and did not change estradiol secretion and CYP19. Similarly results was observed both in prepubertal and cycling pigs. Our results indicate that these direct effects of rosiglitazone on ovarian steroidogenesis provide a framework for testing several potential new mechanisms of PPAR-γ actions on porcine ovarian function. PMID:24681211

  11. Integrin-linked kinase activity modulates the pro-metastatic behavior of ovarian cancer cells

    PubMed Central

    Bruney, Lana; Liu, Yueying; Grisoli, Anne; Ravosa, Matthew J.; Stack, M. Sharon

    2016-01-01

    Epithelial ovarian cancer (EOC) is the most fatal gynecologic cancer in the U.S., resulting in >14,000 deaths/year. Most women are diagnosed at late stage with widely disseminated intra-peritoneal metastatic disease, resulting in a 5-year survival rate of <30%. EOCs spread via direct extension and exfoliation into the peritoneal cavity, adhesion to peritoneal mesothelial cells, mesothelial cell retraction to expose sub-mseothelial matrix and anchoring in the type I collagen-rich matrix to generate secondary lesions. As a molecular-level understanding of EOC metastasis may identify novel therapeutic targets, the current study evaluated the expression and activity of integrin-linked kinase (ILK), a Ser/Thr protein kinase activated upon integrin-mediated adhesion. Results show that ILK is co-expressed in EOC with the pro-metastatic enzyme membrane type 1 matrix metalloproteinase (MT1-MMP) and catalyzed phosphorylation of the cytoplasmic tail of the proteinase. Downregulation of ILK expression or activity reduced adhesion to and invasion of collagen gels and organotypic meso-mimetic cultures. As an initial early event in EOC metastasis is integrin-mediated adhesion, these results suggest that further evaluation of ILK inhibitors as anti-metastatic agents in EOC is warranted. PMID:26959113

  12. Serum Dehydroepiandrosterone Sulphate Concentration Is Not a Predictive Factor in IVF Outcomes before the First Cycle of GnRH Agonist Administration in Women with Normal Ovarian Reserve

    PubMed Central

    Kunicki, Michał; Łukaszuk, Krzysztof; Jakiel, Grzegorz; Liss, Joanna

    2015-01-01

    Objective The aim of our study was to determine whether serum dehydroepiandrosterone sulphate (DHEAS) concentration and the models incorporating it could help clinicians to predict IVF outcomes in women with normal ovarian reserve undergoing their first long protocol. Study Design We performed a retrospective analysis of 459 women undergoing cycles of intracytoplasmic sperm injection (ICSI) for the first time in a long GnRH agonist protocol. Results Embryo transfer was performed in 407 women (88.7%). The fertilisation rate was 78.6%. The clinical pregnancy rate was 44.8% per started cycle and 50.6% per embryo transfer. Our univariate model revealed that the best predictors of clinical pregnancy were the number of mature oocytes, the number of embryos transferred and the number of good quality embryos, account for the clinical parameters that reflect ovarian reserve the best being AMH level and AFC. DHEAS did not predict clinical pregnancy (OR 1.001, 95% CI, 0.999–1.004). After adjusting for the number of embryos transferred and class of embryos in a multivariate model, the best predictors were age (OR 0.918, 95% CI, 0.867–0.972) and AFC (OR 1.022, 95% CI, 0.992–1.053). Serum DHEAS levels were positively correlated with AFC (r = 0.098, P<0.039) and testosterone levels (r = 0.371, P<0.001), as well as the number of mature oocytes (r = 0.109, P<0.019); serum DHEAS levels were negatively correlated with age (r = -0.220, P<0.001), follicle-stimulating hormone (FSH), (r = -0.116, P<0.015) and sex hormone-binding globulin (SHBG), (r = -0.193, P<0.001). Conclusions DHEAS concentration (in addition to the known factors of ovarian reserve) does not predict clinical pregnancy in women with normal ovarian reserve who are undergoing ICSI. PMID:25738591

  13. Calycosin induces apoptosis in human ovarian cancer SKOV3 cells by activating caspases and Bcl-2 family proteins.

    PubMed

    Zhou, Yan; Liu, Qing-Hua; Liu, Chun-Lei; Lin, Li

    2015-07-01

    Calycosin is widely used as a natural active compound for its anti-oxidative and anti-inflammation activity. Recently, several studies have shown that calycosin can inhibit growth and induce apoptosis in human cancer cell lines; however, the mechanisms are not completely clarified yet. In this study, we investigated the effects of calycosin on human ovarian carcinoma SKOV3 cells, as well as the mechanisms. SKOV3 cells were treated with calycosin at a series of concentrations for different times. In vitro, the MTT assay showed that calycosin had obvious anti-proliferation effects on SKOV3 cells in a dose- and time-dependent manner. Cell morphological changes which expressed by Hoechst 33258 staining were compared with apoptotic changes detected by fluorescence microscope. Compared with control group, the group treated with calycosin showed a significant increase in apoptosis rate. Expression of apoptosis related Bax/Bcl-2 and caspases proteins were detected by Western blotting. The results demonstrated that calycosin up-regulated the Bax/Bcl-2 ratio and cleaved caspase-3, cleaved caspase-9 expression in a dose-dependent manner. In summary, calycosin might exert anti-growth and induce-apoptosis activity against ovarian cancer SKOV3 cells through activating caspases and Bcl-2 family proteins, therefore presenting as a promising therapeutic agent for the treatment of ovarian cancer. PMID:25672608

  14. An integrated model of clinical information and gene expression for prediction of survival in ovarian cancer patients.

    PubMed

    Yang, Rendong; Xiong, Jie; Deng, Defeng; Wang, Yiren; Liu, Hequn; Jiang, Guli; Peng, Yangqin; Peng, Xiaoning; Zeng, Xiaomin

    2016-06-01

    Accumulating evidence shows that clinical factors alone are not adequate for predicting the survival of patients with ovarian cancer (OvCa), and many genes have been found to be associated with OvCa prognosis. The objective of this study was to develop a model that integrates clinical information and a gene signature to predict the survival durations of patients diagnosed with OvCa. We constructed mRNA and microRNA expression profiles and gathered the corresponding clinical data of 552 OvCa patients and 8 normal controls from The Cancer Genome Atlas. Using univariate Cox regression followed by a permutation test, elastic net-regulated Cox regression, and ridge regression, we generated a prognosis index consisting of 2 clinical variables, 7 protective mRNAs, 12 risky mRNAs, and 1 protective microRNA. The area under the curve of the receiver operating characteristic of the integrated clinical-and-gene model was 0.756, larger than that of the clinical-alone model (0.686) or the gene-alone model (0.703). OvCa patients in the high-risk group had a significantly shorter overall survival time compared with patients in the low-risk group (hazard ratio = 8.374, 95% confidence interval = 4.444-15.780, P = 4.90 × 10(-11), by the Wald test). The reliability of the gene signature was confirmed by a public external data set from the Gene Expression Omnibus. Our conclusions that we have identified an integrated clinical-and-gene model superior to the traditional clinical-alone model in ascertaining the survival prognosis of patients with OvCa. Our findings may prove valuable for improving the clinical management of OvCa. PMID:27059002

  15. Ovarian Cysts

    MedlinePlus

    ... new cysts. A health problem that may involve ovarian cysts is polycystic ovary syndrome (PCOS). Women with ... male hormones, irregular or no periods and small ovarian cysts. Dept. of Health and Human Services Office ...

  16. Ovarian cancer

    MedlinePlus

    Cancer - ovaries ... Ovarian cancer is the fifth most common cancer among women. It causes more deaths than any other type of female reproductive organ cancer. The cause of ovarian cancer is unknown. Risk ...

  17. Ovarian cancer

    MedlinePlus

    ... of ovarian cancer Already been diagnosed with ovarian cancer to determine how well treatment is working Other tests that may be done include: Complete blood count and blood chemistry Pregnancy test (serum HCG) CT or MRI of ...

  18. Serum folate receptor alpha as a biomarker for ovarian cancer: Implications for diagnosis, prognosis and predicting its local tumor expression.

    PubMed

    Kurosaki, Akira; Hasegawa, Kosei; Kato, Tomomi; Abe, Kenji; Hanaoka, Tatsuya; Miyara, Akiko; O'Shannessy, Daniel J; Somers, Elizabeth B; Yasuda, Masanori; Sekino, Tetsuo; Fujiwara, Keiichi

    2016-04-15

    Folate receptor alpha (FRA) is a GPI-anchored glycoprotein and encoded by the FOLR1 gene. High expression of FRA is observed in specific malignant tumors of epithelial origin, including ovarian cancer, but exhibits very limited normal tissue expression, making it as an attractive target for the ovarian cancer therapy. FRA is known to shed from the cell surface into the circulation which allows for its measurement in the serum of patients. Recently, methods to detect the soluble form of FRA have been developed and serum FRA (sFRA) is considered a highly promising biomarker for ovarian cancer. We prospectively investigated the levels of sFRA in patients clinically suspected of having malignant ovarian tumors. A total of 231 patients were enrolled in this study and analyzed for sFRA as well as tumor expression of FRA by immunohistochemistry. High sFRA was predominantly observed in epithelial ovarian cancer patients, but not in patients with benign or borderline gynecological disease or metastatic ovarian tumors from advanced colorectal cancers. Levels of sFRA were highly correlated to clinical stage, tumor grade and histological type and demonstrated superior accuracy for the detection of ovarian cancer than did serum CA125. High sFRA was significantly associated with shorter progression-free survival in both early and advanced ovarian cancer patients. Finally, tumor FRA expression status was strongly correlated with sFRA levels. Taken together, these data suggest that sFRA might be a useful noninvasive serum biomarkers for future clinical trials assessing FRA-targeted therapy. PMID:26595060

  19. Hormonal monitoring of ovarian activity using the Ovarian Monitor, part I. Validation of home and laboratory results obtained during ovulatory cycles by comparison with radioimmunoassay.

    PubMed

    Blackwell, Leonard F; Brown, James B; Vigil, Pilar; Gross, Barbara; Sufi, Saulat; d'Arcangues, Catherine

    2003-05-01

    A study was conducted to determine the accuracy and reliability of the Home Ovarian Monitor for measuring estrone glucuronide (E1G) and pregnanediol glucuronide (PdG) during ovulatory cycles as a means of monitoring ovarian activity. Approximately 60 ovulating women in three centres collected timed specimens of urine (3h or more) for a total of six cycles each. The women measured the E1G and PdG excretion per 24h in their urine specimens using the Monitor. A local laboratory using the Monitor also measured the excretion. Urine specimens from 18 to 19 cycles were sent frozen to the WHO Reference Laboratory in London where they were analysed for E1G and PdG by the Monitor and by radioimmunoassay (RIA). The correlation coefficients between the Monitor and radioimmunoassay results obtained in London were better than 0.84 in 80% of the cycles. A urine bias caused the Monitor E1G results to be higher than those obtained by radioimmunoassay but the daily patterns were the same. In 50% of the cycles, this bias caused a delay of up to 3 days in identifying the beginning of the E1G rise compared with radioimmunoassay. Timing of the preovulatory E1G peak and the postovulatory PdG rise agreed within the experimental errors of the two systems. The study confirmed that women using the Monitor at home obtained results that were as accurate as those obtained by laboratory procedures. Careful supervision was required to maintain laboratory levels of quality control and interpretation of results. PMID:12798498

  20. Cationic chlorophyl derivatives with SOD mimicking activity suppress the proliferation of human ovarian cancer cells.

    PubMed

    Kobayashi, Y; Maniki, M; Nakamura, K

    1996-06-01

    Derivatives of chlorophyl, e.g. Fe-chlorin e6-Na, alpha, beta, gamma, delta-Tetraphenylporphine-tetrasulfonic acid disulfonic acid salt tetrahydrate (Fe-TPPTS) and alpha, beta, gamma, delta-Tetrakis (4-N-trimethylaminophenyl) porphine, tetra (p-toluensulfonate (Fe-TTMAPP), express SOD mimicking activity. Examination was made of suppressive effects of human cancer cell lines by derivatives of chlorophyl. Fe-TPPTS and Fe-TTMAPP suppressed proliferation of the human ovarian cancer cell lines but Fe-chlorin e6-Na failed to suppress the proliferation. Lipid peroxide was increased by application of Fe-TPPTS and Fe-TTMAPP, but decreased by application of Fe-chlorin e6-Na. SOD activity of the cancer cells did not change by application of these drugs. TPPTS and TTMAPP have a cationic charge but Fe-chlorin e6-Na has an anionic charge. It is suggested that charge of these drugs relates to the suppressive effects of the cancer cell proliferation. PMID:10851538

  1. Glutathione S-transferase activity in follicular fluid from women undergoing ovarian stimulation: role in maturation.

    PubMed

    Meijide, Susana; Hernández, M Luisa; Navarro, Rosaura; Larreategui, Zaloa; Ferrando, Marcos; Ruiz-Sanz, José Ignacio; Ruiz-Larrea, M Begoña

    2014-10-01

    Female infertility involves an emotional impact for the woman, often leading to a state of anxiety and low self-esteem. The assisted reproduction techniques (ART) are used to overcome the problem of infertility. In a first step of the in vitro fertilization therapy women are subjected to an ovarian stimulation protocol to obtain mature oocytes, which will result in competent oocytes necessary for fertilization to occur. Ovarian stimulation, however, subjects the women to a high physical and psychological stress, thus being essential to improve ART and to find biomarkers of dysfunction and fertility. GSH is an important antioxidant, and is also used in detoxification reactions, catalysed by glutathione S-transferases (GST). In the present work, we have investigated the involvement of GST in follicular maturation. Patients with fertility problems and oocyte donors were recruited for the study. From each woman follicles at two stages of maturation were extracted at the preovulatory stage. Follicular fluid was separated from the oocyte by centrifugation and used as the enzyme source. GST activity was determined based on its conjugation with 3,4-dichloronitrobenzene and the assay was adapted to a 96-well microplate reader. The absorbance was represented against the incubation time and the curves were adjusted to linearity (R(2)>0.990). Results showed that in both donors and patients GST activity was significantly lower in mature oocytes compared to small ones. These results suggest that GST may play a role in the follicle maturation by detoxifying xenobiotics, thus contributing to the normal development of the oocyte. Supported by FIS/FEDER (PI11/02559), Gobierno Vasco (Dep. Educación, Universiades e Investigación, IT687-13), and UPV/EHU (CLUMBER UFI11/20 and PES13/58). The work was approved by the Ethics Committee of the UPV/EHU (CEISH/96/2011/RUIZLARREA), and performed according to the UPV/EHU and IVI-Bilbao agreement (Ref. 2012/01). PMID:26461371

  2. Prediction and monitoring of volcanic activities

    SciTech Connect

    Sudradjat, A.

    1986-07-01

    This paper summarizes the state of the art for predicting and monitoring volcanic activities, and it emphasizes the experience obtained by the Volcanological Survey Indonesia for active volcanoes. The limited available funds, the large number of active volcanoes to monitor, and the high population density of the volcanic area are the main problems encountered. Seven methods of volcano monitoring are applied to the active volcanoes of Indonesia: seismicity, ground deformation, gravity and magnetic studies, self-potential studies, petrochemistry, gas monitoring, and visual observation. Seismic monitoring augmented by gas monitoring has proven to be effective, particularly for predicting individual eruptions at the after-initial phase. However, the success of the prediction depends on the characteristics of each volcano. In general, the initial eruption phase is the most difficult phenomenon to predict. The preparation of hazard maps and the continuous awareness of the volcanic eruption are the most practical ways to mitigate volcanic danger.

  3. Ovarian Cyst

    MedlinePlus

    ... accurate way to tell if a woman has ovarian cancer. For example, some women who do have ovarian cancer have a normal CA-125 level. Also, this ... for women who show signs or symptoms of ovarian cancer or who have genetic mutations that increase the ...

  4. Inhibition of P-glycoprotein activity and chemosensitization of multidrug-resistant ovarian carcinoma 2780AD cells by hexanoylglucosylceramide.

    PubMed

    Veldman, R J; Sietsma, H; Klappe, K; Hoekstra, D; Kok, J W

    1999-12-20

    In the present study we show that neutral hexanoyl-(glyco)sphingolipids inhibit P-glycoprotein (Pgp) activity in human ovarian 2780AD cells. By contrast, hexanoylceramide and the gangliosides GM(3) and GM(2) had no effect on Pgp activity, whereas sphingosine had a stimulating effect. In the case of hexanoylglucosylceramide, inhibition of Pgp activity by was reflected by a regained doxorubicin sensitivity of cells, which were grown in medium supplemented with the lipid. Our results lead to the conclusion that a direct transmodulation of Pgp activity by glycolipids occurs, depending on lipid headgroup structure, which can result in reduced resistance to the chemotherapeutic agent doxorubicin. PMID:10600530

  5. Seasonal variations of the ovarian activity and pregnancy rate in the Egyptian buffalo cows (Bubalus bubalis).

    PubMed

    Ali, Ahmed

    2015-06-01

    The objective of this study was to investigate the effect of season on the follicular and luteal dynamics and pregnancy rate in Egyptian buffaloes. A total of 327 genital tracts and 596 animals were used. The genital tracts were examined in winter (n = 58), spring (n = 179), summer (n = 49), and autumn (n = 41) for follicular population, incidence of presence of developed or mature corpus luteum (CL), and diameters of the preovulatory follicle (OF) and the mature CL. Buffaloes were mated in winter (n = 297) and summer (n = 299) and examined for pregnancy rate. Results showed that the mean number of the large follicles was higher in winter (1.21 ± 0.08 mm) and spring (1.04 ± 0.05 mm) than in summer (0.64 ± 0.1 mm) and autumn (0.78 ± 0.1 mm) (P = 0.0001). Likewise, the mean diameter of the OF was greater in winter (14.71 ± 0.7 mm) and spring (14.36 ± 0.5 mm) than in summer (12.4 ± 0.8 mm) and autumn (12 ± 0.8 mm) (P = 0.02). In addition, the mean diameter of the mature CL was higher in winter (15.8 ± 0.4 mm) and spring (15.5 ± 1.1 mm) than in summer (14.2 ± 1 mm) and autumn (13.2 ± 0.7 mm) (P = 0.003). The incidence of presence of developed or mature CL was lower in summer (69.4 %) than in winter (74.1 %), spring (87.2 %), or autumn (85.4 %) (P = 0.01). Double CLs (0.9 %) were observed only in spring. Ovarian cysts (2.5 %) were detected in winter and spring. The pregnancy rate was higher in buffaloes mated in winter (75.4 %) than in those mated in summer (61.9 %) (P = 0.0004). In conclusion, season affects the ovarian activity and reproductive efficiency of buffaloes, where winter and spring are the optimum seasons for breeding. PMID:25778728

  6. Reproductive steroid hormones and ovarian activity in felids of the Leopardus genus.

    PubMed

    Moreira, N.; Monteiro-Filho, E.L.A.; Moraes, W.; Swanson, W.F.; Graham, L.H.; Pasquali, O.L.; Gomes, M.L.F.; Morais, R.N.; Wildt, D.E.; Brown, J.L.

    2001-01-01

    Reproductive endocrine patterns were characterized in female ocelots (Leopardus pardalis; n = 3), tigrinas (Leopardus tigrinus; n = 2), and margays (Leopardus wiedii; n = 2) housed in captivity in southern Brazil. Females were maintained as singletons and exposed to natural fluctuations in photoperiod. Cyclic changes in ovarian steroids were monitored by analyzing estrogen and progestogen metabolites in fecal samples collected five times weekly for 14 to 18 months. Based on intervals between fecal estrogen peaks, mean (+/- SEM) duration of the estrous cycle was 18.4 +/- 1.6 days for the ocelots (range, 7-31 days; n = 75 cycles), 16.7 +/- 1.3 days for the tigrinas (range, 11-27 days; n = 23 cycles), and 17.6 +/- 1.5 days for the margays (range, 11-25 days; n = 32 cycles). Fecal progestogen analyses combined with two laparoscopic observations of the ovaries confirmed that ocelots and tigrinas did not ovulate spontaneously. In contrast, non-mating-induced luteal phases of 40.1 +/- 6.3 days in duration (range, 30-60 days) were observed frequently in both margays. There was no evidence of gonadal seasonality in margays in either follicular or luteal activity. In ocelots, cyclic changes in estrogen excretion were observed during each month of the year; however, only one female cycled continuously. In the other two ocelots, periods of acyclicity of several months' duration were observed. It was not possible to conclude whether tigrinas were aseasonal because estrous cyclicity was observed in only one of two individuals. In the female that cycled, a 3-month period of acyclicity was observed in the late fall/early winter. These data demonstrate similarities among three felid species of the genus Leopardus, including evidence they are polyestrous but experience unexplained periods of ovarian inactivity. Only the margays differed by exhibiting occasional spontaneous, non-mating-induced ovulations. Historically, these species have not bred well in captivity. However, it is

  7. How Predictable Is the Operative Time of Laparoscopic Surgery for Ovarian Endometrioma?

    PubMed Central

    Gambadauro, Pietro; Campo, Vincenzo; Campo, Sebastiano

    2015-01-01

    Endometriosis is a tricky albeit common disease whose management largely relies on laparoscopy. We have studied the operative times of laparoscopic endometrioma surgery in order to assess their predictability and possible predictors. One hundred forty-eight laparoscopies were included, with a median operative time of 70 minutes (mean 75.14; 95% CI: 70.03–80.24). Half of the cases had a duration within 15–20 minutes above or below the median (IQR: 55–93.75), but the whole dataset ranged from 20 to 180 minutes, and the standard deviation was relatively large (31.4). Surgical times were significantly related to technical (number and size of the cysts) and nontechnical factors (age, parity, dysmenorrhea, and family history). At multiple logistic regression, after adjusting for number and size of the cysts, surgical times below the first quartile were associated with older age (>30 years old: aOR: 3.590; 95% CI: 1.417–9.091) and parity (≥1 delivery: aOR: 3.409; 95% CI: 1.343–8.651). Longer times, above the third quartile, were instead predicted by a familial anamnesis of endometriosis (aOR: 3.639; 95% CI: 1.246–10.627). Our findings indicate highly variable surgical times, which are predicted by unexpected nontechnical factors. This is consistent with the complexity of endometriosis and its treatment. Productivity and efficiency in endometriosis surgery should focus on the quality of healthcare outcomes rather than on the time spent in the operating theatres. PMID:26417455

  8. Dynamo theory prediction of solar activity

    NASA Technical Reports Server (NTRS)

    Schatten, Kenneth H.

    1988-01-01

    The dynamo theory technique to predict decadal time scale solar activity variations is introduced. The technique was developed following puzzling correlations involved with geomagnetic precursors of solar activity. Based upon this, a dynamo theory method was developed to predict solar activity. The method was used successfully in solar cycle 21 by Schatten, Scherrer, Svalgaard, and Wilcox, after testing with 8 prior solar cycles. Schatten and Sofia used the technique to predict an exceptionally large cycle, peaking early (in 1990) with a sunspot value near 170, likely the second largest on record. Sunspot numbers are increasing, suggesting that: (1) a large cycle is developing, and (2) that the cycle may even surpass the largest cycle (19). A Sporer Butterfly method shows that the cycle can now be expected to peak in the latter half of 1989, consistent with an amplitude comparable to the value predicted near the last solar minimum.

  9. Stathmin regulates mutant p53 stability and transcriptional activity in ovarian cancer

    PubMed Central

    Sonego, Maura; Schiappacassi, Monica; Lovisa, Sara; Dall'Acqua, Alessandra; Bagnoli, Marina; Lovat, Francesca; Libra, Massimo; D'Andrea, Sara; Canzonieri, Vincenzo; Militello, Loredana; Napoli, Marco; Giorda, Giorgio; Pivetta, Barbara; Mezzanzanica, Delia; Barbareschi, Mattia; Valeri, Barbara; Canevari, Silvana; Colombatti, Alfonso; Belletti, Barbara; Del Sal, Giannino; Baldassarre, Gustavo

    2013-01-01

    Stathmin is a p53-target gene, frequently overexpressed in late stages of human cancer progression. Type II High Grade Epithelial Ovarian Carcinomas (HG-EOC) represents the only clear exception to this observation. Here, we show that stathmin expression is necessary for the survival of HG-EOC cells carrying a p53 mutant (p53MUT) gene. At molecular level, stathmin favours the binding and the phosphorylation of p53MUT by DNA-PKCS, eventually modulating p53MUT stability and transcriptional activity. Inhibition of stathmin or DNA-PKCS impaired p53MUT–dependent transcription of several M phase regulators, resulting in M phase failure and EOC cell death, both in vitro and in vivo. In primary human EOC a strong correlation exists between stathmin, DNA-PKCS, p53MUT overexpression and its transcriptional targets, further strengthening the relevance of the new pathway here described. Overall our data support the hypothesis that the expression of stathmin and p53 could be useful for the identification of high risk patients that will benefit from a therapy specifically acting on mitotic cancer cells. PMID:23610071

  10. The significance of antral follicle size prior to stimulation in predicting ovarian response in a multiple dose GnRH antagonist protocol.

    PubMed

    Lai, Qiaohong; Chen, Cai; Zhang, Zhijun; Zhang, Shu; Yu, Qilin; Yang, Ping; Hu, Jun; Wang, Cong-Yi

    2013-01-01

    Prediction of ovarian responses prior to stimulation is not only useful for patient counseling, but also important in tailoring the optimal dosage of gonadotrophin for individual patients. By prospectively study of 214 women undergoing in vitro fertilization and embryo transfer (IVF-ET) treatment, we obtained data supporting that antral follicle size could be an additional valuable predictive marker other than the antral follicle count (AFC) in predicting ovarian response. Our studies revealed that AFC achieved the best predictive value in relation to the number of oocyte obtained, followed by antral follicle size, basal follicle stimulating hormone (FSH) and body mass index (BMI). Unlike AFC, antral follicle size was noted to be negatively correlated with the dosage (R = -0.493) and duration (R = -0.465) of rFSH stimulation. Antral follicle size was also found with higher negative regression coefficient (B = -0.661) as compared with that of basal FSH concentration (B = -0.326) and BMI (b = -0.281). More importantly, women with antral follicle size 6-7 mm showed significantly higher AFC, oocytes retrieved, fertilized oocytes and grade I/II embryos along with much lower transfer cycle cancellation rate (7.5% vs. 16-17%). Together, our data suggest that basal antral follicle size could be a valued predictive marker in women with IVF-ET treatment, in which women with antral follicle size 6-7 mm are likely predisposed to better IVF-ET outcomes. PMID:23330011

  11. Inhibition of rainbow trout (Oncorhynchus mykiss) P450 aromatase activities in brain and ovarian microsomes by various environmental substances.

    PubMed

    Hinfray, Nathalie; Porcher, Jean-Marc; Brion, François

    2006-11-01

    Aromatase, a key steroidogenic enzyme that catalyses the conversion of androgens to estrogens, represent a target for endocrine disrupting chemicals. However, little is known about the effect of pollutants on aromatase enzymes in fish. In this study, we first optimized a rainbow trout (Oncorhynchus mykiss) microsomal aromatase assay to measure the effects of 43 substances belonging to diverse chemical classes (steroidal and non steroidal aromatase inhibitors, pesticides, heavy metals, organotin compounds, dioxins, polycyclic aromatic hydrocarbons) on brain and ovarian aromatase activities in vitro. Our results showed that 12 compounds were able to inhibit brain and ovarian aromatase activities in a dose-dependent manner with IC50 values ranging from the low nM to the high microM range depending on the substance: steroidal and non steroidal inhibitors of aromatase (4-hydroxyandrostenedione, androstatrienedione, aminogluthethimide), imidazole fungicides (clotrimazole, imazalil, prochloraz), triazole fungicides (difenoconazole, fenbuconazole, propiconazole, triadimenol), the pyrimidine fungicide fenarimol and methylmercury. Overall, this study demonstrates that rainbow trout brain and ovarian microsomal aromatase assay is suitable for evaluating potential aromatase inhibitors in vitro notably with respect to environmental screening. The results highlight that methylmercury and some pesticides that are currently used throughout the world, have the potential to interfere with the biosynthesis of endogenous estrogens in fish. PMID:17081805

  12. Preoperative Neutrophil-to-Lymphocyte Ratio as a Predictive and Prognostic Factor for High-Grade Serous Ovarian Cancer

    PubMed Central

    Bi, Rui; Ju, Xingzhu; Chen, Xiaojun; Yang, Wentao; Wu, Xiaohua

    2016-01-01

    Objective We aimed to demonstrate the clinical and prognostic significance of the preoperative neutrophil-to-lymphocyte ratio (NLR) in high-grade serous ovarian cancer (HGSC). Methods We retrospectively investigated 875 patients who underwent primary staging or debulking surgery for HGSC between April 2005 and June 2013 at our institution. None of these patients received neoadjuvant chemotherapy. NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. Progression-free survival (PFS) and overall survival (OS) were analyzed with the Kaplan-Meier method and log-rank tests for univariate analyses. For multivariate analyses, Cox regression analysis was used to evaluate the effects of the prognostic factors, which were expressed as hazard ratios (HRs). Results The NLRs ranged from 0.30 to 24.0. The median value was 3.24 and used as the cutoff value to discriminate between the high-NLR (≥3.24) and low-NLR (<3.24) groups. A high preoperative NLR level was associated with an advanced FIGO stage, increased CA125 level, more extensive ascites, worse cytoreduction outcome and chemoresistance. For univariate analyses, a high NLR was associated with reduced PFS (p<0.001) and OS (p<0.001). In multivariate analyses, a high NLR was still an independent predictor of PFS (p = 0.011), but not OS (p = 0.148). Conclusion Our study demonstrated that NLR could reflect tumor burden and clinical outcomes to a certain extent and should be regarded as a predictive and prognostic parameter for HGSC. PMID:27203425

  13. TLR4 activates NFkB in human ovarian granulosa tumor cells

    PubMed Central

    Woods, Dori C.; White, Yvonne A. R.; Dau, Caroline; Johnson, A.L.

    2011-01-01

    Previous studies have demonstrated expression of Toll-like receptors (TLRs) in the surface epithelium of normal ovaries (OSE) and in epithelial ovarian tumors. Most notably, OSE-derived cancers express TLR4, which activates the nuclear factor-kappa B (NF-κB) signaling cascade as a mediator of inflammatory response. Currently, there is considerable interest in elucidating the role of TLR-mediated signaling in cancers. Nevertheless, the expression of TLRs in granulosa cell tumors (GCTs) of the ovary, and the extent to which GCT expression of TLRs may influence cell-signaling pathways and/or modulate the efficacy of chemotherapeutics, has yet to be determined. In the present study, human GCT lines (COV434 and KGN) were utilized to evaluate expression of functional TLR4. TLR4 is expressed in GCT cell lines and ligation of TLR4 with bacterial lipopolysaccharide (LPS) led to IκB degradation and activation of NF-κB. NF-κB activation was confirmed by nuclear localization of NF-κB p65 following treatment with LPS and the naturally occurring ligand, HSP60. Notably, immunoneutralization of TLR4 blocked nuclear localization, and inhibition of NF-κB signaling attenuated LPS-induced TNFαplus increased doubling time in both cell lines. Contradictory to reports using human OSE cell lines, inhibition of NF-κB signaling failed to sensitize GCT lines to TRAIL or cisplatin. In summary, findings herein are the first to demonstrate a functional TLR-signaling pathway specifically in GCTs, and indicate that in contrast to OSE-derived cancers, inhibition of NF-κB does not sensitize GCTs to TRAIL or cisplatin. PMID:21616060

  14. FSH supplementation to culture medium is beneficial for activation and survival of preantral follicles enclosed in equine ovarian tissue.

    PubMed

    Aguiar, F L N; Lunardi, F O; Lima, L F; Rocha, R M P; Bruno, J B; Magalhães-Padilha, D M; Cibin, F W S; Nunes-Pinheiro, D C S; Gastal, M O; Rodrigues, A P R; Apgar, G A; Gastal, E L; Figueiredo, J R

    2016-04-01

    This study investigated the effect of adding different concentrations of bovine recombinant follicle-stimulating hormone on the IVC of equine preantral follicles enclosed in ovarian tissue fragments. Randomized ovarian fragments were fixed immediately (fresh noncultured control) or cultured for 1 or 7 days in α-MEM(+) supplemented with 0, 10, 50, and 100 ng/mL FSH and subsequently analyzed by classical histology. Culture media collected on Day 1 or Day 7 and were analyzed for steroids (estradiol and progesterone) and reactive oxygen species (ROS). After Day 1 and Day 7 of culture, 50-ng/mL FSH treatment had a greater (P < 0.05) percentage of morphologically normal follicles when compared to the other groups, except the 10-ng/mL FSH treatment at Day 1 of culture. The percentage of developing follicles (transition, primary, and secondary), and follicular and oocyte diameters were higher (P < 0.05) in the 50-ng/mL FSH treatment compared to the other groups after Day 7 of culture. Furthermore, estradiol secretion and ROS production were maintained (P > 0.05) throughout the culture in the 50-ng/mL FSH treatment. In conclusion, the addition of 50 ng/mL of FSH promoted activation of primordial follicles to developing follicles, improved survival of preantral follicles, and maintained estradiol and ROS production of equine ovarian tissue after 7 days of culture. PMID:26723132

  15. Nilotinib reduced the viability of human ovarian cancer cells via mitochondria-dependent apoptosis, independent of JNK activation.

    PubMed

    Chen, Tze-Chien; Yu, Ming-Chih; Chien, Chih-Chiang; Wu, Ming-Shun; Lee, Yu-Chieh; Chen, Yen-Chou

    2016-03-01

    Nilotinib (AMN) induces apoptosis in various cancer cells; however the effect of AMN on human ovarian cancer cells is still unclear. A reduction in cell viability associated with the occurrence of apoptotic characteristics was observed in human SKOV-3 ovarian cancer cells under AMN but not sorafenib (SORA) or imatinib (STI) stimulation. Activation of apoptotic pathway including increased caspase (Casp)-3 and poly(ADP-ribose) polymerase 1 (PARP1) protein cleavage by AMN was detected with disrupted mitochondrial membrane potential (MMP) accompanied by decreased Bcl-2 protein and increased cytosolic cytochrome (Cyt) c/cleaved Casp-9 protein expressions was found, and AMN-induced cell death was inhibited by peptidyl Casp inhibitors, VAD, DEVD and LEHD. Increased phosphorylated c-Jun N-terminal kinase (JNK) protein expression was detected in AMN- but not SORA- or STI-treated SKOV-3 cells, and the JNK inhibitors, SP600125 and JNKI, showed slight but significant enhancement of AMN-induced cell death in SKOV-3 cells. The intracellular peroxide level was elevated by AMN and H2O2, and N-acetylcysteine (NAC) prevented H2O2- but not AMN-induced peroxide production and apoptosis in SKOV-3 cells. AMN induction of apoptosis with increased intracellular peroxide production and JNK protein phosphorylation was also identified in human A2780 ovarian cancer cells, cisplatin-resistant A2780CP cells, and clear ES-2 cells. The evidence supporting AMN effectively reducing the viability of human ovarian cancer cells via mitochondrion-dependent apoptosis is provided. PMID:26549707

  16. Sequential treatment with betulinic acid followed by 5-fluorouracil shows synergistic cytotoxic activity in ovarian cancer cells

    PubMed Central

    Wang, Ying-Jian; Liu, Jun-Bao; Dou, Yu-Chang

    2015-01-01

    Betulinic acid selectively inhibits the growth of ovarian carcinoma cell lines without affecting the normal cells. In the present study, the effect of 5-fluorouracil (5-FU) and betulinic acid (BA) combination on ovarian carcinoma cells was studied. The results demonstrated that ovarian carcinoma cells on concurrent or 5-FU followed by BA treatment show increased Sub-G1 cell population, increased rate of cell apoptosis and morphological changes in mitochondrial membrane. In OVCAR 432 cells treatment with sequential combination of 5-FU and BA increased the Sub-G1 cell population to 51.3% and growth inhibition rate of > 72%. However, exposure to BA before 5-FU treatment caused a decrease in rate of inhibition to < 35%. Treatment with combination of 5 μM of 5-FU and 1 μM of BA for 48 h, led to an induction of apoptosis in 79.7% and induced morphological changes in OVCAR 432 cells. The Western blot results showed high concentration of cytochrome c in the cell cytosol after 24 h of 5-FU and BA combination treatment. Treatment of BA-responsive RMS-13 cells with 5-FU and BA combination resulted in inhibition of GLI1, GLI2, PTCH1, and IGF2 genes. In addition, we found a significant reduction in hedgehog activity of RMS-13 cells after 5-FU and BA combination treatment by means of a hedgehog-responsive reporter assay. Therefore, 5-FU and BA combination can be a promising regimen for the treatment of ovarian carcinoma. PMID:25755712

  17. Autocrine regulation of growth stimulation in human epithelial ovarian carcinoma by serine-proteinase-catalysed release of the urinary-type-plasminogen-activator N-terminal fragment.

    PubMed Central

    Fishman, D A; Kearns, A; Larsh, S; Enghild, J J; Stack, M S

    1999-01-01

    Ovarian carcinomas secrete single-chain urinary-type plasminogen activator (scuPA) and expression of uPA is up-regulated relative to normal ovarian epithelium, leading to an enhanced proteolytic capacity which may facilitate invasion. Furthermore, the uPA receptor (uPAR) is present on ovarian carcinoma cells and is occupied in tumour tissues. In the present study, incubation of scuPA with serum-free conditioned medium from ovarian carcinoma cells resulted in release of a 14 kDa polypeptide. N-terminal sequence analysis identified this fragment as the uPA N-terminal fragment (NTF), which contains a growth-factor and a kringle domain. NTF generation was abolished by serine-proteinase inhibitors, but not inhibitors of matrix metalloproteinases, and was not enhanced by the addition of plasminogen or plasmin. To determine whether ovarian carcinoma-cell growth is altered by uPA, the effect of exogenous scuPA or NTF on proliferation was analysed. Both NTF and scuPA induced a dose-dependent increase in proliferation, with maximal stimulation obtained at 10-20 nM. Furthermore, blocking the interaction of endogenous uPA with uPAR using anti-NTF antibodies significantly inhibited proliferation. Together these data indicate that, in addition to enhancing the invasive activity of ovarian carcinoma cells via increased pericellular proteolysis, uPA also acts as a mitogen for ovarian carcinoma cells, suggesting a biochemical mechanism whereby uPA may contribute to ovarian carcinoma progression by modulating both cell invasion and proliferation. PMID:10417342

  18. OVARIAN CANCER

    PubMed Central

    Cho, Kathleen R.; Shih, Ie-Ming

    2009-01-01

    Ovarian carcinomas are a heterogeneous group of neoplasms traditionally sub-classified based on type and degree of differentiation. Although current clinical management of ovarian carcinoma largely fails to take this heterogeneity into account, it is becoming evident that each major histological type has characteristic genetic defects that deregulate specific signaling pathways in the tumor cells. Moreover, within the most common histological types, the molecular pathogenesis of low-grade versus high-grade tumors appears to be largely distinct. Mouse models of ovarian carcinoma have been developed that recapitulate many of the morphological features, biological behavior, and gene expression patterns of selected subtypes of ovarian cancer. Such models will likely prove useful for studying ovarian cancer biology and for pre-clinical testing of molecularly targeted therapeutics, which may ultimately lead to better clinical outcomes for women with ovarian cancer. PMID:18842102

  19. FMR1 gene CGG repeat variation within the normal range is not predictive of ovarian response in IVF cycles.

    PubMed

    Morin, Scott J; Tiegs, Ashley W; Franasiak, Jason M; Juneau, Caroline R; Hong, Kathleen H; Werner, Marie D; Zhan, Yiping; Landis, Jessica; Scott, Richard T

    2016-05-01

    The relationship between FMR1 CGG premutation status and decreased ovarian responsiveness is well established. The association between FMR1 CGG repeat number in the currently defined normal range (less than 45 repeats) and ovarian reserve, however, is controversial. This retrospective study examined whether variation in CGG repeat number in the normal range was associated with markers of ovarian response in IVF cycles. The first IVF cycle of 3006 patients with FMR1 CGG repeat analysis was examined. Only patients carrying two alleles with less than 45 CGG repeats were included for analysis. The CGG repeat number furthest from the modal peak was plotted against number of mature oocytes retrieved and no correlation was identified. Patients were also separated into biallelic genotype groups, based on the recently proposed narrower "new normal" range of 26-34 CGG repeats. A linear regression showed that none of the biallelic genotype groups were associated with a decreased oocyte yield. The euploidy rates after comprehensive chromosomal screening were equivalent among the genotype groups. No difference was found in the rate of cycle cancellation for poor response. Despite increasing use, FMR1 CGG repeats in the normal range cannot be used as a predictor of ovarian response to gonadotrophin stimulation. PMID:27013081

  20. Evidence for ovarian granulosa stem cells: telomerase activity and localization of the telomerase ribonucleic acid component in bovine ovarian follicles.

    PubMed

    Lavranos, T C; Mathis, J M; Latham, S E; Kalionis, B; Shay, J W; Rodgers, R J

    1999-08-01

    We have previously postulated that granulosa cells of developing follicles arise from a population of stem cells. Stem cells and cancer cells can divide indefinitely partly because they express telomerase. Telomerase is a ribonucleoprotein enzyme that repairs the ends of telomeres that otherwise shorten progressively upon each successive cell division. In this study we carried out cell cycle analyses and examined telomerase expression to examine our hypothesis. Preantral (60-100 microm) and small (1 mm) follicles, as well as granulosa cells from medium-sized (3 mm) and large (6-8 mm) follicles, were isolated. Cell cycle analyses and expression of Ki-67, a cell cycle-related protein, were undertaken on follicles of each size (n = 3) by flow cytometry; 12% to 16% of granulosa cells in all follicles were in the S phase, and less than 2% were in the G(2)/M phase. Telomerase activity (n = 3) was highest in the small preantral follicles, declining at the 1-mm stage and even further at the 3-mm stage. In situ hybridization histochemistry was carried out on bovine ovaries, and telomerase RNA was detected in the granulosa cells of growing follicles but not primordial follicles. Two major patterns of staining were observed in the membrana granulosa of antral follicles: staining in the middle and antral layers, and staining in the middle and basal layers. No staining was detected in oocytes. Our results strongly support our hypothesis that granulosa cells arise from a population of stem cells. PMID:10411512

  1. CERAPP: Collaborative Estrogen Receptor Activity Prediction Project

    PubMed Central

    Mansouri, Kamel; Abdelaziz, Ahmed; Rybacka, Aleksandra; Roncaglioni, Alessandra; Tropsha, Alexander; Varnek, Alexandre; Zakharov, Alexey; Worth, Andrew; Richard, Ann M.; Grulke, Christopher M.; Trisciuzzi, Daniela; Fourches, Denis; Horvath, Dragos; Benfenati, Emilio; Muratov, Eugene; Wedebye, Eva Bay; Grisoni, Francesca; Mangiatordi, Giuseppe F.; Incisivo, Giuseppina M.; Hong, Huixiao; Ng, Hui W.; Tetko, Igor V.; Balabin, Ilya; Kancherla, Jayaram; Shen, Jie; Burton, Julien; Nicklaus, Marc; Cassotti, Matteo; Nikolov, Nikolai G.; Nicolotti, Orazio; Andersson, Patrik L.; Zang, Qingda; Politi, Regina; Beger, Richard D.; Todeschini, Roberto; Huang, Ruili; Farag, Sherif; Rosenberg, Sine A.; Slavov, Svetoslav; Hu, Xin; Judson, Richard S.

    2016-01-01

    Background: Humans are exposed to thousands of man-made chemicals in the environment. Some chemicals mimic natural endocrine hormones and, thus, have the potential to be endocrine disruptors. Most of these chemicals have never been tested for their ability to interact with the estrogen receptor (ER). Risk assessors need tools to prioritize chemicals for evaluation in costly in vivo tests, for instance, within the U.S. EPA Endocrine Disruptor Screening Program. Objectives: We describe a large-scale modeling project called CERAPP (Collaborative Estrogen Receptor Activity Prediction Project) and demonstrate the efficacy of using predictive computational models trained on high-throughput screening data to evaluate thousands of chemicals for ER-related activity and prioritize them for further testing. Methods: CERAPP combined multiple models developed in collaboration with 17 groups in the United States and Europe to predict ER activity of a common set of 32,464 chemical structures. Quantitative structure–activity relationship models and docking approaches were employed, mostly using a common training set of 1,677 chemical structures provided by the U.S. EPA, to build a total of 40 categorical and 8 continuous models for binding, agonist, and antagonist ER activity. All predictions were evaluated on a set of 7,522 chemicals curated from the literature. To overcome the limitations of single models, a consensus was built by weighting models on scores based on their evaluated accuracies. Results: Individual model scores ranged from 0.69 to 0.85, showing high prediction reliabilities. Out of the 32,464 chemicals, the consensus model predicted 4,001 chemicals (12.3%) as high priority actives and 6,742 potential actives (20.8%) to be considered for further testing. Conclusion: This project demonstrated the possibility to screen large libraries of chemicals using a consensus of different in silico approaches. This concept will be applied in future projects related to other

  2. Is there any diagnostic value of serum protease-activated receptor-1 (PAR1) levels on determination of epithelial ovarian carcinoma?

    PubMed

    Karabulut, S; Akşit, E; Tas, F; Ciftci, R; Aydiner, A; Yildiz, I; Keskin, S; Eralp, Y; Yasasever, C T; Vatansever, S; Disci, R; Saip, P

    2014-05-01

    The role of molecular markers in ovarian cancer is still a matter of debate. Protease-activated receptor-1 (PAR1) might be a good marker in some types of malignant tumors and might provide useful information in diagnosis and prognosis. The objective of this study was to evaluate the serum levels of PAR1 in regard to diagnostic, predictive, and prognostic value in epithelial ovarian cancer (EOC) patients. Forty-four EOC patients were enrolled in this study. Serum PAR1 levels were determined by enzyme-linked immunosorbent assay (ELISA) method. Twenty-five age- and sex-matched healthy controls were included in the analysis. The median age of patients was 58 years old, ranging from 22 to 83 years, where most of them had advanced disease (stage III-IV) (n = 40, 91%). The median serum PAR1 values were significantly elevated in patients compared to healthy controls (1.52 ng/ml vs. 1.13 ng/ml) (p = 0.03), whereas any clinical variables including response to chemotherapy did not associate with serum assay (p > 0.05). Progression-free survival (PFS) and overall survival (OS) of patients who did not respond to chemotherapy nor had platinum resistance in relapsed disease were poorer in the analyses. On the other hand, serum PAR1 levels showed no significant adverse effect on either PFS or OS (p = 0.43 and p = 0.49, respectively). These results proved that baseline serum PAR1 levels of patients with EOC were significantly higher than those of healthy people. However, these assays suggested no predictive or prognostic value in this group of patients. PMID:24390664

  3. Synthesis of a monofunctional platinum compound and its activity alone and in combination with phytochemicals in ovarian tumor models.

    PubMed

    Arzuman, Laila; Beale, Philip; Yu, Jun Qing; Proschogo, Nick; Huq, Fazlul

    2014-12-01

    Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. In this study, a new monofunctional planaramineplatinum(II) complex, namely tris(8-hydroxyquinoline)monochloroplatinum(II) chloride (coded as LH3), was synthesised and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistant A2780 (A2780(ZD0473R)) cancer cell lines, alone and in combination with the phytochemicals curcumin, genistein and resveratrol. Cellular levels of glutathione in A2780 and A2780(cisR) cell lines before and after treatment with LH3 and its combinations with genistein and curcumin were also determined. Interaction of the compounds with salmon sperm DNA, pBR322 plasmid DNA and damage to DNA in A2780 and A2780(cisR) cells due to interaction with LH3-alone and in combination with phytochemicals were also investigated. LH3 was found to be much more active than cisplatin against the resistant tumor models and greatest synergism in activity was observed when combinations of LH3 with genistein and curcumin were administered as a bolus. For combinations of LH3 with the phytochemicals, platinum accumulation and the level of Pt-DNA binding were found to be greater in the resistant A2780(cisR) cell line than in the parental A2780 cell line. Greater activity of LH3 than cisplatin against the resistant ovarian cell lines indicates that it may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy. PMID:25503135

  4. Deletion at 6q24.2-26 predicts longer survival of high-grade serous epithelial ovarian cancer patients.

    PubMed

    Kamieniak, Marta M; Rico, Daniel; Milne, Roger L; Muñoz-Repeto, Ivan; Ibáñez, Kristina; Grillo, Miguel A; Domingo, Samuel; Borrego, Salud; Cazorla, Alicia; García-Bueno, José M; Hernando, Susana; García-Donas, Jesús; Hernández-Agudo, Elena; Y Cajal, Teresa Ramón; Robles-Díaz, Luis; Márquez-Rodas, Ivan; Cusidó, Maite; Sáez, Raquel; Lacambra-Calvet, Carmen; Osorio, Ana; Urioste, Miguel; Cigudosa, Juan C; Paz-Ares, Luis; Palacios, José; Benítez, Javier; García, María J

    2015-02-01

    Standard treatments for advanced high-grade serous ovarian carcinomas (HGSOCs) show significant side-effects and provide only short-term survival benefits due to disease recurrence. Thus, identification of novel prognostic and predictive biomarkers is urgently needed. We have used 42 paraffin-embedded HGSOCs, to evaluate the utility of DNA copy number alterations, as potential predictors of clinical outcome. Copy number-based unsupervised clustering stratified HGSOCs into two clusters of different immunohistopathological features and survival outcome (HR = 0.15, 95%CI = 0.03-0.81; Padj = 0.03). We found that loss at 6q24.2-26 was significantly associated with the cluster of longer survival independently from other confounding factors (HR = 0.06, 95%CI = 0.01-0.43, Padj = 0.005). The prognostic value of this deletion was validated in two independent series, one consisting of 36 HGSOCs analyzed by fluorescent in situ hybridization (P = 0.04) and another comprised of 411 HGSOCs from the Cancer Genome Atlas study (TCGA) (HR = 0.67, 95%CI = 0.48-0.93, Padj = 0.019). In addition, we confirmed the association of low expression of the genes from the region with longer survival in 799 HGSOCs (HR = 0.74, 95%CI = 0.61-0.90, log-rank P = 0.002) and 675 high-FIGO stage HGSOCs (HR = 0.76, 95%CI = 0.61-0.96, log-rank P = 0.02) available from the online tool KM-plotter. Finally, by integrating copy number, RNAseq and survival data of 296 HGSOCs from TCGA we propose a few candidate genes that can potentially explain the association. Altogether our findings indicate that the 6q24.2-26 deletion is an independent marker of favorable outcome in HGSOCs with potential clinical value as it can be analyzed by FISH on tumor sections and guide the selection of patients towards more conservative therapeutic strategies in order to reduce side-effects and improve quality of life. PMID:25454820

  5. Endocrine assessment of ovarian cycle activity in wild female mountain gorillas (Gorilla beringei beringei).

    PubMed

    Habumuremyi, Sosthene; Stephens, Colleen; Fawcett, Katie A; Deschner, Tobias; Robbins, Martha M

    2016-04-01

    Variability of fertility (i.e. number of births per female per year) has been reported in females of many primate species but only a few studies have explored the associated physiological and behavioral patterns. To investigate the proximate mechanisms of variability in fertility of wild female mountain gorillas (Gorilla beringei beringei), we quantified the occurrence of ovulation, matings, and successful pregnancies among females. We examined the profiles of immunoreactive pregnanediol-3-glucuronide (iPdG) for sixteen females (seven nulliparous and nine parous females, including one geriatric female; average sampling period for fecal sample collection and behavioral observations per female=175 days; SD=94 days, range=66-358 days) monitored by the staff of the Dian Fossey Gorilla Fund's Karisoke Research Center in Parc National des Volcans, Rwanda. We quantified ovarian cycles from iPdG profiles using an algorithm that we developed by adjusting the method of Kassam et al. (1996) to the characteristics of ovarian cycle profiles based on fecal hormone measurements. The mean length of ovarian cycles was 29±4 days (median: 28 days, N=13 cycles), similar to ovarian cycle lengths of other great apes and humans. As expected, we found that female mountain gorillas exhibit longer follicular phases (mean±SD: 21±3 days, N=13 cycles) than luteal phases (mean±SD: 8±3 days, N=13 cycles). We also found that the frequency of ovarian cycles was greater in parous females (i.e. 20 ovarian cycles across 44 periods of 28 days; 45.5%) than in nulliparous females (i.e. two ovarian cycles across 34 periods of 28 days; 6%). However, the frequency of days on which matings were observed did not differ significantly between parous and nulliparous females, nor between pregnant and non-pregnant females. Five pregnancies were detected with iPdG levels, but only three resulted in live births, indicating miscarriages of the other two. In sum, this study provides information on the underlying

  6. Anticancer activity of pristimerin in ovarian carcinoma cells is mediated through the inhibition of prosurvival Akt/NF-κB/mTOR Signaling

    PubMed Central

    Gao, Xiaohua; Liu, Yongbo; Deeb, Dorrah; Arbab, Ali S.; Gautam, Subhash C.

    2014-01-01

    Pristimerin is a quinonemethide triterpenoid that has shown anticancer activity against some cancer types. However, the antitumor effects of pristimerin (PM) in ovarian cancer cells have not been adequately studied. The objective of the present study was to determine the anticancer activity and its mechanism of action in human ovarian carcinoma cell lines. PM strongly inhibited the proliferation of ovarian cancer cells by inducing apoptosis characterized by increased annexin V-binding, cleavage of poly (ADP-ribose) polymerase (PARP-1) and procaspases-3, -8 and -9. Furthermore, PM caused mitochondrial depolarization. Western blot analysis showed inhibition of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-κB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins in cells treated with PM. Treatment with PM also inhibited the expression of NF-κB-regulated antiapoptotic Bcl-2, Bcl-xL, c-IAP1 and survivin. Thus, our data showing potent antiproliferative and apoptosis-inducing activity of PM in ovarian carcinoma cells through the inhibition of AKT/NF-κB/mTOR signaling pathway warrant further investigation of PM for the management of ovarian cancer. PMID:25509983

  7. Ovarian haemangioma.

    PubMed

    Gunes, H A; Egilmez, R; Dulger, M

    1990-12-01

    Although ovaries have a very rich vasculature, haemangiomas of the ovary are extremely rare. There are only another 39 cases of ovarian haemangioma recorded in the literature. We describe an 11-year-old girl with an ovarian haemangioma who presented clinically with an acute abdomen. The patient has been well without complications for a year. PMID:2102218

  8. Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer.

    PubMed

    Huang, Bihui; Yin, Mingzhu; Li, Xia; Cao, Guosheng; Qi, Jin; Lou, Ge; Sheng, Shijie; Kou, Junping; Chen, Kang; Yu, Boyang

    2016-05-10

    Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC. PMID:27050277

  9. Short-Term PTEN Inhibition Improves In Vitro Activation of Primordial Follicles, Preserves Follicular Viability, and Restores AMH Levels in Cryopreserved Ovarian Tissue From Cancer Patients

    PubMed Central

    Novella-Maestre, Edurne; Herraiz, Sonia; Rodríguez-Iglesias, Beatriz; Díaz-García, César; Pellicer, Antonio

    2015-01-01

    Introduction In vitro activation and growth of primordial dormant follicles to produce fertilizable oocytes would provide a useful instrument for fertility preservation. The employment of Phosphatase and TENsin homolog (PTEN) inhibitors, in combination with Protein kinase B (Akt) stimulating molecules, has been previously employed to increase follicular activation through the stimulation of the PTEN-Akt pathway. Methods We aim to establish improved in vitro activation also for cancer patients whose ovarian tissue has already been cryopreserved. Fresh and previously cryopreserved human ovarian cortex were exposed to short-term, low-concentration and ovary-specific treatment with only a PTEN inhibitor. Results Our in vitro activation protocol enhances the activation mechanisms of primordial follicles in both fresh and cryopreserved samples, and enlarges growing populations without inducing apoptosis in either follicles or the surrounding stroma. Treatment augments estradiol secretion and restores the expression levels of the previously diminished Anti-Müllerian hormone by means of cryopreservation procedures. Genomic modulation of the relative expression of PTEN pathway genes was found in treated samples. Conclusion The in vitro activation protocol offers new alternatives for patients with cryopreserved tissue as it increases the pool of viable activated follicles available for in vitro growth procedures. The combination of ovarian tissue cryopreservation and in vitro activation of primordial follicles, the main ovarian reserve component, will be a major advancement in fertility preservation. PMID:26024525

  10. Suberoylanilide Hydroxamic Acid (SAHA) enhances olaparib activity by targeting homologous recombination DNA repair in ovarian cancer

    PubMed Central

    Konstantinopoulos, Panagiotis A.; Wilson, Andrew J.; Saskowski, Jeanette; Wass, Erica; Khabele, Dineo

    2015-01-01

    Objectives Approximately 50% of serous epithelial ovarian cancers (EOC) contain molecular defects in homologous recombination (HR) DNA repair pathways. Poly(ADP-ribose) polymerase inhibitors (PARPi) have efficacy in HR-deficient, but not HR-proficient, EOC tumors as a single agent. Our goal was to determine whether the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), can sensitize HR-proficient ovarian cancer cells to the PARPi AZD-2281 (olaparib). Methods Ovarian cancer cell lines (SKOV-3, OVCAR-8, NCI/ADR-Res, UWB1.289 BRCA1null and UWB1.289 + BRCA1 wild-type) were treated with saline vehicle, olaparib, SAHA or olaparib/SAHA. Sulforhodamine B (SRB) assessed cytotoxicity and immunofluorescence and Western blot assays assessed markers of apoptosis (cleaved PARP) and DNA damage (pH2AX and RAD51). Drug effects were also tested in SKOV-3 xenografts in Nude mice. Affymetrix microarray experiments were performed in vehicle and SAHA-treated SKOV-3 cells. Results In a microarray analysis, SAHA induced coordinated down-regulation of HR pathway genes, including RAD51 and BRCA1. Nuclear co-expression of RAD51 and pH2AX, a marker of efficient HR repair, was reduced approximately 40% by SAHA treatment alone and combined with olaparib. SAHA combined with olaparib induced apoptosis and pH2AX expression to a greater extent than either drug alone. Olaparib reduced cell viability at increasing concentrations and SAHA enhanced these effects in 4 of 5 cell lines, including BRCA1 null and wild-type cells, in vitro and in SKOV-3 xenografts in vivo. Conclusions These results provide preclinical rationale for targeting DNA damage response pathways by combining small molecule PARPi with HDACi as a mechanism for reducing HR efficiency in ovarian cancer. PMID:24631446

  11. Cell cycle arrest or survival signaling through αv integrins, activation of PKC and ERK1/2 lead to anoikis resistance of ovarian cancer spheroids.

    PubMed

    Carduner, Ludovic; Picot, Cédric R; Leroy-Dudal, Johanne; Blay, Lyvia; Kellouche, Sabrina; Carreiras, Franck

    2014-01-15

    Ovarian cancer is the most lethal gynecologic cancer mainly due to spheroids organization of cancer cells that disseminate within the peritoneal cavity. We have investigated the molecular mechanisms by which ovarian cancer spheroids resist anoikis, choosing as models the 2 well-characterized human ovarian cancer cell lines IGROV1 and SKOV3. These cell lines have the propensity to float as clusters, and were isolated from tumor tissue and ascites, respectively. To form spheroids, IGROV1 and SKOV3 ovarian adenocarcinoma cells were maintained under anchorage-independent culture conditions, in which both lines survive at least a week. A short apoptotic period prior to a survival signaling commitment was observed for IGROV1 cells whereas SKOV3 cells entered G0/G1 phase of the cell cycle. This difference in behavior was due to different signals. With regard to SKOV3 cells, activation of p38 and an increase in p130/Rb occurred once anchorage-independent culture was established. Analyses of the survival signaling pathway switched on by IGROV1 cells showed that activation of ERK1/2 was required to evade apoptosis, an effect partly dependent on PKC activation and αv integrins. αv-integrin expression is essential for survival through activation of ERK1/2 phosphorylation. The above data indicate that ovarian cancer cells can resist anoikis in the spheroid state by arrest in the cell cycle or through activation of αv-integrin-ERK-mediated survival signals. Such signaling might result in the selection of resistant cells within disseminating spheroids, favoring further relapse in ovarian cancers. PMID:24291221

  12. A novel cisplatin mediated apoptosis pathway is associated with acid sphingomyelinase and FAS proapoptotic protein activation in ovarian cancer.

    PubMed

    Maurmann, L; Belkacemi, L; Adams, N R; Majmudar, P M; Moghaddas, S; Bose, R N

    2015-07-01

    Platinum-based anticancer drugs, including cisplatin and carboplatin, have been cornerstones in the treatment of solid tumors. We report here that these DNA-damaging agents, particularly cisplatin, induce apoptosis through plasma membrane disruption, triggering FAS death receptor via mitochondrial (intrinsic) pathways. Our objectives were to: quantify the composition of membrane metabolites; and determine the potential involvement of acid sphingomyelinase (ASMase) in the FAS-mediated apoptosis in ovarian cancer after cisplatin treatment. The resulting analysis revealed enhanced apoptosis as measured by: increased phosphocholine, and glycerophosphocholine; elevated cellular energetics; and phosphocreatine and nucleoside triphosphate concentrations. The plasma membrane alterations were accompanied by increased ASMase activity, leading to the upregulation of FAS, FASL and related pro-apoptotic BAX and PUMA genes. Moreover FAS, FASL, BAX, PUMA, CASPASE-3 and -9 proteins were upregulated. Our findings implicate ASMase activity and the intrinsic pathways in cisplatin-mediated membrane demise, and contribute to our understanding of the mechanisms by which ovarian tumors may become resistant to cisplatin. PMID:25846011

  13. Neutrophil to lymphocyte ratio in the pre-treatment phase of final-line chemotherapy predicts the outcome of patients with recurrent ovarian cancer

    PubMed Central

    NAKAMURA, KEIICHIRO; NAGASAKA, TAKESHI; NISHIDA, TAKESHI; HARUMA, TOMOKO; OGAWA, CHIKAKO; KUSUMOTO, TOMOYUKI; SEKI, NORIKO; HIRAMATSU, YUJI

    2016-01-01

    Inflammation and tumor immunology are associated with prognosis in a variety of cancers. The aim of the present retrospective study was to identify associations between the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), cancer antigen 125 (CA125) concentrations, tumor response, performance status (PS) and survival of patients that developed recurrent ovarian cancer subsequent to receiving chemotherapy. The NLR and PLR measured prior to fourth-line chemotherapy were significantly increased compared with those measured prior to second-line chemotherapy (P=0.029 and 0.049, respectively). By using receiver operating characteristic curves, the cut-off values were determined for the NLR, PLR and CA125 levels that were measured during the pre-treatment phase, which predicted the outcomes. According to univariate analyses, pre-treatment NLR >3.91, PLR >299.0 and PS 2 were each significantly associated with poor outcomes (P=0.001, 0.005 and 0.021, respectively). According to multivariate analyses, only pre-treatment NLR was associated with poor outcome (P=0.035). The present findings indicate that pre-treatment NLR is an important predictor of prognosis in patients with ovarian cancer that experience recurrence following chemotherapy. PMID:27313726

  14. Prediction of primary somatosensory neuron activity during active tactile exploration

    PubMed Central

    Campagner, Dario; Evans, Mathew Hywel; Bale, Michael Ross; Erskine, Andrew; Petersen, Rasmus Strange

    2016-01-01

    Primary sensory neurons form the interface between world and brain. Their function is well-understood during passive stimulation but, under natural behaving conditions, sense organs are under active, motor control. In an attempt to predict primary neuron firing under natural conditions of sensorimotor integration, we recorded from primary mechanosensory neurons of awake, head-fixed mice as they explored a pole with their whiskers, and simultaneously measured both whisker motion and forces with high-speed videography. Using Generalised Linear Models, we found that primary neuron responses were poorly predicted by whisker angle, but well-predicted by rotational forces acting on the whisker: both during touch and free-air whisker motion. These results are in apparent contrast to previous studies of passive stimulation, but could be reconciled by differences in the kinematics-force relationship between active and passive conditions. Thus, simple statistical models can predict rich neural activity elicited by natural, exploratory behaviour involving active movement of sense organs. DOI: http://dx.doi.org/10.7554/eLife.10696.001 PMID:26880559

  15. Ovarian Cancer FAQ

    MedlinePlus

    ... Ovarian Cancer Patient Education FAQs Ovarian Cancer Patient Education Pamphlets - Spanish Ovarian Cancer FAQ096, April 2015 PDF Format Ovarian ... Your Practice Patient Safety & Quality Payment Reform (MACRA) Education & Events Annual ... Pamphlets Teen Health About ACOG About Us Leadership & ...

  16. Changes in O-Linked N-Acetylglucosamine (O-GlcNAc) Homeostasis Activate the p53 Pathway in Ovarian Cancer Cells.

    PubMed

    de Queiroz, Rafaela Muniz; Madan, Rashna; Chien, Jeremy; Dias, Wagner Barbosa; Slawson, Chad

    2016-09-01

    O-GlcNAcylation is a dynamic post-translational modification consisting of the addition of a single N-acetylglucosamine sugar to serine and threonine residues in proteins by the enzyme O-linked β-N-acetylglucosamine transferase (OGT), whereas the enzyme O-GlcNAcase (OGA) removes the modification. In cancer, tumor samples present with altered O-GlcNAcylation; however, changes in O-GlcNAcylation are not consistent between tumor types. Interestingly, the tumor suppressor p53 is modified by O-GlcNAc, and most solid tumors contain mutations in p53 leading to the loss of p53 function. Because ovarian cancer has a high frequency of p53 mutation rates, we decided to investigate the relationship between O-GlcNAcylation and p53 function in ovarian cancer. We measured a significant decrease in O-GlcNAcylation of tumor tissue in an ovarian tumor microarray. Furthermore, O-GlcNAcylation was increased, and OGA protein and mRNA levels were decreased in ovarian tumor cell lines not expressing the protein p53. Treatment with the OGA inhibitor Thiamet-G (TMG), silencing of OGA, or overexpression of OGA and OGT led to p53 stabilization, increased nuclear localization, and increased protein and mRNA levels of p53 target genes. These data suggest that changes in O-GlcNAc homeostasis activate the p53 pathway. Combination treatment of the chemotherapeutic cisplatin with TMG decreased tumor cell growth and enhanced cell cycle arrest without impairing cytotoxicity. The effects of TMG on tumor cell growth were partially dependent on wild type p53 activation. In conclusion, changes in O-GlcNAc homeostasis activate the wild type p53 pathway in ovarian cancer cells, and OGA inhibition has the potential as an adjuvant treatment for ovarian carcinoma. PMID:27402830

  17. Ricinus communis L. stem bark extracts regulate ovarian cell functions and secretory activity and their response to Luteinising hormone.

    PubMed

    Nath, S; Kadasi, A; Grossmann, R; Sirotkin, A V; Kolesarova, A; Talukdar, A D; Choudhury, M D

    2015-01-01

    Ricinus communis L. has ethnopharmacological contraceptive reputation but its stem bark has unexplored mechanisms of action in female reproductive system. In the present study, the effect of methanolic and aqueous extracts from the stem bark of the plant was examined on basic porcine ovarian granulosa cell functions and its response to Luteinising hormone (LH)-the upstream hormonal regulator. Systemic treatment of methanolic and aqueous extracts stimulated cell proliferation (proliferating cell nuclear antigen, PCNA) and also promoted cell apoptosis (caspase-3). Aqueous extract has inverted the stimulatory effect of LH on PCNA but not on caspase-3. Methanolic extract stimulated as well as inhibited progesterone release and stimulated testosterone secretion. Whereas aqueous extract inhibited both steroid releases and suppressed the stimulatory effect of LH on progesterone release and promoted the inhibitory effect of LH on testosterone release. In conclusion, the present study unveils the mechanism of action of R. communis stem bark in in vitro condition. These suggest its possible contraceptive efficacy by exerting its regulatory role over LH and on basic ovarian cell functions and secretion activity. PMID:26311247

  18. Distinct prognostic values of four-Notch-receptor mRNA expression in ovarian cancer.

    PubMed

    Zhou, Xinling; Teng, Lingling; Wang, Min

    2016-05-01

    Notch signaling pathway includes ligands and Notch receptors, which are frequently deregulated in several human malignancies including ovarian cancer. Aberrant activation of Notch signaling has been linked to ovarian carcinogenesis and progression. In the current study, we used the "Kaplan-Meier plotter" (KM plotter) database, in which updated gene expression data and survival information from a total of 1306 ovarian cancer patients were used to access the prognostic value of four Notch receptors in ovarian cancer patients. Hazard ratio (HR), 95 % confidence intervals, and log-rank P were calculated. Notch1 messenger RNA (mRNA) high expression was not found to be correlated to overall survival (OS) for all ovarian cancer, as well as in serous and endometrioid cancer patients followed for 20 years. However, Notch1 mRNA high expression is significantly associated with worsen OS in TP53 wild-type ovarian cancer patients, while it is significantly associated with better OS in TP53 mutation-type ovarian cancer patients. Notch2 mRNA high expression was found to be significantly correlated to worsen OS for all ovarian cancer patients, as well as in grade II ovarian cancer patients. Notch3 mRNA high expression was found to be significantly correlated to better OS for all ovarian cancer patients, but not in serous cancer patients and endometrioid cancer patients. Notch4 mRNA high expression was not found to be significantly correlated to OS for all ovarian cancer patients, serous cancer patients, and endometrioid cancer patients. These results indicate that there are distinct prognostic values of four Notch receptors in ovarian cancer. This information will be useful for better understanding of the heterogeneity and complexity in the molecular biology of ovarian cancer and for developing tools to more accurately predict their prognosis. Based on our results, Notch1 could be a potential drug target of TP53 wild-type ovarian cancer and Notch2 could be a potential drug

  19. Identification of predictive factors of response to the BH3-mimetic molecule ABT-737: an ex vivo experiment in human serous ovarian carcinoma.

    PubMed

    Lheureux, Stéphanie; N'Diaye, Monique; Blanc-Fournier, Cécile; Dugué, Audrey Emmanuelle; Clarisse, Bénédicte; Dutoit, Soizic; Giffard, Florence; Abeilard, Edwige; Briand, Mélanie; Labiche, Alexandre; Grellard, Jean-Michel; Crouet, Hubert; Martin, Sandrine; Joly, Florence; Poulain, Laurent

    2015-03-01

    Ovarian cancers are addicted to Bcl-xL and Mcl-1, antiapoptotic members of the Bcl-2 family. Bcl-xL can be inhibited by the BH3-mimetic ABT-737. In vitro, ABT-737 can induce apoptosis of cancer cells, and its activity is potentiated by Mcl-1 inactivation. Herein, we assessed the sensitivity of human ovarian tumor nodes to ABT-737 when combined with carboplatin, which can indirectly inhibit Mcl-1. Fresh samples from 25 patients with high-grade serous ovarian cancer (HGSOC) who were chemo-naïve and had undergone surgery were prospectively exposed ex vivo to ABT-737 ± carboplatin. The treatment effect was studied on sliced tumor nodes by assessment of cleaved-caspase 3 immunostaining. We also studied the association between baseline Bcl-2 family protein expression (via immunohistochemistry) and the response of nodes to treatment. ABT-737 induced apoptosis as a single agent but its efficacy was not improved by the addition of carboplatin. Bim was frequently expressed (20/25) and its absence or low expression was associated with the absence of response to ABT-737, p value = 0.019 by Fisher's test and sensitivity = 93%, (95% confidence interval, 66-100). Moreover, we observed that in tumors in which Bim was expressed, a low expression of phospho-Erk1/2 or Mcl-1 improved the proportion of responses. This pilot study showed that ABT-737 has promise as monotherapy for HGSOC in a specific subgroup of tumors. Bim, Mcl-1, and phospho-Erk1/2 appeared to be relevant biomarkers that could be used for the selection of patients in the design of clinical trials using Navitoclax (an orally available compound related to ABT-737). PMID:25066666

  20. Ovarian hypofunction

    MedlinePlus

    ... may be caused by genetic factors such as chromosome abnormalities. It may also occur with certain autoimmune disorders that disrupt the normal function of the ovaries. Chemotherapy and radiation therapy can also cause ovarian hypofunction.

  1. Ovarian Cysts

    MedlinePlus

    ... information Endometriosis fact sheet Ovarian cancer fact sheet Polycystic ovary syndrome fact sheet The javascript used in this widget ... ovaries make many small cysts. This is called polycystic ovary syndrome (PCOS). PCOS can cause problems with the ovaries ...

  2. Ovarian cysts

    MedlinePlus

    ... cysts due to hormone-related conditions such as polycystic ovary syndrome . Symptoms Ovarian cysts often cause no symptoms. An ... You may need other treatments if you have polycystic ovary syndrome or another disorder that can cause cysts. Outlook ( ...

  3. Metabolic and energy status during the dry period is crucial for the resumption of ovarian activity postpartum in dairy cows.

    PubMed

    Castro, N; Kawashima, C; van Dorland, H A; Morel, I; Miyamoto, A; Bruckmaier, R M

    2012-10-01

    It is well known that the degree of negative energy balance in high-producing dairy cows is the major cause of delayed resumption of the ovarian cyclicity that closely relates to fertility. Recent evidence suggests that the energetic situation during early lactation critically affects nutrient partitioning, metabolism, and the reproductive axis, whereas the effect of energy status during the dry period is widely unknown. The aim of the present study was to investigate the effect of energy status throughout the entire dry period until early lactation on the onset of the ovarian cyclicity. Blood samples were taken in 23 cows from dry off at 8 wk before expected parturition to 8 wk postpartum for the analyses of metabolites and hormones, and milk samples were obtained 3 times weekly from d 7 of lactation onward to confirm luteal activity and pregnancy by milk progesterone analysis. Energy balance (EB) was measured weekly during the last 6 wk of the dry period and every other week after parturition. Liver biopsies were obtained at 8 wk before expected calving, within 1 d after calving, and at 4 wk postpartum to measure the mRNA abundance of various gluconeogenic enzymes and metabolic hormone receptors. Cows showing luteal activity within 3 wk postpartum were defined as ovulatory during the first follicular wave postpartum (OC), whereas cows without luteal activity within 3 wk postpartum were defined as anovulatory (AC). Energy balance and, concomitantly, plasma concentrations of glucose, insulin, insulin-like growth factor-1, 3,5,3'-triiodothyronine, and thyroxine were higher in OC than in AC during the dry period. Plasma thyroxine concentrations and body condition score during the postpartum period were higher in OC than in AC. At the mRNA level (19 cows), hepatic insulin receptor decreased from dry off to early lactation, and mRNA of pyruvate carboxylase was highest at parturition and decreased in early lactation in AC only, whereas both parameters remained unchanged

  4. LOH at 6q and 10q in fractionated circulating DNA of ovarian cancer patients is predictive for tumor cell spread and overall survival

    PubMed Central

    2012-01-01

    Background We recently showed that LOH proximal to M6P/IGF2R locus (D6S1581) in primary ovarian tumors is predictive for the presence of disseminated tumor cells (DTC) in the bone marrow (BM). For therapy-monitoring, it would be highly desirable to establish a blood-based biomarker. Therefore, we quantified circulating DNA (cirDNA) in sera of 63 ovarian cancer patients before surgery and after chemotherapy, measured incidence of LOH at four cancer-relevant chromosomal loci, correlated LOH with tumor cell spread to the BM and evaluated prognostic significance of LOH. Methods cirDNA was fractionated into high- and low molecular-weight fraction (HMWF, LMWF) for LOH-profiling, utilizing PCR-based fluorescence microsatellite analysis. BM aspirates were analyzed for DTC by immunocytochemistry using the pan-cytokeratin antibody A45-B/B3. Results cirDNA levels in the HMWF before surgery were predictive for residual tumor load (p = 0.017). After chemotherapy, we observed a significant decline of cirDNA in the LMWF (p = 0.0001) but not in the HMWF. LOH was prevalently detected in the LMWF with an overall frequency of 67%, only moderately ablating after chemotherapy (45%). Before surgery, LOH in the LMWF at marker D10S1765 and D13S218 significantly correlated with tumor grading and FIGO stage (p = 0.033, p = 0.004, respectively). In both combined fractions, LOH at D6S1581 additionally associated with overall survival (OS) (p = 0.030). Moreover, solely LOH at D10S1765 in LMWF after therapy correlated with DTC in BM after therapy (p = 0.017). Conclusion We demonstrate the applicability and necessity of DNA-fractionation prior to analyzing circulating LOH and identify LOH at D10S1765 and D6S1581 as novel blood-based biomarkers for ovarian cancer, being relevant for therapy-monitoring. PMID:22849543

  5. Quantitative measurement of adiposity using CT images to predict the benefit of bevacizumab-based chemotherapy in epithelial ovarian cancer patients

    PubMed Central

    WANG, YUNZHI; THAI, THERESA; MOORE, KATHLEEN; DING, KAI; MCMEEKIN, SCOTT; LIU, HONG; ZHENG, BIN

    2016-01-01

    The present study aims to quantitatively measure adiposity-related image features and to test the feasibility of applying multivariate statistical data analysis-based prediction models to generate a novel clinical marker and predict the benefit of epithelial ovarian cancer (EOC) patients with and without maintenance bevacizumab-based chemotherapy. A dataset involving computed tomography (CT) images acquired from 59 patients diagnosed with advanced EOC was retrospectively collected. Among them, 32 patients received maintenance bevacizumab following primary chemotherapy, while 27 did not. A computer-aided detection scheme was developed to automatically segment visceral and subcutaneous fat areas depicted on CT images of abdominal sections, and 7 adiposity-related image features were computed. Upon combining these features with the measured body mass index, multivariate data analyses were performed using three statistical models (multiple linear, logistic and Cox proportional hazards regressions) to analyze the association between the model-generated prediction results and the treatment outcome, including progression-free survival (PFS) and overall survival (OS) of the patients. The results demonstrated that applying all three prediction models yielded a significant association between the adiposity-related image features and patients' PFS or OS in the group of the patients who received maintenance bevacizumab (P<0.010), while there was no significant difference when these prediction models were applied to predict both PFS and OS in the group of patients that did not receive maintenance bevacizumab. Therefore, the present study demonstrated that the use of a quantitative adiposity-related image feature-based statistical model may generate a novel clinical marker to predict who will benefit among EOC patients receiving maintenance bevacizumab-based chemotherapy. PMID:27347200

  6. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer

    PubMed Central

    Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-01-01

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  7. Accumulation of ALDH1-positive cells after neoadjuvant chemotherapy predicts treatment resistance and prognosticates poor outcome in ovarian cancer.

    PubMed

    Ayub, Tiyasha H; Keyver-Paik, Mignon-Denise; Debald, Manuel; Rostamzadeh, Babak; Thiesler, Thore; Schröder, Lars; Barchet, Winfried; Abramian, Alina; Kaiser, Christina; Kristiansen, Glen; Kuhn, Walther; Kübler, Kirsten

    2015-06-30

    Although ovarian cancer is a highly chemosensitive disease, it is only infrequently cured. One of the major reasons lies in the presence of drug-resistant cancer stem-like cells, sufficient to fuel recurrence. We phenotyped cancer stem-like cells by flow cytometry and immunohistochemistry in 55 matched samples before and after taxane/platinum-based neoadjuvant chemotherapy. All used markers of stemness (ALDH1, CD24, CD117, CD133) isolated low frequencies of malignant cells. ALDH1 was the most valuable marker for tracking stemness in vivo. The enrichment of ALDH1 expression after treatment was associated with a poor response to chemotherapy, with platinum resistance and independently prognosticated unfavorable outcome. Our results suggest that increased ALDH1 expression after treatment identifies patients with aggressive tumor phenotypes. PMID:25999351

  8. Neural predictive control for active buffet alleviation

    NASA Astrophysics Data System (ADS)

    Pado, Lawrence E.; Lichtenwalner, Peter F.; Liguore, Salvatore L.; Drouin, Donald

    1998-06-01

    The adaptive neural control of aeroelastic response (ANCAR) and the affordable loads and dynamics independent research and development (IRAD) programs at the Boeing Company jointly examined using neural network based active control technology for alleviating undesirable vibration and aeroelastic response in a scale model aircraft vertical tail. The potential benefits of adaptive control includes reducing aeroelastic response associated with buffet and atmospheric turbulence, increasing flutter margins, and reducing response associated with nonlinear phenomenon like limit cycle oscillations. By reducing vibration levels and thus loads, aircraft structures can have lower acquisition cost, reduced maintenance, and extended lifetimes. Wind tunnel tests were undertaken on a rigid 15% scale aircraft in Boeing's mini-speed wind tunnel, which is used for testing at very low air speeds up to 80 mph. The model included a dynamically scaled flexible fail consisting of an aluminum spar with balsa wood cross sections with a hydraulically powered rudder. Neural predictive control was used to actuate the vertical tail rudder in response to strain gauge feedback to alleviate buffeting effects. First mode RMS strain reduction of 50% was achieved. The neural predictive control system was developed and implemented by the Boeing Company to provide an intelligent, adaptive control architecture for smart structures applications with automated synthesis, self-optimization, real-time adaptation, nonlinear control, and fault tolerance capabilities. It is designed to solve complex control problems though a process of automated synthesis, eliminating costly control design and surpassing it in many instances by accounting for real world non-linearities.

  9. Limits of Predictability of Solar Activity

    NASA Astrophysics Data System (ADS)

    Kremliovsky, M. N.

    1995-07-01

    The study of a nonlinear chaotic map of 11-year cycle maxima evolution recently derived from observations is presented with the purpose of predicting the features of the long-term variability of solar activity. It is stressed that dynamical forecast is limited by the Lyapunov time and a statistical approach can be justified due to the ergodic properties of the chaotic evolution. The Gleissberg variation is described as a chaotic walk and its distribution over length is shown to be broad. The global minima are identified as laminar slots of temporal intermittency and their typical distribution over length is also given. We note that a long sunspot cycle can be used as a precursor of the global minimum and a close sequence of global minima (once in approximately 1500 2000 years) may be responsible for the climatic changes (Little Ice Ages).

  10. Role of JNK Activation and Mitochondrial Bax Translocation in Allicin-Induced Apoptosis in Human Ovarian Cancer SKOV3 Cells

    PubMed Central

    Xu, Ling; Yu, Jin; Zhai, Dongxia; Zhang, Danying; Shen, Wei; Bai, Lingling; Cai, Zailong; Yu, Chaoqin

    2014-01-01

    Background. Allicin, the major component of freshly crushed garlic, is one of the most biologically active compounds of garlic; it has been reported to induce apoptosis in cancer cells; however, the mechanism by which allicin exerts its apoptotic effects is not fully understood. The aim of the present study was to further elucidate the apoptotic pathways induced by allicin in the human ovarian cancer cell line SKOV3. Methods. Cell proliferation and apoptosis were measured by cell-counting assay and flow cytometry analysis. Activation of the signaling pathway was screened by human phospho-kinase array analysis, and the activated pathway and its related proteins were further confirmed by western blot analysis. Results. Allicin induced SKOV3 cell apoptosis and JNK phosphorylation in a time- and dose-dependent manner, but these were significantly blocked by SP600125 (an inhibitor of JNK). The findings suggest that JNK phosphorylation is related to the action of allicin on SKOV3 cells. Furthermore, JNK activation induced Bcl-2 family activation, triggered mitochondria-mediated signaling pathways, and led to the translocation of a considerable amount of Bax and cytochrome c release. Conclusions. JNK activation and mitochondrial Bax translocation are involved in allicin-induced apoptosis in SKOV3 cells. Our data input new insights to the literature of allicin-induced apoptosis. PMID:25097657

  11. Radiosensitivity profiles from a panel of ovarian cancer cell lines exhibiting genetic alterations in p53 and disparate DNA-dependent protein kinase activities

    SciTech Connect

    Langland, Gregory T.; Yannone, Steven M.; Langland, Rachel A.; Nakao, Aki; Guan, Yinghui; Long, Sydney B.T.; Vonguyen, Lien; Chen, David J.; Gray, Joe W; Chen, Fanqing

    2009-09-07

    The variability of radiation responses in ovarian tumors and tumor-derived cell lines is poorly understood. Since both DNA repair capacity and p53 status can significantly alter radiation sensitivity, we evaluated these factors along with radiation sensitivity in a panel of sporadic human ovarian carcinoma cell lines. We observed a gradation of radiation sensitivity among these sixteen lines, with a five-fold difference in the LD50 between the most radiosensitive and the most radioresistant cells. The DNA-dependent protein kinase (DNA-PK) is essential for the repair of radiation induced DNA double-strand breaks in human somatic cells. Therefore, we measured gene copy number, expression levels, protein abundance, genomic copy and kinase activity for DNA-PK in all of our cell lines. While there were detectable differences in DNA-PK between the cell lines, there was no clear correlation with any of these differences and radiation sensitivity. In contrast, p53 function as determined by two independent methods, correlated well with radiation sensitivity, indicating p53 mutant ovarian cancer cells are typically radioresistant relative to p53 wild-type lines. These data suggest that the activity of regulatory molecules such as p53 may be better indicators of radiation sensitivity than DNA repair enzymes such as DNAPK in ovarian cancer.

  12. Anti-proliferative activity and cell cycle arrest induced by evodiamine on paclitaxel-sensitive and -resistant human ovarian cancer cells

    PubMed Central

    Zhong, Zhang-Feng; Tan, Wen; Wang, Sheng-Peng; Qiang, Wen-An; Wang, Yi-Tao

    2015-01-01

    Chemo-resistance is the main factor for poor prognosis in human ovarian epithelial cancer. Active constituents derived from Chinese medicine with anti-cancer potential might circumvent this obstacle. In our present study, evodiamine (EVO) derived from Evodia rutaecarpa (Juss.) Benth suppressed the proliferation of human epithelial ovarian cancer, A2780 and the related paclitaxel-resistant cell lines and did not cause cytotoxicity, as confirmed by the significant decline of clone formation and the representative alterations of CFDA-SE fluorescence. Meanwhile, EVO induced cell cycle arrest in a dose- and time-dependent manner. This disturbance might be mediated by the cooperation of Cyclin B1 and Cdc2, including the up-regulation of Cyclin B1, p27, and p21, and activation failure of Cdc2 and pRb. MAPK signaling pathway regulation also assisted in this process. Furthermore, chemo-sensitivity potential was enhanced as indicated in A2780/PTXR cells by the down-regulation of MDR-1 expression, accompanied by MDR-1 function suppression. Taken together, we confirmed initially that EVO exerted an anti-proliferative effect on human epithelial ovarian cancer cells, A2780/WT and A2780/PTXR, induced G2/M phase cell cycle arrest, and improved chemo-resistance. Overall, we found that EVO significantly suppressed malignant proliferation in human epithelial ovarian cancer, thus proving to be a potential anti-cancer agent in the future. PMID:26553648

  13. Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer.

    PubMed

    Previs, Rebecca A; Armaiz-Pena, Guillermo N; Lin, Yvonne G; Davis, Ashley N; Pradeep, Sunila; Dalton, Heather J; Hansen, Jean M; Merritt, William M; Nick, Alpa M; Langley, Robert R; Coleman, Robert L; Sood, Anil K

    2015-12-01

    There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-α, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8-MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (microvessel density, MVD) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, P < 0.01 and 96% in the HeyA8 model, P < 0.03) compared with vehicle (P < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (P < 0.03). The greatest reduction in MVD (P < 0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared with other groups (P < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development. PMID:26516159

  14. Solar-terrestrial predictions proceedings. Volume 4: Prediction of terrestrial effects of solar activity

    NASA Technical Reports Server (NTRS)

    Donnelly, R. E. (Editor)

    1980-01-01

    Papers about prediction of ionospheric and radio propagation conditions based primarily on empirical or statistical relations is discussed. Predictions of sporadic E, spread F, and scintillations generally involve statistical or empirical predictions. The correlation between solar-activity and terrestrial seismic activity and the possible relation between solar activity and biological effects is discussed.

  15. Age related increase in mTOR activity contributes to the pathological changes in ovarian surface epithelium

    PubMed Central

    Bajwa, Preety; Nagendra, Prathima B.; Nielsen, Sarah; Sahoo, Subhransu S.; Bielanowicz, Amanda; Lombard, Janine M.; Wilkinson, Erby J.; Miller, Richard A.; Tanwar, Pradeep S.

    2016-01-01

    Ovarian cancer is a disease of older women. However, the molecular mechanisms of ovarian aging and their contribution to the pathogenesis of ovarian cancer are currently unclear. mTOR signalling is a major regulator of aging as suppression of this pathway extends lifespan in model organisms. Overactive mTOR signalling is present in up to 80% of ovarian cancer samples and is associated with poor prognosis. This study examined the role of mTOR signalling in age-associated changes in ovarian surface epithelium (OSE). Histological examination of ovaries from both aged mice and women revealed OSE cell hyperplasia, papillary growth and inclusion cysts. These pathological lesions expressed bonafide markers of ovarian cancer precursor lesions, Pax8 and Stathmin 1, and were presented with elevated mTOR signalling. To understand whether overactive mTOR signalling is responsible for the development of these pathological changes, we analysed ovaries of the Pten trangenic mice and found significant reduction in OSE lesions compared to controls. Furthermore, pharmacological suppression of mTOR signalling significantly decreased OSE hyperplasia in aged mice. Treatment with mTOR inhibitors reduced human ovarian cancer cell viability, proliferation and colony forming ability. Collectively, we have established the role of mTOR signalling in age-related OSE pathologies and initiation of ovarian cancer. PMID:27036037

  16. Pre-test prediction models of BRCA1 or BRCA2 mutation in breast/ovarian families attending familial cancer clinics

    PubMed Central

    de la Hoya, M; Diez, O; Perez-Segura, P; Godino, J; Fernandez, J; Sanz, J; Alonso, C; Baiget, M; Diaz-Rubio, E; Caldes, T

    2003-01-01

    Objective: To test whether statistical models developed to calculate pre-test probability of being a BRCA1/2 carrier can differentiate better between the breast/ovarian families to be referred to the DNA test laboratory. Study design: A retrospective analysis was performed in 109 Spanish breast/ovarian families previously screened for germline mutations in both the BRCA1 and BRCA2 genes. Four easy to use logistic regression models originally developed in Spanish (HCSC model), Dutch (LUMC model), Finnish (HUCH model), and North American (U Penn model) families and one model based on empirical data of Frank 2002 were tested. A risk counsellor was asked to assign a subjective pre-test probability for each family. Sensitivity, specificity, negative and positive predictive values, and areas under receiver operator characteristics (ROC) curves were calculated in each case. Correlation between predicted probability and mutation prevalence was tested. All statistical tests were two sided. Results: Overall, the models performed well, improving the performances of a genetic counsellor. The median ROC curve area was 0.80 (range 0.77-0.82). At 100% sensitivity, the median specificity was 30% (range 25-33%). At 92% sensitivity, the median specificity was 42% (range 33.3-54.2%) and the median negative predictive value was 93% (range 89.7-98%). BRCA1 families tended to score higher risk than BRCA2 families in all models tested. Conclusions: All models increased the discrimination power of an experienced risk counsellor, suggesting that their use is valuable in the context of clinical counselling and genetic testing to optimise selection of patients for screening and allowing for more focused management. Models developed in different ethnic populations performed similarly well in a Spanish series of families, suggesting that models targeted to specific populations may not be necessary in all cases. Carrier probability as predicted by the models is consistent with actual prevalence

  17. Predictive value of the age-adjusted charlson comorbidity index on perioperative complications and survival in patients undergoing primary debulking surgery for advanced epithelial ovarian cancer

    PubMed Central

    Suidan, Rudy S.; Leitao, Mario M.; Zivanovic, Oliver; Gardner, Ginger J.; Long Roche, Kara C.; Sonoda, Yukio; Levine, Douglas A.; Jewell, Elizabeth L.; Brown, Carol L.; Abu-Rustum, Nadeem R.; Charlson, Mary E.; Chi, Dennis S.

    2016-01-01

    Objective To assess the ability of the Age-Adjusted Charlson Comorbidity index (ACCI) to predict perioperative complications and survival in patients undergoing primary debulking for advanced epithelial ovarian cancer (EOC). Methods Data were analyzed for all patients with stage IIIB-IV EOC who underwent primary cytoreduction from 1/2001–1/2010 at our institution. Patients were divided into 3 groups based on an ACCI of 0–1, 2–3, and ≥4. Clinical and survival outcomes were assessed and compared. Results We identified 567 patients; 199 (35%) had an ACCI of 0–1, 271 (48%) had an ACCI of 2–3, and 97 (17%) had an ACCI of ≥4. The ACCI was significantly associated with the rate of complete gross resection (0–1=44%, 2–3=32%, and ≥4=32%; p=0.02), but was not associated with the rate of minor (47% vs 47% vs 43%, p=0.84) or major (18% vs 19% vs 16%, p=0.8) complications. The ACCI was also significantly associated with progression-free (PFS) and overall survival (OS). Median PFS for patients with an ACCI of 0–1, 2–3, and ≥4 was 20.3, 16, and 15.4 months, respectively (p=0.02). Median OS for patients with an ACCI of 0–1, 2–3, and ≥4 was 65.3, 49.9, and 42.3 months, respectively (p<0.001). On multivariate analysis, the ACCI remained a significant prognostic factor for both PFS (p=0.02) and OS (p<0.001). Conclusions The ACCI was not associated with perioperative complications in patients undergoing primary cytoreduction for advanced EOC, but was a significant predictor of PFS and OS. Prospective clinical trials in ovarian cancer should consider stratifying for an age-comorbidity covariate. PMID:26037900

  18. Expression profile of COL2A1 and the pseudogene SLC6A10P predicts tumor recurrence in high-grade serous ovarian cancer.

    PubMed

    Ganapathi, Mahrukh K; Jones, Wendell D; Sehouli, Jalid; Michener, Chad M; Braicu, Ioana E; Norris, Eric J; Biscotti, Charles V; Vaziri, Susan A J; Ganapathi, Ram N

    2016-02-01

    Tumor recurrence, following initial response to adjuvant chemotherapy, is a major problem in women with high-grade serous ovarian cancer (HGSOC). Microarray analysis of primary tumors has identified genes that may be useful in risk stratification/overall survival, but are of limited value in predicting the >70% rate for tumor recurrence. In this study, we performed RNA-Seq analysis of primary and recurrent HGSOC to first identify unique differentially expressed genes. From this dataset, we selected 21 archetypical coding genes and one noncoding RNA, based on statistically significant differences in their expression profile between tumors, for validation by qPCR in a larger cohort of 110 ovarian tumors (71 primary and 39 recurrent) and for testing association of specific genes with time-to-recurrence (TTR). Kaplan-Meier tests revealed that high expression of collagen type II, alpha 1 (COL2A1) was associated with delayed TTR (HR = 0.47, 95% CI: 0.27-0.82, p = 0.008), whereas low expression of the pseudogene, solute carrier family 6 member 10 (SLC6A10P), was associated with longer TTR (HR = 0.53, 95% CI: 0.30-0.93, p = 0.027). Notably, TTR was significantly delayed for tumors that simultaneously highly expressed COL2A1 and lowly expressed SLC6A10P (HR = 0.21, 95% CI: 0.082-0.54, p = 0.0011), an estimated median of 95 months as compared to an estimated median of 16 months for subjects expressing other levels of COL2A1 and SLC6A10P. Thus, evaluating expression levels of COL2A1 and SLC6A10P at primary surgery could be beneficial for clinically managing recurrence of HGSOC. PMID:26311224

  19. Integrated self-assembling drug delivery system possessing dual responsive and active targeting for orthotopic ovarian cancer theranostics.

    PubMed

    Lin, Chun-Jui; Kuan, Chen-Hsiang; Wang, Li-Wen; Wu, Hsi-Chin; Chen, Yunching; Chang, Chien-Wen; Huang, Rih-Yang; Wang, Tzu-Wei

    2016-06-01

    Ovarian cancers are the leading cause for mortality among gynecologic malignancies with five-year survival rate less than 30%. The purpose of this study is to develop a redox and pH-sensitive self-assembling hyaluronic acid nanoparticle with active targeting peptide for anticancer drug delivery. Anti-cancer drug is grafted onto hyaluronic acid (HA) via cis-aconityl linkage and disulfide bond to possess pH sensitivity and redox property, respectively. This conjugate is amphiphilic and can self-assemble into nanoparticle (NP) in aqueous solution. The results show that the nanoconjugate is successfully developed and the grafting ratio of cystamine (cys) is 17.8% with drug loading amount about 6.2% calculated by (1)H NMR spectra. The particle size is approximately 229.0 nm using dynamic light scatting measurement, and the morphology of nanoparticles is observed as spherical shape by transmission electron microscope. The pH and redox sensitivities are evaluated by changing either pH value or concentration of dithiothreitol in the medium. It is proved that the drug carrier is capable of achieving sustained controlled release of anti-cancer drug to 95% within 150 h. The intracellular uptake is observed by fluorescent microscope and the images show that conjugating luteinizing hormone-releasing hormone (LHRH) peptide can enhance specific uptake of nanoparticles by OVCAR-3 cancer cells; thus, resulting in inhibitory cell growth to less than 20% in 72 h in vitro. Orthotopic ovarian tumor model is also established to evaluate the therapeutic and diagnostic efficacy using non-invasive in vivo imaging system. The representative results demonstrate that LHRH-conjugated NPs possess a preferable tumor imaging capability and an excellent antitumor ability to almost 30% of original size in 20 days. PMID:26974704

  20. The Aminosteroid Derivative RM-133 Shows In Vitro and In Vivo Antitumor Activity in Human Ovarian and Pancreatic Cancers

    PubMed Central

    Kenmogne, Lucie Carolle; Ayan, Diana; Roy, Jenny; Maltais, René; Poirier, Donald

    2015-01-01

    Ovarian and pancreatic cancers are two of the most aggressive and lethal cancers, whose management faces only limited therapeutic options. Typically, these tumors spread insidiously accompanied first with atypical symptoms, and usually shift to a drug resistance phenotype with the current pharmaceutical armamentarium. Thus, the development of new drugs acting via a different mechanism of action represents a clear priority. Herein, we are reporting for the first time that the aminosteroid derivative RM-133, developed in our laboratory, displays promising activity on two models of aggressive cancers, namely ovarian (OVCAR-3) and pancreatic (PANC-1) cancers. The IC50 value of RM-133 was 0.8 μM and 0.3 μM for OVCAR-3 and PANC-1 cell lines in culture, respectively. Based on pharmacokinetic studies on RM-133 using 11 different vehicles, we selected two main vehicles: aqueous 0.4% methylcellulose:ethanol (92:8) and sunflower oil:ethanol (92:8) for in vivo studies. Using subcutaneous injection of RM-133 with the methylcellulose-based vehicle, growth of PANC-1 tumors xenografted to nude mice was inhibited by 63%. Quite interestingly, RM-133 injected subcutaneously with the methylcellulose-based or sunflower-based vehicles reduced OVCAR-3 xenograft growth by 122% and 100%, respectively. After the end of RM-133 treatment using the methylcellulose-based vehicle, OVCAR-3 tumor growth inhibition was maintained for ≥ 1 week. RM-133 was also well tolerated in the whole animal, no apparent sign of toxicity having been detected in the xenograft studies. PMID:26660672

  1. Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival1

    PubMed Central

    Mullany, Lisa K.; Wong, Kwong-Kwok; Marciano, David C.; Katsonis, Panagiotis; King-Crane, Erin R.; Ren, Yi Athena; Lichtarge, Olivier; Richards, JoAnne S.

    2015-01-01

    Evolutionary Action analyses of The Cancer Gene Atlas data sets show that many specific p53 missense and gain-of-function mutations are selectively overrepresented and functional in high-grade serous ovarian cancer (HGSC). As homozygous alleles, p53 mutants are differentially associated with specific loss of heterozygosity (R273; chromosome 17); copy number variation (R175H; chromosome 9); and up-stream, cancer-related regulatory pathways. The expression of immune-related cytokines was selectively related to p53 status, showing for the first time that specific p53 mutants impact, and are related to, the immune subtype of ovarian cancer. Although the majority (31%) of HGSCs exhibit loss of heterozygosity, a significant number (24%) maintain a wild-type (WT) allele and represent another HGSC subtype that is not well defined. Using human and mouse cell lines, we show that specific p53 mutants differentially alter endogenous WT p53 activity; target gene expression; and responses to nutlin-3a, a small molecular that activates WT p53 leading to apoptosis, providing “proof of principle” that ovarian cancer cells expressing WT and mutant alleles represent a distinct ovarian cancer subtype. We also show that siRNA knock down of endogenous p53 in cells expressing homozygous mutant alleles causes apoptosis, whereas cells expressing WT p53 (or are heterozygous for WT and mutant p53 alleles) are highly resistant. Therefore, despite different gene regulatory pathways associated with specific p53 mutants, silencing mutant p53 might be a suitable, powerful, global strategy for blocking ovarian cancer growth in those tumors that rely on mutant p53 functions for survival. Knowing p53 mutational status in HGSC should permit new strategies tailored to control this disease. PMID:26585234

  2. The Activities and Impact of State Programs to Address Hereditary Breast and Ovarian Cancer, 2011–2014

    PubMed Central

    Trivers, Katrina F.; Rodriguez, Juan L.; Cox, Summer L.; Crane, Barbara E.; Duquette, Debra

    2015-01-01

    In 2011, the Division of Cancer Prevention and Control (DCPC), at the United States Centers for Disease Control and Prevention (CDC), released a three-year funding opportunity announcement (FOA) for a competitive, non-research cooperative agreement. The agreement enhanced the capacities of state health departments to promote the application of best practices for evidence-based breast cancer genomics through education, surveillance, and policy activities. The FOA required that applicants focus on activities related to hereditary breast and ovarian cancer (HBOC). The DCPC funded three states: Georgia, Michigan, and Oregon. Georgia was a first-time recipient of cancer genomics funding, whereas Michigan and Oregon had long standing activities in cancer genomics and had received CDC funding in the past. By the end of the funding period, each state had well-functioning and impactful state-based programs in breast cancer genomics. This article highlights the impact of a few key state activities by using CDC’s Science Impact Framework. There were challenges to implementing public health genomics programs, including the need to develop relevant partnerships, the highly technical nature of the subject matter, a lack of genetic services in certain areas, and the difficulty in funding genetic services. Georgia, Michigan, and Oregon have served as models for others interested in initiating or expanding cancer genomics programs, and they helped to determine what works well for promoting and integrating public health genomics into existing systems. PMID:27417805

  3. Future missions studies: Combining Schatten's solar activity prediction model with a chaotic prediction model

    NASA Technical Reports Server (NTRS)

    Ashrafi, S.

    1991-01-01

    K. Schatten (1991) recently developed a method for combining his prediction model with our chaotic model. The philosophy behind this combined model and his method of combination is explained. Because the Schatten solar prediction model (KS) uses a dynamo to mimic solar dynamics, accurate prediction is limited to long-term solar behavior (10 to 20 years). The Chaotic prediction model (SA) uses the recently developed techniques of nonlinear dynamics to predict solar activity. It can be used to predict activity only up to the horizon. In theory, the chaotic prediction should be several orders of magnitude better than statistical predictions up to that horizon; beyond the horizon, chaotic predictions would theoretically be just as good as statistical predictions. Therefore, chaos theory puts a fundamental limit on predictability.

  4. Extracellular acidification activates ovarian cancer G-protein-coupled receptor 1 and GPR4 homologs of zebra fish

    SciTech Connect

    Mochimaru, Yuta; Azuma, Morio; Oshima, Natsuki; Ichijo, Yuta; Satou, Kazuhiro; Matsuda, Kouhei; Asaoka, Yoichi; Nishina, Hiroshi; Nakakura, Takashi; Mogi, Chihiro; Sato, Koichi; Okajima, Fumikazu; Tomura, Hideaki

    2015-02-20

    Mammalian ovarian G-protein-coupled receptor 1 (OGR1) and GPR4 are identified as a proton-sensing G-protein-coupled receptor coupling to multiple intracellular signaling pathways. In the present study, we examined whether zebra fish OGR1 and GPR4 homologs (zOGR1 and zGPR4) could sense protons and activate the multiple intracellular signaling pathways and, if so, whether the similar positions of histidine residue, which is critical for sensing protons in mammalian OGR and GPR4, also play a role to sense protons and activate the multiple signaling pathways in the zebra fish receptors. We found that extracellular acidic pH stimulated CRE-, SRE-, and NFAT-promoter activities in zOGR1 overexpressed cells and stimulated CRE- and SRE- but not NFAT-promoter activities in zGPR4 overexpressed cells. The substitution of histidine residues at the 12th, 15th, 162th, and 264th positions from the N-terminal of zOGR1 with phenylalanine attenuated the proton-induced SRE-promoter activities. The mutation of the histidine residue at the 78th but not the 84th position from the N-terminal of zGPR4 to phenylalanine attenuated the proton-induced SRE-promoter activities. These results suggest that zOGR1 and zGPR4 are also proton-sensing G-protein-coupled receptors, and the receptor activation mechanisms may be similar to those of the mammalian receptors. - Highlights: • Zebra fish OGR1 and GPR4 homologs (zOGR1, zGPR4) are proton-sensing receptors. • The signaling pathways activated by zOGR1 and zGPR4 are different. • Histidine residues critical for sensing protons are conserved.

  5. Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol

    PubMed Central

    Griesinger, Georg; Verweij, Pierre J. M.; Gates, Davis; Devroey, Paul; Gordon, Keith; Stegmann, Barbara J.; Tarlatzis, Basil C.

    2016-01-01

    Study Question What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels? Summary Answer The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm. What Is Known Already In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1–2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. Study Design, Size, Duration From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. Participants/Materials, Setting, Methods The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a

  6. Extracellular acidification activates ovarian cancer G-protein-coupled receptor 1 and GPR4 homologs of zebra fish.

    PubMed

    Mochimaru, Yuta; Azuma, Morio; Oshima, Natsuki; Ichijo, Yuta; Satou, Kazuhiro; Matsuda, Kouhei; Asaoka, Yoichi; Nishina, Hiroshi; Nakakura, Takashi; Mogi, Chihiro; Sato, Koichi; Okajima, Fumikazu; Tomura, Hideaki

    2015-02-20

    Mammalian ovarian G-protein-coupled receptor 1 (OGR1) and GPR4 are identified as a proton-sensing G-protein-coupled receptor coupling to multiple intracellular signaling pathways. In the present study, we examined whether zebra fish OGR1 and GPR4 homologs (zOGR1 and zGPR4) could sense protons and activate the multiple intracellular signaling pathways and, if so, whether the similar positions of histidine residue, which is critical for sensing protons in mammalian OGR and GPR4, also play a role to sense protons and activate the multiple signaling pathways in the zebra fish receptors. We found that extracellular acidic pH stimulated CRE-, SRE-, and NFAT-promoter activities in zOGR1 overexpressed cells and stimulated CRE- and SRE- but not NFAT-promoter activities in zGPR4 overexpressed cells. The substitution of histidine residues at the 12th, 15th, 162th, and 264th positions from the N-terminal of zOGR1 with phenylalanine attenuated the proton-induced SRE-promoter activities. The mutation of the histidine residue at the 78th but not the 84th position from the N-terminal of zGPR4 to phenylalanine attenuated the proton-induced SRE-promoter activities. These results suggest that zOGR1 and zGPR4 are also proton-sensing G-protein-coupled receptors, and the receptor activation mechanisms may be similar to those of the mammalian receptors. PMID:25576873

  7. Antivascular Therapy for Epithelial Ovarian Cancer

    PubMed Central

    Duhoux, Francois P.; Machiels, Jean-Pascal

    2010-01-01

    Ovarian cancer is the fifth largest cancer killer in women. Improved understanding of the molecular pathways implicated in the pathogenesis of ovarian cancer has led to the investigation of novel targeted therapies. Ovarian cancer is characterized by an imbalance between pro- and antiangiogenic factors in favor of angiogenesis activation. Various antivascular strategies are currently under investigation in ovarian cancer. They can schematically be divided into antiangiogenic and vascular-disrupting therapies. This paper provides a comprehensive review of these new treatments targeting the tumor vasculature in this disease. Promising activities have been detected in phase II trials, and results of phase III clinical trials are awaited eagerly. PMID:20072701

  8. Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

    PubMed Central

    Saxena, Pikee; Prakash, Anupam; Nigam, Aruna

    2011-01-01

    BACKGROUND: Insulin resistance (IR) is central to the pathogenesis of polycystic ovarian syndrome (PCOS), but tests for determining IR are elaborate, tedious and expensive. AIMS: To evaluate if “2-hour post-glucose insulin level” is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women. SETTINGS AND DESIGN: Observational study at infertility clinic of a tertiary care center. MATERIALS AND METHODS: 50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups. STATISTICAL ANALYSIS: Statistical analysis was performed using SPSS (Chicago, IL, USA). RESULTS: Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC) of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. “2-hour post-glucose insulin levels” were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and –0.732, respectively). CONCLUSIONS: “2-hour post-glucose insulin levels” appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits. PMID:21772735

  9. In vitro effects of diethylstilbestrol, genistein, 4-tert-butylphenol, and 4-tert-octylphenol on steroidogenic activity of isolated immature rat ovarian follicles

    SciTech Connect

    Myllymaeki, Sari . E-mail: saanmy@utu.fi; Haavisto, Tapio; Vainio, Minna; Toppari, Jorma; Paranko, Jorma

    2005-04-01

    Isolated rat ovarian follicles grow and produce steroid hormones in vitro and so provide a good model for studying the effects of hormonally active compounds on follicular steroidogenesis. We have evaluated the effects of diethylstilbestrol (DES), genistein (GEN) and two alkylphenols, 4-tert-butylphenol (BP) and 4-tert-octylphenol (OP) on the growth, survival, and steroid hormone and cAMP production by isolated 14-day-old rat (Sprague-Dawley) ovarian follicles. During a 5-day culture, FSH was obligatory for follicle growth and increased estradiol and testosterone secretion in a dose-dependent manner. DES (10{sup -6} M) caused the strongest decline in estradiol and testosterone levels but did not have detectable effects on either cAMP production or aromatase enzyme activity. GEN caused a prominent decrease in cAMP and testosterone levels without significant changes in secreted estradiol. The latter, apparently, was due to a dose-dependent stimulation of aromatase enzyme activity in the presence of genistein. Both BP and OP decreased estradiol and testosterone secretion in a dose-dependent manner while no effect on aromatase activity was observed. OP, unlike BP, decreased forskolin-induced cAMP levels. Xenoestrogens at the used concentrations did not interfere with the growth and survival of the follicles. The results indicate that isolated ovarian follicles representing intact morphological and functional units offer a sensitive model system for elucidating the female-specific reproductive effects of environmental chemicals.

  10. What Is Ovarian Cancer?

    MedlinePlus

    ... the key statistics about ovarian cancer? What is ovarian cancer? Cancer starts when cells in the body begin ... section . Other cancers that are similar to epithelial ovarian cancer Primary peritoneal carcinoma Primary peritoneal carcinoma (PPC) is ...

  11. CRAFFT: An Activity Prediction Model based on Bayesian Networks

    PubMed Central

    Nazerfard, Ehsan; Cook, Diane J.

    2014-01-01

    Recent advances in the areas of pervasive computing, data mining, and machine learning offer unique opportunities to provide health monitoring and assistance for individuals facing difficulties to live independently in their homes. Several components have to work together to provide health monitoring for smart home residents including, but not limited to, activity recognition, activity discovery, activity prediction, and prompting system. Compared to the significant research done to discover and recognize activities, less attention has been given to predict the future activities that the resident is likely to perform. Activity prediction components can play a major role in design of a smart home. For instance, by taking advantage of an activity prediction module, a smart home can learn context-aware rules to prompt individuals to initiate important activities. In this paper, we propose an activity prediction model using Bayesian networks together with a novel two-step inference process to predict both the next activity features and the next activity label. We also propose an approach to predict the start time of the next activity which is based on modeling the relative start time of the predicted activity using the continuous normal distribution and outlier detection. To validate our proposed models, we used real data collected from physical smart environments. PMID:25937847

  12. JRK is a positive regulator of β-catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer.

    PubMed

    Pangon, L; Ng, I; Giry-Laterriere, M; Currey, N; Morgan, A; Benthani, F; Tran, P N; Al-Sohaily, S; Segelov, E; Parker, B L; Cowley, M J; Wright, D C; St Heaps, L; Carey, L; Rooman, I; Kohonen-Corish, M R J

    2016-06-01

    The loss of β-catenin inhibitory components is a well-established mechanism of carcinogenesis but β-catenin hyperactivity can also be enhanced through its coactivators. Here we first interrogated a highly validated genomic screen and the largest repository of cancer genomics data and identified JRK as a potential new oncogene and therapeutic target of the β-catenin pathway. We proceeded to validate the oncogenic role of JRK in colon cancer cells and primary tumors. Consistent with a β-catenin activator function, depletion of JRK in several cancer cell lines repressed β-catenin transcriptional activity and reduced cell proliferation. Importantly, JRK expression was aberrantly elevated in 21% of colorectal cancers, 15% of breast and ovarian cancers and was associated with increased expression of β-catenin target genes and increased cell proliferation. This study shows that JRK is required for β-catenin hyperactivity regardless of the adenomatous polyposis coli/β-catenin mutation status and targeting JRK presents new opportunities for therapeutic intervention in cancer. PMID:26455321

  13. Influence of repeated dinoprost treatment on ovarian activity in cycling dairy cows.

    PubMed

    Kaneko, Kazuyuki; Takagi, Nobuaki

    2014-02-01

    To study the ovarian response to the long-term effect of PGF2α, 16 cows were treated with 25 mg tromethamine dinoprost (Pronalgon F; Pfizer, Tokyo, Japan) for 21 days after natural ovulation. Five control cows were treated with sterile physiological saline. The follicle and corpus luteum (CL) development were monitored using a real-time ultrasound instrument. In addition, the plasma concentration of progesterone (P4) was determined. In nine of the 16 Pronalgon-treated cows, the first dominant follicle (1st DF), second dominant follicle (2nd DF), and third dominant follicle ovulated consecutively (group A). In five cows, the 1st and 2nd DFs ovulated consecutively (group B). The developing CL started to regress approximately 5 days after each ovulation without maturation in groups A and B. In the two remaining Pronalgon-treated cows, there was no further ovulation after natural ovulation (group C). In one cow in group C, the 1st DF became atretic and the 2nd DF became cystic with the diameter of the cystic follicle reaching 31.2 mm on Day 30. In another cow, the 1st DF became cystic with a diameter of 30.9 mm on Day 18. Although P4 began to increase after each ovulation in all of the Pronalgon-treated cows, it decreased immediately after each ovulation without a large increase, peaking at approximately 1 ng/mL. Furthermore, the number of days when P4 was >1 ng/mL from natural ovulation to Day 21 was 2.6 ± 0.7 days, which was significantly less than that in the control cows (16.0 ± 0.6 days). These results indicate that the long-term effect of PGF2α has an important role in ovulation of all dominant follicles and might induce cystic ovaries in cows. PMID:24286690

  14. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-01-01

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration. PMID:27271583

  15. Delivery of Constitutively Active Mutant MKK6(E) With TAT-OSBP Induces Apoptosis in Human Ovarian Carcinoma HO8910 Cells.

    PubMed

    Liao, Hua; Kang, Jia-li; Jiang, Wen-yan; Deng, Cui; Yuan, Jin; Shuai, Rong

    2015-11-01

    Biologically active peptides and proteins are novel agents that show promise in the development of anticancer drugs. Their relatively low cell permeability and poor tumor selectivity, however, impede their widespread applicability. In this study, we evaluated the tumor selectivity, cellular internalization, and biological activity of a cell-permeable ovarian cancer cell-specific therapeutic protein consisting of TAT-OSBP and constitutively active MKK6(E), an upstream kinase of the p38 signaling pathway that mediates cellular apoptosis. OSBP, a 7-amino-acid peptide with high affinity for human ovarian cancer HO8910 cells, was conjugated to the cell-penetrating peptide (TAT) to form a tumor-selective peptide (TAT-OSBP), which was further conjugated with EGFP or MKK6(E). Flow cytometry and fluorescent microscopy were performed to evaluate the tumor-targeted penetration of TAT-OSBP-EGFP. The inhibitory effects of TAT-OSBP-MKK6(E) were determined by cell proliferation and apoptosis assays. The internalization efficiency of TAT-OSBP-EGFP was significantly higher than that of TAT-EGFP. TAT-OSBP-EGFP selectively penetrated HO8910 cells. TAT-OSBP-MKK6(E) fusion protein inhibited cancer cell growth to varying degrees, with the highest level of inhibition in HO8910 cells. Moreover, TAT-OSBP-MKK6(E) significantly induced apoptosis of HO8910 cells. However, there was no significant difference in apoptosis in the normal ovarian epithelial cells treated with either TAT-OSBP-MKK6(E) or TAT-MKK6(E). Our results demonstrate that TAT-OSBP-MKK6(E) is a novel artificially designed molecule, which induces apoptosis and selectively targets human ovarian carcinoma HO8910 cells. Our study provides novel insights that may aid in the development of a new generation of anticancer drugs. PMID:26495757

  16. Effect of GnRH treatment on ovarian activity and reproductive performance of low-prolific Rahmani ewes.

    PubMed

    Hashem, N M; El-Azrak, K M; Nour El-Din, A N M; Taha, T A; Salem, M H

    2015-01-15

    This study was designed to evaluate the effect of GnRH treatment during different times of the reproductive cycle on ovarian activity, progesterone (P4) concentration, and subsequent fertility of low-prolific, subtropical, Rahmani ewes during breeding season. Forty-five ewes were synchronized for estrus using a double injection of 0.5 mL of PGF2α agonist (125-μg cloprostenol), 11 days apart. Ewes showing estrus (Day 0) were treated with 1 mL of GnRH agonist (4-μg buserelin) on the day of estrus (GnRH0, n = 12) or 7 days post-mating (GnRH7, n = 10) or on both days (GnRH0+7, n = 11) or not (control, n = 12). Ovarian response to the treatment and diagnosis of pregnancy were ultrasonographically monitored. Also, serum P4 concentration was determined weekly throughout 28 days post-mating. Results showed that neither total number of follicles nor their populations were changed on Day 0 or 7 days post-mating by the GnRH treatment. GnRH treatment on Day 0 or Day 7 post-mating or both days did not enhance ovulation rate compared with the control. The mean numbers of accessory CL increased (P < 0.05) in the GnRH7 group than those in the control and GnRH0 groups, whereas it was intermediate in the GnRH0+7 group. The greatest (P < 0.05) overall mean of serum P4 concentration was for the GnRH7 and GnRH0+7 groups, followed by the GnRH0 and control groups. Serum P4 concentration increased (P < 0.05) on Day 14 post-mating and continued higher (P < 0.05) until Day 28 post-mating in the GnRH7 and GnRH0+7 groups compared with the control. Regardless of the time of GnRH administration, GnRH treatment reduced (P < 0.05) pregnancy loss from Day 40 post-mating to parturition and tended to enhance (P < 0.20) lambing rate compared with the control. In conclusion, a single dose of GnRH at the time of estrus or 7 days post-mating could be used as an effective protocol to decrease pregnancy loss from Day 40 after mating to parturition in low-prolific Rahmani ewes. PMID:25442386

  17. Seasonal variations in reproductive activity of the blue crab, Callinectes sapidus: Vitellogenin expression and levels of vitellogenin in the hemolymph during ovarian development.

    PubMed

    Thongda, Willawan; Chung, J Sook; Tsutsui, Naoaki; Zmora, Nilli; Katenta, Anna

    2015-01-01

    In general, season affects the physiology and behavior of most animals. Warmer temperatures accelerate growth and reproduction of ectotherms, whereas these processes are slowed or halted in colder temperatures. Female blue crabs, Callinectes sapidus inhabiting the Chesapeake Bay, exhibit a seasonal migratory behavior that is closely tied with spawning and the release of larvae. To better understand reproductive activities of the migratory adult females, we examined two reproductive parameters of these crabs sampled monthly (April-December, 2006): the levels of vitellogenin (VtG) in the hemolymph and VtG expression in the hepatopancreas and ovary. The full-length cDNA of VtG (CasVtG-ova) has been isolated from the ovary. The putative CasVtG sequence found in the ovary is >99% identical to that of the hepatopancreas and is related most closely to the sequences reported in other crab species. In female C. sapidus, the hepatopancreas produces over 99% of the total VtG toward the ovarian development. Ovarian stages 2 and 3 in the sampled females are characterized by significant high levels of VtG in hemolymph and VtG expression in both the hepatopancreas and ovary. However, during the southbound migration in fall, females at ovarian stages 2 and 3 have decreased VtG levels, compared to those in spring and summer. The decreased vitellogenesis activity during the fall migration suggests seasonal adaptation to ensure successful spawning and the larval release. PMID:25218941

  18. Primary Ovarian Insufficiency.

    PubMed

    Laven, Joop S E

    2016-07-01

    Primary ovarian insufficiency (POI), also known as premature ovarian failure or premature menopause, is defined as cessation of menstruation before the expected age of menopause. Potential etiologies for POI can be divided into genetic, autoimmune, and iatrogenic categories. This review will try to summarize the genetic basis of POI focusing on recent data that are available using newer genetic techniques such as genome-wide association studies, whole-exome sequencing (WES), or next-generation sequencing techniques. By using these techniques, many genes have arisen that play some role in the pathophysiology of POI. Some of them have been replicated in other studies; however, the majority has not been proven yet to be unequivocally causative through functional validation studies. Elucidating the genetic and molecular basis of POI is of paramount importance not only in understanding ovarian physiology but also in providing genetic counseling and fertility guidance. Once additional variants are detected, it might become possible to predict the age of (premature) menopause in women at risk for POI. Women having certain perturbations of POI can be offered the option of oocyte cryopreservation, with later thawing and use in assisted reproductive technology at an appropriate age. PMID:27513024

  19. Association analysis of a chemo-response signature identified within The Cancer Genome Atlas aimed at predicting genetic risk for chemo-response in ovarian cancer

    PubMed Central

    Salinas, Erin A; Newtson, Andreea M; Leslie, Kimberly K; Gonzalez-Bosquet, Jesus

    2016-01-01

    Background: A gene signature associated with chemo-response in ovarian cancer was created through integration of biological data in The Cancer Genome Atlas (TCGA) and validated in five independent microarray experiments. Our study aimed to determine if single nucleotide polymorphisms (SNPs) within the 422-gene signature were associated with a genetic predisposition to platinum-based chemotherapy response in serous ovarian cancer. Methods: An association analysis between SNPs within the 422-gene signature and chemo-response in serous ovarian cancer was performed under the log-additive genetic model using the ‘SNPassoc’ package within the R environment (p<0.0001). Subsequent validation of statistically significant SNPs was done in the Ovarian Cancer Association Consortium (OCAC) database. Results: 19 SNPs were found to be associated with chemo-response with statistical significance. None of the SNPs found significant in TCGA were validated within OCAC for the outcome of interest, chemo-response. Conclusions: SNPs associated with chemo-response in ovarian cancer within TGCA database were not validated in a larger database of patients and controls from OCAC. New strategies integrating somatic and germline information may help to characterize genetic predictors for treatment response in ovarian cancer. PMID:27186327

  20. The Built Environment Predicts Observed Physical Activity

    PubMed Central

    Kelly, Cheryl; Wilson, Jeffrey S.; Schootman, Mario; Clennin, Morgan; Baker, Elizabeth A.; Miller, Douglas K.

    2014-01-01

    Background: In order to improve our understanding of the relationship between the built environment and physical activity, it is important to identify associations between specific geographic characteristics and physical activity behaviors. Purpose: Examine relationships between observed physical activity behavior and measures of the built environment collected on 291 street segments in Indianapolis and St. Louis. Methods: Street segments were selected using a stratified geographic sampling design to ensure representation of neighborhoods with different land use and socioeconomic characteristics. Characteristics of the built environment on-street segments were audited using two methods: in-person field audits and audits based on interpretation of Google Street View imagery with each method blinded to results from the other. Segments were dichotomized as having a particular characteristic (e.g., sidewalk present or not) based on the two auditing methods separately. Counts of individuals engaged in different forms of physical activity on each segment were assessed using direct observation. Non-parametric statistics were used to compare counts of physically active individuals on each segment with built environment characteristic. Results: Counts of individuals engaged in physical activity were significantly higher on segments with mixed land use or all non-residential land use, and on segments with pedestrian infrastructure (e.g., crosswalks and sidewalks) and public transit. Conclusion: Several micro-level built environment characteristics were associated with physical activity. These data provide support for theories that suggest changing the built environment and related policies may encourage more physical activity. PMID:24904916

  1. An Immunohistochemical Algorithm for Ovarian Carcinoma Typing

    PubMed Central

    Rahimi, Kurosh; Rambau, Peter F.; Naugler, Christopher; Le Page, Cécile; Meunier, Liliane; de Ladurantaye, Manon; Lee, Sandra; Leung, Samuel; Goode, Ellen L.; Ramus, Susan J.; Carlson, Joseph W.; Li, Xiaodong; Ewanowich, Carol A.; Kelemen, Linda E.; Vanderhyden, Barbara; Provencher, Diane; Huntsman, David; Lee, Cheng-Han; Gilks, C. Blake; Mes Masson, Anne-Marie

    2016-01-01

    There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ2 Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials. PMID:26974996

  2. An Immunohistochemical Algorithm for Ovarian Carcinoma Typing.

    PubMed

    Köbel, Martin; Rahimi, Kurosh; Rambau, Peter F; Naugler, Christopher; Le Page, Cécile; Meunier, Liliane; de Ladurantaye, Manon; Lee, Sandra; Leung, Samuel; Goode, Ellen L; Ramus, Susan J; Carlson, Joseph W; Li, Xiaodong; Ewanowich, Carol A; Kelemen, Linda E; Vanderhyden, Barbara; Provencher, Diane; Huntsman, David; Lee, Cheng-Han; Gilks, C Blake; Mes Masson, Anne-Marie

    2016-09-01

    There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma samples from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials. PMID:26974996

  3. Experiences of predictive testing in young people at risk of Huntington's disease, familial cardiomyopathy or hereditary breast and ovarian cancer

    PubMed Central

    MacLeod, Rhona; Beach, Anna; Henriques, Sasha; Knopp, Jasmin; Nelson, Katie; Kerzin-Storrar, Lauren

    2014-01-01

    While debate has focused on whether testing of minors for late onset genetic disorders should be carried out if there is no medical benefit, less is known about the impact on young people (<25 years) who have had predictive testing often many years before the likely onset of symptoms. We looked at the experiences of young people who had had predictive testing for a range of conditions with variable ages at onset and options for screening and treatment. A consecutive series of 61 young people who had a predictive test aged 15–25 years at the Clinical Genetic Service, Manchester, for HD, HBOC (BrCa 1 or 2) or FCM (Hypertrophic Cardiomyopathy or Dilated Cardiomyopathy), were invited to participate. Thirty-six (36/61; 59%) agreed to participate (10 HD, 16 HBOC and 10 FCM) and telephone interviews were audiotaped, transcribed and analysed using Interpretative Phenomenological Analysis. None of the participants expressed regret at having the test at a young age. Participants saw the value of pretest counselling not in facilitating a decision, but rather as a source of information and support. Differences emerged among the three groups in parent/family involvement in the decision to be tested. Parents in FCM families were a strong influence in favour of testing, in HBOC the decision was autonomous but usually congruent with the views of parents, whereas in HD the decision was autonomous and sometimes went against the opinions of parents/grandparents. Participants from all three groups proposed more tailoring of predictive test counselling to the needs of young people. PMID:23860040

  4. Extremely low frequency electromagnetic field sensitizes cisplatin-resistant human ovarian adenocarcinoma cells via P53 activation.

    PubMed

    Baharara, Javad; Hosseini, Nasrin; Farzin, Tayebe Ramezani

    2016-08-01

    In the following study, extremely low frequency electromagnetic fields (EL-EMF) radiation was used to restore sensitivity in the cisplatin-resistant A2780 ovarian cancer cells. For this purpose A2780 cells were treated with different doses of cisplatin and EL-EMF (50 Hz, 200 gauss, and 2 h) alone. Cytotoxicity was the measurement using MTT assay. After calculating IC50 for cisplatin (90 µg/ml) a lower concentration from IC50 (30 and 60 µg/ml) was used to be combined with EL-EMF. We compare the effects of each cisplatin, EL-EMF and combination groups using acridine orange-propidium iodide (AO/PI) and DAPI staining, caspase 3/9 activation assay and Annexin/PI assay. We also assessed changes in P53 and Matrix metalloproteinases 2 (MMPs) gene expression with semi-quantitative RT-PCR. Results indicated an EL-EMF-dependent proliferative decrease which was found <10 %, and occurred independently of cisplatin. The decreased proliferation rate for 30 and 60 µg/ml cisplatin was about 20 and 40 %, respectively, while for synergistic groups 30 and 60 µg/ml cisplatin with 2 h EL-EMF exposer, showed 47 and 71 % decrease in viability in rats. DAPI staining indicated that chromatin break down significantly increased in synergistic groups. Acridine orange staining also confirmed MTT assay results. Caspase activity significantly increased in the combined groups. Semi-quantitative RT-PCR showed that in synergistic groups of cisplatin and EL-EMF, expression of P53 was increased but the expression level of MPP-2 gene decreased. Results from this study showed that changes generated by the non-invasive EL-EMF can make resistant cells sensitive to cisplatin. PMID:26370097

  5. Poor ovarian reserve.

    PubMed

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  6. Poor ovarian reserve

    PubMed Central

    Jirge, Padma Rekha

    2016-01-01

    Poor ovarian reserve (POR) is an important limiting factor for the success of any treatment modality for infertility. It indicates a reduction in quantity and quality of oocytes in women of reproductive age group. It may be age related as seen in advanced years of reproductive life or may occur in young women due to diverse etiological factors. Evaluating ovarian reserve and individualizing the therapeutic strategies are very important for optimizing the success rate. Majority or women with POR need to undergo in vitro fertilization to achieve pregnancy. However, pregnancy rate remains low despite a plethora of interventions and is associated with high pregnancy loss. Early detection and active management are essential to minimize the need for egg donation in these women. PMID:27382229

  7. A randomized trial of diet and physical activity in women treated for stage II-IV ovarian cancer: Rationale and design of the Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES): An NRG Oncology/Gynecologic Oncology Group (GOG-225) Study.

    PubMed

    Thomson, Cynthia A; Crane, Tracy E; Miller, Austin; Garcia, David O; Basen-Engquist, Karen; Alberts, David S

    2016-07-01

    Ovarian cancer is the most common cause of gynecological cancer death in United States women. Efforts to improve progression free survival (PFS) and quality of life (QoL) after treatment for ovarian cancer are necessary. Observational studies suggest that lifestyle behaviors, including diet and physical activity, are associated with lower mortality in this population. The Lifestyle Intervention for Ovarian Cancer Enhanced Survival (LIVES) NRG 0225 study is a randomized, controlled trial designed to test the hypothesis that a 24month lifestyle intervention will significantly increase PFS after oncological therapy for stage II-IV ovarian cancer. Women are randomized 1:1 to a high vegetable and fiber, low-fat diet with daily physical activity goals or an attention control group. Secondary outcomes to be evaluated include QoL and gastrointestinal health. Moreover an a priori lifestyle adherence score will be used to evaluate relationships between adoption of the diet and activity goals and PFS. Blood specimens are collected at baseline, 6, 12 and 24months for analysis of dietary adherence (carotenoids) in addition to mechanistic biomarkers (lipids, insulin, telomere length). Women are enrolled at NRG clinic sites nationally and the telephone based lifestyle intervention is delivered from The University of Arizona call center by trained health coaches. A study specific multi-modal telephone, email, and SMS behavior change software platform is utilized for information delivery, coaching and data capture. When completed, LIVES will be the largest behavior-based lifestyle intervention trial conducted among ovarian cancer survivors. PMID:27394382

  8. Expression of α2,6-sialic acid-containing and Lewis-active glycolipids in several types of human ovarian carcinomas

    PubMed Central

    TANAKA, KYOKO; MIKAMI, MIKIO; AOKI, DAISUKE; KIGUCHI, KAZUSHIGE; ISHIWATA, ISAMU; IWAMORI, MASAO

    2010-01-01

    To identify glycolipid antigens associated with histologically defined types of ovarian carcinomas, we determined the amounts of α2,6-sialyl and Lewis-active glycolipids, the specific activities of the α2,3- and α2,6-sialyltransferases, and the gene expression of sugar transferases in mucinous and serous cystadenocarcinoma, clear cell adenocarcinoma and endometrioid carcinoma tissues and cell lines derived from them. α2,6-sialyl glycolipid IV6NeuAcα-nLc4Cer detected with a newly developed monoclonal antibody, Y916, was present in 5/7 serous cystadenocarcinoma cases in relatively higher amounts than those in the other carcinoma tissues. On the other hand, the amounts of Lewis-active glycolipids in serous cystadenocarcinoma tissues were lower than those in the other carcinoma tissues. No correlation was observed between the structures of Lewis glycolipids and the histological classification. The gene expression of α2,3- and α2,6-sialyltransferases and α1,3/4-fucosyltransferase for the synthesis of Lewis-active glycolipids was not positively correlated with the amounts of the respective glycolipids, probably due to the epigenetic regulation of transferases in the overall metabolic pathways for lacto-series glycolipids. However, the amounts of GM3 and GD3 with short carbohydrate chains correlated with the relative intensities of GM3 and GD3 synthase gene expression, respectively. Among ovarian carcinoma-derived cell lines, the serous cystadenocarcinoma-derived ones exhibited a lower frequency of Lewis-active glycolipid expression than the other carcinoma-derived ones, which was similar to that in the respective tissues. Thus, malignancy-related Lewis-active glycolipids were shown to be regulated in different modes in ovarian serous cystadenocarcinomas and the other carcinomas. PMID:22870113

  9. Synthesis, antiproliferative activity and molecular properties predictions of galloyl derivatives.

    PubMed

    da Silva, Marciane Maximo; Comin, Marina; Duarte, Thiago Santos; Foglio, Mary Ann; de Carvalho, João Ernesto; do Vieira, Maria Carmo; Formagio, Anelise Samara Nazari

    2015-01-01

    The present study was designed to investigate the in vitro antiproliferative activity against ten human cancer cell lines of a series of galloyl derivatives bearing substituted-1,3,4-oxadiazole and carbohydrazide moieties. The compounds were also assessed in an in silico study of the absorption, distribution, metabolism and excretion (ADME) in the human body using Lipinski's parameters, the topological polar surface area (TPSA) and percentage of absorption (%ABS). In general, the introduction of N'-(substituted)-arylidene galloyl hydrazides 4-8 showed a moderate antitumor activity, while the 2-methylthio- and 2-thioxo-1,3,4-oxadiazol-5-yl derivatives 9 and 10 led to increased inhibition of cancer cell proliferation. The precursor compound methyl gallate 2 and the intermediary galloyl hydrazide 3 showed greater antiproliferative activity with GI50 values < 5.54 µM against all human tumor cell lines tested. A higher inhibition effect against ovarian cancer (OVCAR-3) (GI50 = 0.05-5.98 µM) was also shown, with compounds 2, 3, 9 and 10 with GI50 ≤ 0.89 µM standing out in this respect. The in silico study revealed that the compounds showed good intestinal absorption. PMID:25816079

  10. Targeted Therapies in Epithelial Ovarian Cancer

    PubMed Central

    Dean, Emma; El-Helw, Loaie; Hasan, Jurjees

    2010-01-01

    Molecularly targeted therapy is relatively new to ovarian cancer despite the unquestionable success with these agents in other solid tumours such as breast and colorectal cancer. Advanced ovarian cancer is chemosensitive and patients can survive several years on treatment. However chemotherapy diminishes in efficacy over time whilst toxicities persist. Newer biological agents that target explicit molecular pathways and lack specific chemotherapy toxicities such as myelosuppression offer the advantage of long-term therapy with a manageable toxicity profile enabling patients to enjoy a good quality of life. In this review we appraise the emerging data on novel targeted therapies in ovarian cancer. We discuss the role of these compounds in the front-line treatment of ovarian cancer and in relapsed disease; and describe how the development of predictive clinical, molecular and imaging biomarkers will define the role of biological agents in the treatment of ovarian cancer. PMID:24281034

  11. Predicting mining activity with parallel genetic algorithms

    USGS Publications Warehouse

    Talaie, S.; Leigh, R.; Louis, S.J.; Raines, G.L.

    2005-01-01

    We explore several different techniques in our quest to improve the overall model performance of a genetic algorithm calibrated probabilistic cellular automata. We use the Kappa statistic to measure correlation between ground truth data and data predicted by the model. Within the genetic algorithm, we introduce a new evaluation function sensitive to spatial correctness and we explore the idea of evolving different rule parameters for different subregions of the land. We reduce the time required to run a simulation from 6 hours to 10 minutes by parallelizing the code and employing a 10-node cluster. Our empirical results suggest that using the spatially sensitive evaluation function does indeed improve the performance of the model and our preliminary results also show that evolving different rule parameters for different regions tends to improve overall model performance. Copyright 2005 ACM.

  12. Molecular imaging in ovarian cancer.

    PubMed

    Reyners, A K L; Broekman, K E; Glaudemans, A W J M; Brouwers, A H; Arts, H J G; van der Zee, A G J; de Vries, E G E; Jalving, M

    2016-04-01

    Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer. PMID:27141066

  13. Electromechanical activities of human uteri during extra-corporeal perfusion with ovarian steroids.

    PubMed

    Bulletti, C; Prefetto, R A; Bazzocchi, G; Romero, R; Mimmi, P; Polli, V; Lanfranchi, G A; Labate, A M; Flamigni, C

    1993-10-01

    A new experimental system was designed to study human uterine activities based on the extra-corporeal perfusion of isolated human uteri. Electromechanical activities in the uterine wall were recorded using bipolar silver-silver electrodes, endoluminal pressure catheters and a dedicated acquisition, storage and analytical system. The electrical signals recorded were isolated spikes and rhythmic activities; the last being primarily associated with organized mechanical events. Perfusion media containing 17 beta-oestradiol alone or with progesterone were used for those uteri obtained during proliferative (n = 5) or secretory (n = 5) phases of the menstrual cycle, respectively. Progesterone caused a reduction of frequency (P < 0.001) and duration (P < 0.001) of the rhythmic electrical activity, and decreased the endoluminal pressure at both detection sites (P < 0.01). 17 beta-Oestradiol increased both frequency (P < 0.001) and duration (P < 0.001) of the rhythmic electrical activity as well as the endoluminal pressure at two different detection sites (3 and 5 cm from the fundus) (P < 0.05). Significant differences between the fundus and cervix sites in the uterine wall were detected. In conclusion, uterine perfusion would be useful to examine the effects of uterotonic and tocolytic drugs before administration to humans, at no risk to the patients. Oestrogens increase and progesterone decreases both electrical and mechanical uterine activities. PMID:8300807

  14. Measuring Active Learning to Predict Course Quality

    ERIC Educational Resources Information Center

    Taylor, John E.; Ku, Heng-Yu

    2011-01-01

    This study investigated whether active learning within computer-based training courses can be measured and whether it serves as a predictor of learner-perceived course quality. A major corporation participated in this research, providing access to internal employee training courses, training representatives, and historical course evaluation data.…

  15. Arterivirus and Nairovirus Ovarian Tumor Domain-Containing Deubiquitinases Target Activated RIG-I To Control Innate Immune Signaling

    PubMed Central

    van Kasteren, Puck B.; Beugeling, Corrine; Ninaber, Dennis K.; Frias-Staheli, Natalia; van Boheemen, Sander; García-Sastre, Adolfo; Snijder, Eric J.

    2012-01-01

    The innate immune response constitutes the first line of defense against viral infection and is extensively regulated through ubiquitination. The removal of ubiquitin from innate immunity signaling factors by deubiquitinating enzymes (DUBs) therefore provides a potential opportunity for viruses to evade this host defense system. It was previously found that specific proteases encoded by the unrelated arteri- and nairoviruses resemble the ovarian tumor domain-containing (OTU) family of DUBs. In arteriviruses, this domain has been characterized before as a papain-like protease (PLP2) that is also involved in replicase polyprotein processing. In nairoviruses, the DUB resides in the polymerase protein but is not essential for RNA replication. Using both in vitro and cell-based assays, we now show that PLP2 DUB activity is conserved in all members of the arterivirus family and that both arteri- and nairovirus DUBs inhibit RIG-I-mediated innate immune signaling when overexpressed. The potential relevance of RIG-I-like receptor (RLR) signaling for the innate immune response against arterivirus infection is supported by our finding that in mouse embryonic fibroblasts, the production of beta interferon primarily depends on the recognition of arterivirus RNA by the pattern-recognition receptor MDA5. Interestingly, we also found that both arteri- and nairovirus DUBs inhibit RIG-I ubiquitination upon overexpression, suggesting that both MDA5 and RIG-I have a role in countering infection by arteriviruses. Taken together, our results support the hypothesis that arteri- and nairoviruses employ their deubiquitinating potential to inactivate cellular proteins involved in RLR-mediated innate immune signaling, as exemplified by the deubiquitination of RIG-I. PMID:22072774

  16. Leucine leucine-37 uses formyl peptide receptor-like 1 to activate signal transduction pathways, stimulate oncogenic gene expression, and enhance the invasiveness of ovarian cancer cells.

    PubMed

    Coffelt, Seth B; Tomchuck, Suzanne L; Zwezdaryk, Kevin J; Danka, Elizabeth S; Scandurro, Aline B

    2009-06-01

    Emerging evidence suggests that the antimicrobial peptide, leucine leucine-37 (LL-37), could play a role in the progression of solid tumors. LL-37 is expressed as the COOH terminus of human cationic antimicrobial protein-18 (hCAP-18) in ovarian, breast, and lung cancers. Previous studies have shown that the addition of LL-37 to various cancer cell lines in vitro stimulates proliferation, migration, and invasion. Similarly, overexpression of hCAP-18/LL-37 in vivo accelerates tumor growth. However, the receptor or receptors through which these processes are mediated have not been thoroughly examined. In the present study, expression of formyl peptide receptor-like 1 (FPRL1) was confirmed on ovarian cancer cells. Proliferation assays indicated that LL-37 does not signal through a G protein-coupled receptor, such as FPRL1, to promote cancer cell growth. By contrast, FPRL1 was required for LL-37-induced invasion through Matrigel. The peptide stimulated mitogen-activated protein kinase and Janus-activated kinase/signal transducers and activators of transcription signaling cascades and led to the significant activation of several transcription factors, through both FPRL1-dependent and FPRL1-independent pathways. Likewise, expression of some LL-37-stimulated genes was attenuated by the inhibition of FPRL1. Increased expression of CXCL10, EGF, and PDGF-BB as well as other soluble factors was confirmed from conditioned medium of LL-37-treated cells. Taken together, these data suggest that LL-37 potentiates a more aggressive behavior from ovarian cancer cells through its interaction with FPRL1. PMID:19491199

  17. Leucine Leucine-37 Uses Formyl Peptide Receptor–Like 1 to Activate Signal Transduction Pathways, Stimulate Oncogenic Gene Expression, and Enhance the Invasiveness of Ovarian Cancer Cells

    PubMed Central

    Coffelt, Seth B.; Tomchuck, Suzanne L.; Zwezdaryk, Kevin J.; Danka, Elizabeth S.; Scandurro, Aline B.

    2009-01-01

    Emerging evidence suggests that the antimicrobial peptide, leucine leucine-37 (LL-37), could play a role in the progression of solid tumors. LL-37 is expressed as the COOH terminus of human cationic antimicrobial protein-18 (hCAP-18) in ovarian, breast, and lung cancers. Previous studies have shown that the addition of LL-37 to various cancer cell lines in vitro stimulates proliferation, migration, and invasion. Similarly, overexpression of hCAP-18/LL-37 in vivo accelerates tumor growth. However, the receptor or receptors through which these processes are mediated have not been thoroughly examined. In the present study, expression of formyl peptide receptor–like 1 (FPRL1) was confirmed on ovarian cancer cells. Proliferation assays indicated that LL-37 does not signal through a G protein–coupled receptor, such as FPRL1, to promote cancer cell growth. By contrast, FPRL1 was required for LL-37–induced invasion through Matrigel. The peptide stimulated mitogen-activated protein kinase and Janus-activated kinase/signal transducers and activators of transcription signaling cascades and led to the significant activation of several transcription factors, through both FPRL1-dependent and FPRL1-independent pathways. Likewise, expression of some LL-37–stimulated genes was attenuated by the inhibition of FPRL1. Increased expression of CXCL10, EGF, and PDGF-BB as well as other soluble factors was confirmed from conditioned medium of LL-37–treated cells. Taken together, these data suggest that LL-37 potentiates a more aggressive behavior from ovarian cancer cells through its interaction with FPRL1. PMID:19491199

  18. Synthesis of tris(quinoline)monochloroplatinum(II) Chloride and its Activity Alone and in Combination with Capsaicin and Curcumin in Human Ovarian Cancer Cell Lines.

    PubMed

    Arzuman, Laila; Beale, Philip; Yu, Jun Q; Huq, Fazlul

    2016-06-01

    Currently used platinum drugs fail to provide long-term cure for ovarian cancer mainly because of acquired drug resistance. With the idea that the difference may translate into an altered spectrum of activity, monofunctional planaramineplatinum(II) complex tris(quinoline)monochloro-platinum chloride (coded as LH5) was synthesized and investigated for its activity against human ovarian A2780, cisplatin-resistant A2780 (A2780(cisR)) and ZD0473-resistnat A2780 (A2780(ZD0473R)) cancer cell lines alone and in combination with the phytochemicals capsaicin (Caps) and curcumin (Cur) as a function of concentration and sequence of administration. Cell viability was quantified using the MTT reduction assay, while combination was used as a quantitative measure of the combined drug action. LH5 is found to be more active than cisplatin (CS) against both resistant cell lines. Combination of LH5 with capsaicin showed synergism in all three cell lines, with the bolus being most synergistic. Lack of association between the levels of platinum accumulation and platinum-DNA with cytotoxicity can be seen to indicate that binding with DNA may not be the main determinant of activity of LH5. Greater activity of LH5 compared to cisplatin, especially against the resistant cell lines, indicates that the compound may have the potential for development as a novel anticancer drug and that its combination with phytochemicals can serve to further enhance drug efficacy. PMID:27272792

  19. Interaction of Snail and p38 mitogen-activated protein kinase results in shorter overall survival of ovarian cancer patients.

    PubMed

    Hipp, Susanne; Berg, Daniela; Ergin, Bilge; Schuster, Tibor; Hapfelmeier, Alexander; Walch, Axel; Avril, Stefanie; Schmalfeldt, Barbara; Höfler, Heinz; Becker, Karl-Friedrich

    2010-12-01

    Epithelial ovarian cancer is a highly metastatic disease and the leading cause of death among cancer of the female genital tract. Abnormal epidermal growth factor receptor (EGFR) signalling has been shown to be involved in epithelial-mesenchymal transition (EMT), an early step during metastasis. Additionally, over-expression of the E-cadherin repressor Snail, a key regulator of EMT, has previously been found to be associated with unfavourable prognostic features. Thus, the aim of our study was to elucidate the role of EGFR-dependent signalling pathways for Snail expression in ovarian cancer. For this purpose, we analysed 25 formalin-fixed and paraffin-embedded (FFPE) primary tumours and their corresponding metastases for the expression of 25 signalling pathway molecules by reverse phase protein arrays. We found a significant correlation of Snail with EGFR((Tyr1086)) and p38 MAPK((Thr180/Tyr182)) in primary ovarian carcinoma and with EGFR((Tyr1086)) in their corresponding metastasis. Additionally, we showed that high expression levels of Snail in primary tumours combined with high expression levels of the phosphorylated p38 MAPK((Thr180/Tyr182)) in metastasis lead to an increased risk for death in ovarian carcinoma patients. Thus, for future combinatorial cancer therapy, drug combinations that best target the deregulated protein network in each individual patient should be selected. PMID:20957493

  20. A prediction of geomagnetic activity for solar cycle 23

    NASA Astrophysics Data System (ADS)

    Cliver, E. W.; Ling, A. G.; Wise, J. E.; Lanzerotti, L. J.

    1999-04-01

    Using a database of 13 solar cycles of geomagnetic aa data, we obtained correlations between cycle averages of geomagnetic activity (and sunspot number) and the numbers of days with disturbance levels above certain aa thresholds. We then used a precursor-type relation to predict an average aa index of 23.1 nT for cycle 23 and inserted this average aa value into the above correlations to forecast the integral size distribution of geomagnetic activity for the new cycle. The predicted size distribution is similar to that observed for cycles 21 and 22 but most closely resembles that of solar cycle 18 (1944-1954), which was slightly smaller than cycles 21 and 22. Our prediction agrees reasonably well with the ``climatology-based'' forecast made by the intergovernmental panel tasked to predict geomagnetic activity for the coming solar cycle and is significantly different from their ``precursor-based'' prediction.

  1. Cyclin E-dependent protein kinase activity regulates niche retention of Drosophila ovarian follicle stem cells

    PubMed Central

    Wang, Zhu A.; Kalderon, Daniel

    2009-01-01

    Whether stem cells have unique cell cycle machineries and how they integrate with niche interactions remains largely unknown. We identified a hypomorphic cyclin E allele WX that strongly impairs the maintenance of follicle stem cells (FSCs) in the Drosophila ovary but does not reduce follicle cell proliferation or germline stem cell maintenance. CycEWX protein can still bind to the cyclin-dependent kinase catalytic subunit Cdk2, but forms complexes with reduced protein kinase activity measured in vitro. By creating additional CycE variants with different degrees of kinase dysfunction and expressing these and CycEWX at different levels, we found that higher CycE-Cdk2 kinase activity is required for FSC maintenance than to support follicle cell proliferation. Surprisingly, cycEWX FSCs were lost from their niches rather than arresting proliferation. Furthermore, FSC function was substantially restored by expressing either excess DE-cadherin or excess E2F1/DP, the transcription factor normally activated by CycE-Cdk2 phosphorylation of retinoblastoma proteins. These results suggest that FSC maintenance through niche adhesion is regulated by inputs that normally control S phase entry, possibly as a quality control mechanism to ensure adequate stem cell proliferation. We speculate that a positive connection between central regulators of the cell cycle and niche retention may be a common feature of highly proliferative stem cells. PMID:19966222

  2. Cortical activity patterns predict speech discrimination ability

    PubMed Central

    Engineer, Crystal T; Perez, Claudia A; Chen, YeTing H; Carraway, Ryan S; Reed, Amanda C; Shetake, Jai A; Jakkamsetti, Vikram; Chang, Kevin Q; Kilgard, Michael P

    2010-01-01

    Neural activity in the cerebral cortex can explain many aspects of sensory perception. Extensive psychophysical and neurophysiological studies of visual motion and vibrotactile processing show that the firing rate of cortical neurons averaged across 50–500 ms is well correlated with discrimination ability. In this study, we tested the hypothesis that primary auditory cortex (A1) neurons use temporal precision on the order of 1–10 ms to represent speech sounds shifted into the rat hearing range. Neural discrimination was highly correlated with behavioral performance on 11 consonant-discrimination tasks when spike timing was preserved and was not correlated when spike timing was eliminated. This result suggests that spike timing contributes to the auditory cortex representation of consonant sounds. PMID:18425123

  3. Quantification of activity by alpha-camera imaging and small-scale dosimetry within ovarian carcinoma micrometastases treated with targeted alpha therapy.

    PubMed

    Chouin, N; Lindegren, S; Jensen, H; Albertsson, P; Bäck, T

    2012-12-01

    Targeted alpha therapy (TAT) a promising treatment for small, residual, and micrometastatic diseases has questionable efficacy against malignant lesions larger than the α-particle range, and likely requires favorable intratumoral activity distribution. Here, we characterized and quantified the activity distribution of an alpha-particle emitter radiolabelled antibody within >100-µm micrometastases in a murine ovarian carcinoma model. Nude mice bearing ovarian micrometastases were injected intra-peritoneally with 211At-MX35 (total injected activity 6 MBq, specific activity 650 MBq/mg). Animals were sacrificed at several time points, and peritoneal samples were excised and prepared for alpha-camera imaging. Spatial and temporal activity distributions within micrometastases were derived and used for small-scale dosimetry. We observed two activity distribution patterns: uniform distribution and high stable uptake (>100% IA/g at all time points) in micrometastases with no visible stromal compartment, and radial distribution (high activity on the edge and poor uptake in the core) in tumor cell lobules surrounded by fibroblasts. Activity distributions over time were characterized by a peak (140% IA/g at 4 h) in the outer tumor layer and a sharp drop beyond a depth of 50 µm. Small-scale dosimetry was performed on a multi-cellular micrometastasis model, using time-integrated activities derived from the experimental data. With injected activity of 400 kBq, tumors exhibiting uniform activity distribution received <25 Gy (EUD=13 Gy), whereas tumors presenting radial activity distribution received mean absorbed doses of <8 Gy (EUD=5 Gy). These results provide new insight into important aspects of TAT, and may explain why micrometastases >100 µm might not be effectively treated by the examined regimen. PMID:23358400

  4. New Model Predicts Fire Activity in South America

    NASA Video Gallery

    UC Irvine scientist Jim Randerson discusses a new model that is able to predict fire activity in South America using sea surface temperature observations of the Pacific and Atlantic Ocean. The find...

  5. PREDICTING PREFERENTIAL ADSORPTION OF ORGANICS BY ACTIVATED CARBON

    EPA Science Inventory

    Preferential adsorption of organic compounds onto activated carbon from dilute aqueous solutions was studied to develop a comprehensive theoretical basis for predicting adsorption of multicomponent solutes. The research program investigates why some solutes are strong adsorbers, ...

  6. Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance.

    PubMed

    He, Y; Wu, A C; Harrington, B S; Davies, C M; Wallace, S J; Adams, M N; Palmer, J S; Roche, D K; Hollier, B G; Westbrook, T F; Hamidi, H; Konecny, G E; Winterhoff, B; Chetty, N P; Crandon, A J; Oliveira, N B; Shannon, C M; Tinker, A V; Gilks, C B; Coward, J I; Lumley, J W; Perrin, L C; Armes, J E; Hooper, J D

    2016-01-28

    Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC

  7. An Update on Ovarian Aging and Ovarian Reserve Tests

    PubMed Central

    Amanvermez, Ramazan; Tosun, Migraci

    2016-01-01

    Ovaries are the female organs that age more quickly than other tissues such as the uterus, the pituitary gland or pancreas. Different from males, an interesting question is why and how the females lose fertility so rapidly. During the aging process, both the number and quality of the oocytes in the ovaries decrease and reach to a point beyond that no more viable offspring may be produced and the associated cyclic endocrinological activities cease, entering the menopause in females at an average age of 50 years. Females who delayed childbearing with or without their willing until their 30 years or 40 years constitute the largest portion of the total infertility population. Ovarian reserve tests (ORTs) provide an indirect estimate of a female’s diminishing ovarian reserve or remaining follicular pool. This article briefly reviews recent progresses in relation to ovarian aging and ORTs. PMID:26985328

  8. Activation of A2b adenosine receptor regulates ovarian cancer cell growth: involvement of Bax/Bcl-2 and caspase-3.

    PubMed

    Hajiahmadi, Sima; Panjehpour, Mojtaba; Aghaei, Mahmoud; Shabani, Mahdi

    2015-08-01

    A2b adenosine receptor (A2bAR) acts as a potent regulator of cell growth in various cell lines. The present study was designed to understand the controlling mechanism of A2bAR agonist (NECA)-induced apoptosis in ovarian cancer cells. Real-time PCR and western blotting assays were used to evaluate the gene and protein expression profiles of A2bAR, respectively. MTT assay was used to study the cell proliferation effect of A2bAR agonist (NECA). Detection of apoptosis was conducted using annexin V-FITC/PI staining, caspase-3 activation assay, and the expression of Bax and Bcl-2 proteins analysis. The mitochondrial membrane potential (ΔΨM) was analyzed by employing JC-1 prob. The mRNA and protein expression levels of A2bAR in ovarian cancer cells were detected. NECA significantly reduced cell viability in a dose-dependent manner in OVCAR-3 and Caov-4 cell lines. The growth inhibition effect of NECA was related to the induction of cell apoptosis, which was manifested by annexin V-FITC staining, activation of caspase-3, and loss of mitochondrial membrane potentials (ΔΨm). In addition, downregulation of the regulatory protein Bcl-2 and upregulation of Bax protein by NECA were also observed. These findings demonstrated that NECA induces apoptosis via the mitochondrial signaling pathway. Thus, A2bAR agonists may be a potential agent for induction of apoptosis in ovarian cancer cells. PMID:25877700

  9. Targeting the EGF Receptor for Ovarian Cancer Therapy

    PubMed Central

    Zeineldin, Reema; Muller, Carolyn Y.; Stack, M. Sharon; Hudson, Laurie G.

    2010-01-01

    Ovarian carcinoma is the leading cause of death from gynecologic malignancy in the US. Factors such as the molecular heterogeneity of ovarian tumors and frequent diagnosis at advanced stages hamper effective disease treatment. There is growing emphasis on the identification and development of targeted therapies to disrupt molecular pathways in cancer. The epidermal growth factor (EGF) receptor is one such protein target with potential utility in the management of ovarian cancer. This paper will discuss contributions of EGF receptor activation to ovarian cancer pathogenesis and the status of EGF receptor inhibitors and EGF receptor targeted therapies in ovarian cancer treatment. PMID:20066160

  10. OVARIAN CANCER: INVOLVEMENT OF THE MATRIX METALLOPROTEINASES

    PubMed Central

    Al-Alem, Linah; Curry, Thomas E.

    2016-01-01

    Ovarian cancer is the leading cause of death from gynecologic malignancies. Reasons for the high mortality rate associated with ovarian cancer include a late diagnosis at which time the cancer has metastasized throughout the peritoneal cavity. Cancer metastasis is facilitated by the remodeling of the extracellular tumor matrix by a family of proteolytic enzymes known as the matrix metalloproteinases (MMPs). There are 23 members in the MMP family, many of which have been reported to be associated with ovarian cancer. In the current paradigm, ovarian tumor cells and the surrounding stromal cells stimulate the synthesis and/or activation of various MMPs to aid in tumor growth, invasion, and eventual metastasis. This review sheds light on the different MMPs in the various types of ovarian cancer and their impact on the progression of this gynecologic malignancy. PMID:25918438

  11. Noscapine Increases the Sensitivity of Drug-Resistant Ovarian Cancer Cell Line SKOV3/DDP to Cisplatin by Regulating Cell Cycle and Activating Apoptotic Pathways.

    PubMed

    Shen, Wei; Liang, Bingfeng; Yin, Jie; Li, Xiurong; Cheng, Jianxin

    2015-05-01

    Cisplatin is a first-line chemotherapy drug against ovarian cancer. However, its strong toxic side effects and the development of cisplatin resistance in human cancer cells seriously influence the effects of chemotherapy and quality of life in patients. Noscapine (Nos), a non-toxic benzylisoquinoline alkaloid extracted from opium, has been recently reported to have anti-cancer activity, but the mechanism of that effect has not been clearly established. In the present study, we investigated cytotoxicity of Nos in combination with cisplatin (DDP) in drug-resistant human ovarian cancer cell line SKOV3/DDP in vitro and in vivo null mice xenograft model. Cell proliferation was measured by MTT assay, flow cytometry was used to analyze cell cycle and apoptosis, protein expression of several apoptotic factors was investigated by flow cytometry and immunohistochemical method, and their mRNA expression levels were determined by real-time PCR. In vitro experiments showed that Nos significantly inhibited proliferation of SKOV3/DDP cells. DDP/Nos-combined treatment notably enhanced DDP-induced inhibition of cell proliferation and increased the pro-apoptotic effect of DDP in SKOV3/DDP cells. DDP/Nos administration increased the proportion of G2/M cells, reduced both protein and mRNA expression of anti-apoptotic factors XIAP, surviving and NF-kB, and augmented protein and mRNA levels of pro-apoptotic caspase-3. In vivo experiments revealed that Nos/DDP treatment increased the apoptotic rate of xenograft tumors in null mice. Tumor volume decreased from 1.733 ± 0.155 g in mice treated with DDP alone to 1.191 ± 0.106 g in animals treated with Nos/DDP. These observations suggest that Nos increases the anti-cancer activity of DDP against the drug-resistant ovarian cancer cell line SKOV3/DDP by modulating the cell cycle and activating apoptotic pathways. The study provides a new chemotherapy strategy for the treatment of DDP-resistant human ovarian cancer. PMID:25510462

  12. Caffeic acid phenethyl ester activates pro-apoptotic and epithelial-mesenchymal transition-related genes in ovarian cancer cells A2780 and A2780cis.

    PubMed

    Gherman, Claudia; Braicu, Ovidiu Leonard; Zanoaga, Oana; Jurj, Anca; Pileczki, Valentina; Maralani, Mahafarin; Drigla, Flaviu; Braicu, Cornelia; Budisan, Liviuta; Achimas-Cadariu, Patriciu; Berindan-Neagoe, Ioana

    2016-02-01

    Ovarian cancer is a highly aggressive pathology, displaying a poor prognosis and chemoresistance to classical therapy. The present study was conducted to evaluate the effect of caffeic acid phenethyl ester (CAPE) on survival of ovarian cancer cell lines, A2780 (sensitive to cisplatin) and A2780cis (resistant to cisplatin). MTT assay was used to evaluate cell viability, while the apoptotic processes were examined by flow cytometry and qRT-PCR. A reduction of cell proliferation and activation of the apoptosis was observed in both cell lines. qRT-PCR evaluation demonstrated the activation of the pro-apoptotic genes (BAD, CASP8, FAS, FADD, p53) in both cell lines. The limited therapeutic effect in A2780 cells is explained by the activation of epithelial-mesenchymal transition-related genes (ZEB1, ZEB2, or TGFBB1) as displayed by Ingenuity Network analysis. Overall data suggest that CAPE can be used as an alternative in sensitizing cells to chemotherapy. PMID:26838168

  13. Reduction of liver function delays resumption of postpartum ovarian activity and alters the synthesis of acute phase proteins in dairy cows.

    PubMed

    Montagner, Paula; Krause, Ana Rita Tavares; Schwegler, Elizabeth; Weschenfelder, Marina Menoncin; Rabassa, Viviane Rohrig; Schneider, Augusto; Pereira, Rubens Alves; Brauner, Cássio Cassal; Del Pino, Francisco Augusto Burkert; Gonçalves, Fernanda Medeiros; Corrêa, Marcio Nunes

    2016-06-01

    The aim of this study was to evaluate the concentration of acute phase proteins, milk production, and resumption of postpartum ovarian activity of clinically healthy dairy cows in a semi-extensive system with different Liver Functionality Index (LFI) values. The animals were divided into two groups: Low LFI (LLFI: -7 to -12; n: 10) and High LFI (HLFI: -7 to -4; n: 10). Animals with LLFI had lower paraoxonase activity and lower albumin concentration in the pre- and postpartum periods (P<0.05), higher non-esterified fatty acids prepartum (P<0.005), and higher haptoglobin concentration postpartum (P<0.01). The LLFI group showed lower resumption of ovarian activity until 44days postpartum (29%; P<0.05) than HLFI (86%). Milk production did not differ between groups. Therefore, this study suggests that the LFI is an important biomarker of synthesis of acute phase proteins and the first ovulation interval, and it can be used to improve the production and reproductive performance. PMID:27234541

  14. Ovarian aging and premature ovarian failure

    PubMed Central

    Şükür, Yavuz Emre; Kıvançlı, İçten Balık; Özmen, Batuhan

    2014-01-01

    Physiological reproductive aging occurs as a result of a decrease in the number and quality of oocytes in ovarian cortex follicles. Although the reason for the decrease in the quality of the pool and follicular oocytes is not fully understood, endocrine, paracrine, genetic, and metabolic factors are thought to be effective. Nowadays, in order to understand the mechanisms of ovarian aging, genomic research has gained importance. The effect of co-factors, such as telomerase and ceramide, in the ovarian aging process is only getting ascertained with new research studies. The most important tests in the assessment of ovarian aging are antral follicle count and anti-Mullerian hormone. PMID:25317048

  15. Oncolytic reovirus against ovarian and colon cancer.

    PubMed

    Hirasawa, Kensuke; Nishikawa, Sandra G; Norman, Kara L; Alain, Tommy; Kossakowska, Anna; Lee, Patrick W K

    2002-03-15

    Reovirus selectively replicates in and destroys cancer cells with an activated Ras signaling pathway. In this study, we evaluated the feasibility of using reovirus (serotype 3, strain Dearing) as an antihuman colon and ovarian cancer agent. In in vitro studies, reovirus infection in human colon and ovarian cell lines was assessed by cytopathic effect as detected by light microscopy, [(35)S]Methionine labeling of infected cells for viral protein synthesis and progeny virus production by plaque assay. We observed that reovirus efficiently infected all five human colon cancer cell lines (Caco-2, DLD-1, HCT-116, HT-29, and SW48) and four human ovarian cancer cell lines (MDAH2774, PA-1, SKOV3, and SW626) which were tested, but not a normal colon cell line (CCD-18Co) or a normal ovarian cell line (NOV-31). We also observed that the Ras activity in the human colon and ovarian cancer cell lines was elevated compared with that in normal colon and ovarian cell lines. In animal models, intraneoplastic as well as i.v. inoculation of reovirus resulted in significant regression of established s.c. human colon and ovarian tumors implanted at the hind flank. Histological studies revealed that reovirus infection in vivo was restricted to tumor cells, whereas the surrounding normal tissue remained uninfected. Additionally, in an i.p. human ovarian cancer xenograft model, inhibition of ascites tumor formation and the survival of animals treated with live reovirus was significantly greater than of control mice treated with UV-inactivated reovirus. Reovirus infection in ex vivo primary human ovarian tumor surgical samples was also confirmed, further demonstrating the potential of reovirus therapy. These results suggest that reovirus holds promise as a novel agent for human colon and ovarian cancer therapy. PMID:11912142

  16. Does MAP2 have a role in predicting the development of anti-NMDAR encephalitis associated with benign ovarian teratoma? A report of six new pediatric cases.

    PubMed

    Cundiff, Caitlin A; Elawabdeh, Nancy; Naguib, Mina M; Jactel, Samuel N; Demellawy, Dina El; Abramowsky, Carlos R; Durham, Megan M; Youssef, Lara; Wittkamp, Michael L; Shehata, Bahig M

    2015-01-01

    Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is a potentially fatal neurologic syndrome in which patients present with a spectrum of central nervous system deficits. Sixty percent of the cases can be attributed to the presence of tumors, most often ovarian teratomas. This report examines 6 pediatric patients who presented with neurologic deficits associated with the presence of such tumors. These cases illustrate a perplexing phenomenon, where benign teratomas could have a possible association with anti-NMDAR encephalitis. The purpose of this study was to compare the histology and immunohistochemistry of tumors associated with this syndrome to ovarian teratomas found in patients presenting with no neurologic symptoms. After obtaining institutional review board approval, 57 cases of ovarian teratomas were identified at our institution over 12 years. Six patients were identified with anti-NMDAR encephalitis. A panel of immunostains, including S100, GFAP, MAP2, and NeuN was applied to patients' tumor sections as well as the 6 controls from age-matched patients. No qualitative histologic or immunohistochemical differences were seen between the study cases and control group. Because no qualitative differences were identified between the study cases and the control group, testing of paired serum and cerebrospinal fluid remains the best method for diagnosis of anti-NMDAR encephalitis. Tumor banking with molecular analysis of ovarian teratomas, including whole-genome sequencing and comparative genomic hybridization between ovarian tissue saved from patients with and without anti-NMDAR encephalitis, is necessary to fully understand the etiopathogenesis of anti-NMDAR encephalitis. PMID:25569473

  17. Comparison of follicular fluid and serum levels of Inhibin A and Inhibin B with calculated indices used as predictive markers of ovarian hyperstimulation syndrome in IVF patients

    PubMed Central

    Moos, Jiri; Rezabek, Karel; Filova, Vanda; Moosova, Martina; Pavelkova, Jana; Peknicova, Jana

    2009-01-01

    Background Ovarian Hyperstimulation Syndrome (OHSS) is a severe health complication observed in some patients undergoing hormonal stimulation during IVF. Presence of OHSS is often associated with a high count of growing follicles responding to FSH hyperstimulation. However, the number of responding follicles may not be sufficient enough to predict the onset and severity of OHSS. The aim of this study was to find whether follicular fluid (FF) and serum concentrations of Inhibin A and Inhibin B in patients undergoing IVF treatment may serve as a predictor of OHSS status independent of the growing follicles count. Methods Serum and follicular fluid of fifty-three women undertaking the IVF program were separated into four groups according to their OHSS status and growing follicles count and analyzed for serum and FF concentrations of Inhibin A and Inhibin B. The resulting data were combined with clinical and demographic data to calculate indices independent of the growing follicles count. Results Serum Inhibin A and Inhibin B concentrations showed no significant difference between the severe OHSS group and the control group without OHSS. Moreover, the serum concentrations of Inhibin A and Inhibin B were strongly correlated with the growing follicles count. Their concentrations in the high responders group (>18 follicles) were significantly higher (p < 0.00001, p < 0.0001) when compared with normal and low responders (<18 follicles). To suppress the dependence on the growing follicle count, three indices were constructed and calculated. The best association with OHSS status and independence of the growing follicle count was achieved by using the Inhibin B TFF/SBM index calculated as follows: [concentration in FF] × [growing follicle count]/[concentration in serum] × [body mass]. The Inhibin B TFF/SBM index showed a clear difference (p = 0,00433) between the group with severe OHSS and the control group, while showing no apparent correlation with the growing follicle

  18. Symptoms of Ovarian Cancer

    MedlinePlus

    ... Informed Cancer Home What Are the Symptoms of Ovarian Cancer? Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Gynecologic cancer symptoms diaries Ovarian cancer may cause one or more of these signs ...

  19. Premature Ovarian Failure

    MedlinePlus

    Premature ovarian failure (POF) is when a woman's ovaries stop working before she is 40. POF is different from ... There is no treatment that will restore normal ovarian function. However, many health care providers suggest taking ...

  20. Predicting Physical Activity in Arab American School Children

    ERIC Educational Resources Information Center

    Martin, Jeffrey J.; McCaughtry, Nate; Shen, Bo

    2008-01-01

    Theoretically grounded research on the determinants of Arab American children's physical activity is virtually nonexistent. Thus, the purpose of our investigation was to evaluate the ability of the theory of planned behavior (TPB) and social cognitive theory (SCT) to predict Arab American children's moderate-to-vigorous physical activity (MVPA).…

  1. Ovarian activity and oocyte quality associated with the biochemical profile of serum and follicular fluid from Girolando dairy cows postpartum.

    PubMed

    Alves, Benner G; Alves, Kele A; Lúcio, Aline C; Martins, Muller C; Silva, Thiago H; Alves, Bruna G; Braga, Lucas S; Silva, Thiago V; Viu, Marco A O; Beletti, Marcelo E; Jacomini, José O; Santos, Ricarda M; Gambarini, Maria L

    2014-05-01

    This study was designed to evaluate the influence of heat stress (HS) on the metabolic profile of serum and follicular fluid (FF), ovarian follicle development, and oocyte quality of Girolando dairy cows. Oocytes, blood, and FF (follicles ≥9mm) samples were obtained at 30, 45, 60, 75, and 90 days postpartum in the summer and winter seasons. During transvaginal follicular aspiration, rectal temperature (RT), body condition score (BCS), number of ovarian follicles, and quality of oocytes were recorded. The ambient air temperature (AT) and relative humidity (RH) were also recorded to calculate the temperature humidity index (THI). Glucose, total cholesterol (TC), triglycerides (TG), urea, sodium (Na), potassium (K), and calcium (Ca) concentrations were determined using serum and FF samples. The RT, THI, and BCS loss were greater (P<0.01) in the summer; however, glucose, Na, and K serum concentrations decreased in the same season (P<0.05). Degenerated oocytes were positively associated (P<0.05) with THI (r=0.14) and AT (r=0.13), and negatively associated with glucose (r=-0.12) and K (r=-0.11) serum concentrations. HS induces metabolic changes, which compromise the number of ovarian follicles and the follicular environment, thus resulting in morphologically damaged oocytes. PMID:24674823

  2. Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1)*

    PubMed Central

    Musrap, Natasha; Tuccitto, Alessandra; Karagiannis, George S.; Saraon, Punit; Batruch, Ihor; Diamandis, Eleftherios P.

    2015-01-01

    Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies. This increased resistance and the ability to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed abdominal surfaces and organs. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets. Thus, we attempted to gain insight into the proteomic changes that occur during anchorage-independent cancer cell aggregation. As such, an ovarian cancer cell line, OV-90, was cultured in adherent and non-adherent conditions using stable isotope labeling with amino acids in cell culture (SILAC). Anchorage-dependent cells (OV-90AD) were grown in tissue culture flasks, whereas anchorage-independent cells (OV-90AI) were grown in suspension using the hanging-drop method. Cellular proteins from both conditions were then identified using LC-MS/MS, which resulted in the quantification of 1533 proteins. Of these, 13 and 6 proteins were up-regulated and down-regulated, respectively, in aggregate-forming cells compared with cells grown as monolayers. Relative gene expression and protein expression of candidates were examined in other cell line models of aggregate formation (TOV-112D and ES-2), which revealed an increased expression of calcium-activated chloride channel regulator 1 (CLCA1). Moreover, inhibitor and siRNA transfection studies demonstrated an apparent effect of CLCA1 on cancer cell aggregation. Further elucidation of the role of CLCA1 in the pathogenesis of ovarian cancer is warranted. PMID:26004777

  3. Comparative Proteomics of Ovarian Cancer Aggregate Formation Reveals an Increased Expression of Calcium-activated Chloride Channel Regulator 1 (CLCA1).

    PubMed

    Musrap, Natasha; Tuccitto, Alessandra; Karagiannis, George S; Saraon, Punit; Batruch, Ihor; Diamandis, Eleftherios P

    2015-07-10

    Ovarian cancer is a lethal gynecological disease that is characterized by peritoneal metastasis and increased resistance to conventional chemotherapies. This increased resistance and the ability to spread is often attributed to the formation of multicellular aggregates or spheroids in the peritoneal cavity, which seed abdominal surfaces and organs. Given that the presence of metastatic implants is a predictor of poor survival, a better understanding of how spheroids form is critical to improving patient outcome, and may result in the identification of novel therapeutic targets. Thus, we attempted to gain insight into the proteomic changes that occur during anchorage-independent cancer cell aggregation. As such, an ovarian cancer cell line, OV-90, was cultured in adherent and non-adherent conditions using stable isotope labeling with amino acids in cell culture (SILAC). Anchorage-dependent cells (OV-90AD) were grown in tissue culture flasks, whereas anchorage-independent cells (OV-90AI) were grown in suspension using the hanging-drop method. Cellular proteins from both conditions were then identified using LC-MS/MS, which resulted in the quantification of 1533 proteins. Of these, 13 and 6 proteins were up-regulated and down-regulated, respectively, in aggregate-forming cells compared with cells grown as monolayers. Relative gene expression and protein expression of candidates were examined in other cell line models of aggregate formation (TOV-112D and ES-2), which revealed an increased expression of calcium-activated chloride channel regulator 1 (CLCA1). Moreover, inhibitor and siRNA transfection studies demonstrated an apparent effect of CLCA1 on cancer cell aggregation. Further elucidation of the role of CLCA1 in the pathogenesis of ovarian cancer is warranted. PMID:26004777

  4. Effect of Calcium Soap of Fatty Acids Supplementation on Serum Biochemical Parameters and Ovarian Activity during Out-of-the-Breeding Season in Crossbred Ewes

    PubMed Central

    El-Nour, Hayat H. M.; Nasr, Soad M.; Hassan, Walid R.

    2012-01-01

    This experiment aimed to evaluate the effect of calcium soap of fatty acid (CSFA) supplementation on serum biochemical and hormones and ovarian activity during out-of-the-breeding season in ewes. Twelve crossbred ewes, 2-3 years of age and weighting 45–55 kg, were allocated into two equal groups. The first group was control and the other was treated with 50 g/head of CSFA. All ewes were fed basal diet and treated with 60 mg of medroxy progesterone acetate intravaginal sponge for 12 day. At the third day of sponge removal, the CSFA-treated group was given 50 g/head of CSFA daily for two estrous cycles. During the estrus phase, ovarian activity was detected using ultrasonography in both groups. All ewes were then subjected to natural breeding and conception rate. Blood samples were collected from all ewes during treatment period. Results revealed significant (P < 0.05) increases in serum cholesterol, triglycerides, low-density lipoprotein cholesterol, glucose, and progesterone levels with decrease in calcium and phosphorous levels in treated group. In treated group, normal-size ovaries and more than one follicle on the ovaries were detected and pregnancy rate increased. In conclusion, CSFA supplementation was effective to maintain the reproductive performance when ewes were out of the breeding season. PMID:22629155

  5. Microsurgery of ovarian endometriosis.

    PubMed

    Brosens, I A; Boeckx, W; Page, G

    1988-04-01

    A long-term follow-up study of 92 patients with ovarian endometriosis treated with microsurgical techniques showed that although endometriosis may persist in many patients, only seven patients required repeat ovarian surgery. Microsurgical techniques are to be recommended for the treatment of ovarian endometriosis and the prevention of postoperative adhesive disease of the ovaries. PMID:3372697

  6. Flutter prediction for a wing with active aileron control

    NASA Technical Reports Server (NTRS)

    Penning, K.; Sandlin, D. R.

    1983-01-01

    A method for predicting the vibrational stability of an aircraft with an analog active aileron flutter suppression system (FSS) is expained. Active aileron refers to the use of an active control system connected to the aileron to damp vibrations. Wing vibrations are sensed by accelerometers and the information is used to deflect the aileron. Aerodynamic force caused by the aileron deflection oppose wing vibrations and effectively add additional damping to the system.

  7. Synthesis, characterization, theoretical prediction of activities and evaluation of biological activities of some sulfacetamide based hydroxytriazenes.

    PubMed

    Agarwal, Shilpa; Baroliya, Prabhat K; Bhargava, Amit; Tripathi, I P; Goswami, A K

    2016-06-15

    Six new N [(4-aminophenyl)sulfonyl]acetamide based hydroxytriazenes have been synthesized and characterized using elemental analysis, IR, 1H NMR, 13C NMR and MASS spectral analysis. Further, their theoretical predictions for probable activities have been taken using PASS (Prediction of Activity Spectra for Substance). Although a number of activities have been predicted but specifically anti-inflammatory, antiradical, anti-diabetic activities have been experimentally validated which proves that theoretical predictions agree with the experimental results. The object of the Letter is to establish Computer Aided Drug Design (CADD) using our compounds. PMID:27136718

  8. Prediction of fine-tuned promoter activity from DNA sequence

    PubMed Central

    Siwo, Geoffrey; Rider, Andrew; Tan, Asako; Pinapati, Richard; Emrich, Scott; Chawla, Nitesh; Ferdig, Michael

    2016-01-01

    The quantitative prediction of transcriptional activity of genes using promoter sequence is fundamental to the engineering of biological systems for industrial purposes and understanding the natural variation in gene expression. To catalyze the development of new algorithms for this purpose, the Dialogue on Reverse Engineering Assessment and Methods (DREAM) organized a community challenge seeking predictive models of promoter activity given normalized promoter activity data for 90 ribosomal protein promoters driving expression of a fluorescent reporter gene. By developing an unbiased modeling approach that performs an iterative search for predictive DNA sequence features using the frequencies of various k-mers, inferred DNA mechanical properties and spatial positions of promoter sequences, we achieved the best performer status in this challenge. The specific predictive features used in the model included the frequency of the nucleotide G, the length of polymeric tracts of T and TA, the frequencies of 6 distinct trinucleotides and 12 tetranucleotides, and the predicted protein deformability of the DNA sequence. Our method accurately predicted the activity of 20 natural variants of ribosomal protein promoters (Spearman correlation r = 0.73) as compared to 33 laboratory-mutated variants of the promoters (r = 0.57) in a test set that was hidden from participants. Notably, our model differed substantially from the rest in 2 main ways: i) it did not explicitly utilize transcription factor binding information implying that subtle DNA sequence features are highly associated with gene expression, and ii) it was entirely based on features extracted exclusively from the 100 bp region upstream from the translational start site demonstrating that this region encodes much of the overall promoter activity. The findings from this study have important implications for the engineering of predictable gene expression systems and the evolution of gene expression in naturally occurring

  9. Vascular endothelial growth factor expression correlates with serum CA125 and represents a useful tool in prediction of refractoriness to platinum-based chemotherapy and ascites formation in epithelial ovarian cancer

    PubMed Central

    Wei, Ai-Qun; Robertson, Gregory; Morris, David L.

    2015-01-01

    There is an increasing need for the identification of novel biological markers and potential therapeutic targets in epithelial ovarian cancer (EOC). Given the critical role of growth factors in the biology of EOC, we aimed in the present study to evaluate the intratumoral expressions of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) proteins and their clinical relevance in a cohort of 100 patients with EOC. All patients received platinum-based chemotherapy after surgery. A comparative immunohistochemical study of normal ovarian and EOC tissues showed that both growth factors were expressed at higher levels in tumor samples. In our statistical analysis, while no association existed between the FGF expression status and the clinicopathological characteristics of patients, intratumoral VEGF was identified as a potential biomarker for the prediction of ascites formation. In addition, the expression status of VEGF appeared to independently predict overall survival and response to chemotherapy. Furthermore, a direct association was demonstrated between the pre-treatment VEGF expression and serum CA125 after three cycles of chemotherapy. In sum, we report for the first time to our knowledge the correlation between intratumoral VEGF and serum CA125 in EOC. Our data also shows the prognostic value of VEGF expression in EOC. These results suggest the potential value of intratumoral VEGF in patient stratification. Dual inhibition of VEGF and CA125 might bring about a better outcome for patients with EOC. PMID:26143638

  10. Structure based activity prediction of HIV-1 reverse transcriptase inhibitors.

    PubMed

    de Jonge, Marc R; Koymans, Lucien M H; Vinkers, H Maarten; Daeyaert, Frits F D; Heeres, Jan; Lewi, Paul J; Janssen, Paul A J

    2005-03-24

    We have developed a fast and robust computational method for prediction of antiviral activity in automated de novo design of HIV-1 reverse transcriptase inhibitors. This is a structure-based approach that uses a linear relation between activity and interaction energy with discrete orientation sampling and with localized interaction energy terms. The localization allows for the analysis of mutations of the protein target and for the separation of inhibition and a specific binding to the enzyme. We apply the method to the prediction of pIC(50) of HIV-1 reverse transcriptase inhibitors. The model predicts the activity of an arbitrary compound with a q(2) of 0.681 and an average absolute error of 0.66 log value, and it is fast enough to be used in high-throughput computational applications. PMID:15771460

  11. Diet and Physical Activity Change or Usual Care in Improving Progression-Free Survival in Patients With Previously Treated Stage II, III, or IV Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2016-02-09

    Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Malignant Ovarian Brenner Tumor; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Primary Peritoneal Serous Adenocarcinoma; Stage IIA Fallopian Tube Cancer; Stage IIA Ovarian Cancer; Stage IIB Fallopian Tube Cancer; Stage IIB Ovarian Cancer; Stage IIC Fallopian Tube Cancer; Stage IIC Ovarian Cancer; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer; Undifferentiated Fallopian Tube Carcinoma; Undifferentiated Ovarian Carcinoma

  12. A neural network model for olfactory glomerular activity prediction

    NASA Astrophysics Data System (ADS)

    Soh, Zu; Tsuji, Toshio; Takiguchi, Noboru; Ohtake, Hisao

    2012-12-01

    Recently, the importance of odors and methods for their evaluation have seen increased emphasis, especially in the fragrance and food industries. Although odors can be characterized by their odorant components, their chemical information cannot be directly related to the flavors we perceive. Biological research has revealed that neuronal activity related to glomeruli (which form part of the olfactory system) is closely connected to odor qualities. Here we report on a neural network model of the olfactory system that can predict glomerular activity from odorant molecule structures. We also report on the learning and prediction ability of the proposed model.

  13. Effect of Amino Acids on the Generation of Ginsenoside Rg3 Epimers by Heat Processing and the Anticancer Activities of Epimers in A2780 Human Ovarian Cancer Cells

    PubMed Central

    Park, Jun Yeon; Choi, Pilju; Lee, Dahae; Kim, Taejung; Jung, Eun Bee; Hwang, Buyng-Su; Kang, Ki Sung; Ham, Jungyeob

    2016-01-01

    Ginsenosides are the active components of Panax ginseng. Many research studies indicate that these deglycosylated, less-polar ginsenosides have better bioactivity than the major ginsenosides. In the present study, we sought to verify the enhanced anticancer effect of P. ginseng extract after undergoing the Maillard reaction as well as elucidate the underlying mechanism of action. The effects of 9 amino acids were tested; among them, the content of 20(S)-Rg3 in the ginseng extract increased to more than 30, 20, and 20% when processed with valine, arginine, and alanine, respectively, compared with that after normal heat processing. The ginseng extract that was heat-processed with arginine exhibited the most potent inhibitory effect on A2780 ovarian cancer cell proliferation. Therefore, the generation of 20(S)-Rg3 was suggested to be involved in this effect. Moreover, the inhibitory effect of 20(S)-Rg3 on A2780 cell proliferation was significantly stronger than that of 20(R)-Rg3. Protein expression levels of cleaved caspase-3, caspase-8, caspase-9, and PARP in the A2780 ovarian cancer cells markedly increased, whereas the expression of BID decreased after 20(S)-Rg3 treatment. Therefore, we confirmed that the anticancer effects of the products of ginseng that was heat-processed with arginine are mediated mainly via the generation of the less-polar ginsenoside 20(S)-Rg3. PMID:27051448

  14. Effect of Amino Acids on the Generation of Ginsenoside Rg3 Epimers by Heat Processing and the Anticancer Activities of Epimers in A2780 Human Ovarian Cancer Cells.

    PubMed

    Park, Jun Yeon; Choi, Pilju; Lee, Dahae; Kim, Taejung; Jung, Eun Bee; Hwang, Buyng-Su; Kang, Ki Sung; Ham, Jungyeob

    2016-01-01

    Ginsenosides are the active components of Panax ginseng. Many research studies indicate that these deglycosylated, less-polar ginsenosides have better bioactivity than the major ginsenosides. In the present study, we sought to verify the enhanced anticancer effect of P. ginseng extract after undergoing the Maillard reaction as well as elucidate the underlying mechanism of action. The effects of 9 amino acids were tested; among them, the content of 20(S)-Rg3 in the ginseng extract increased to more than 30, 20, and 20% when processed with valine, arginine, and alanine, respectively, compared with that after normal heat processing. The ginseng extract that was heat-processed with arginine exhibited the most potent inhibitory effect on A2780 ovarian cancer cell proliferation. Therefore, the generation of 20(S)-Rg3 was suggested to be involved in this effect. Moreover, the inhibitory effect of 20(S)-Rg3 on A2780 cell proliferation was significantly stronger than that of 20(R)-Rg3. Protein expression levels of cleaved caspase-3, caspase-8, caspase-9, and PARP in the A2780 ovarian cancer cells markedly increased, whereas the expression of BID decreased after 20(S)-Rg3 treatment. Therefore, we confirmed that the anticancer effects of the products of ginseng that was heat-processed with arginine are mediated mainly via the generation of the less-polar ginsenoside 20(S)-Rg3. PMID:27051448

  15. VANDETANIB, DESIGNED TO INHBIT VEGFR2 AND EGFR SIGNALLING, HAD NO CLINICAL ACTIVITY AS MONOTHERAPY FOR RECURRENT OVARIAN CANCER AND NO DETECTABLE MODULATION OF VEGFR2

    PubMed Central

    Annunziata, Christina M.; Walker, Amanda J.; Minasian, Lori; Yu, Minshu; Kotz, Herbert; Wood, Bradford J.; Calvo, Katherine; Choyke, Peter; Kimm, Daniel; Steinberg, Seth; Kohn, Elise C.

    2009-01-01

    Purpose: To evaluate clinical activity and target modulation of vandetanib in women with recurrent ovarian cancer. Experimental Design: A phase II trial of orally administered vandetanib 300mg daily was designed to include analyses of target inhibition through paired biopsies and dynamic imaging. Core 18g needle biopsies and dynamic contrast-enhanced (DCE) MRI were obtained prior to initiation of therapy and 6wk into therapy. Biopsy samples were subjected to reverse-phase protein lysate array endpoint analysis. Cytokine concentrations were measured by ELISA in serially collected plasma samples. Results: Twelve patients entered the study and accrual terminated in first stage due to lack of response or disease stabilization beyond 6 months. Adverse events included rash, diarrhea, and QTc prolongation, but not hypertension. Exploratory analyses showed that EGFR phosphorylation was reduced in the 8 paired biopsy sets obtained; VEGFR2 phosphorylation was not consistently affected, nor were DCE-MRI permeability and flow parameters. Serial plasma VEGF concentrations were variable, and did not significantly change in the 11 patients assessed. Conclusions: Vandetanib 300 mg daily monotherapy had no significant clinical benefit in this disease setting. Proteomic analysis of paired biopsies detected both phosphorylated-EGFR and phosphorylated-VEGFR2 in ovarian tumor tissue, but only phosphorylated-EGFR measurably inhibited by vandetanib. PMID:20068097

  16. Ovarian biopsy in the evaluation of amenorrhea.

    PubMed

    Karam, K; Mroueh, A

    1978-01-01

    Endoscopic ovarian biopsies were performed on 78 amenorrheic patients in an attempt to determine the etiology of their amenorrhea and predict its prognosis, correlating the histologic examination with physical findings, endocrine patterns and cytogenetic studies. Ovarian follicles were present while gonadotropins were high in 14 cases (6 primary, 8 secondary) and there were no follicles in 4 cases (3 primary, 1 secondary) whose gonadotropins were low. Secondary sex characteristics were well developed without prior estrogen stimulation in 5 cases of primary amenorrhea who had no follicles and whose gonadotropins were either low, 3, or high, 2. The mere presence of ovarian follicles was not enough to make them responsive to gonadotropin stimulation whether endogenous or exogenous; a phenomenon that had to do with the quality and quantity of germinal follicles available. The histologic examination of ovarian tissue for the evaluation of amenorrhea has been made feasible and relatively safe through recent advances in endoscopic techniques. PMID:151477

  17. Prevention of chemotherapy-induced ovarian damage.

    PubMed

    Roness, Hadassa; Kashi, Oren; Meirow, Dror

    2016-01-01

    Recent advances in our understanding of the mechanisms underlying the impact of cytotoxic drugs on the ovary have opened up new directions for the protection of the ovary from chemotherapy-induced damage. These advances have spurred the investigation of pharmacological agents to prevent ovarian damage at the time of treatment. Prevention of ovarian damage and follicle loss would provide significant advantages over existing fertility preservation techniques. This manuscript reviews new methods for the prevention of chemotherapy-induced ovarian damage, including agents that act on the PI3K/PTEN/Akt follicle activation pathway, apoptotic pathways, the vascular system, and other potential methods of reducing chemotherapy-induced ovotoxicity. PMID:26677788

  18. Solar Activity Forecasting for use in Orbit Prediction

    NASA Technical Reports Server (NTRS)

    Schatten, Kenneth

    2001-01-01

    Orbital prediction for satellites in low Earth orbit (LEO) or low planetary orbit depends strongly on exospheric densities. Solar activity forecasting is important in orbital prediction, as the solar UV and EUV inflate the upper atmospheric layers of the Earth and planets, forming the exosphere in which satellites orbit. Geomagnetic effects also relate to solar activity. Because of the complex and ephemeral nature of solar activity, with different cycles varying in strength by more than 100%, many different forecasting techniques have been utilized. The methods range from purely numerical techniques (essentially curve fitting) to numerous oddball schemes, as well as a small subset, called 'Precursor techniques.' The situation can be puzzling, owing to the numerous methodologies involved, somewhat akin to the numerous ether theories near the turn of the last century. Nevertheless, the Precursor techniques alone have a physical basis, namely dynamo theory, which provides a physical explanation for why this subset seems to work. I discuss this solar cycle's predictions, as well as the Sun's observed activity. I also discuss the SODA (Solar Dynamo Amplitude) index, which provides the user with the ability to track the Sun's hidden, interior dynamo magnetic fields. As a result, one may then update solar activity predictions continuously, by monitoring the solar magnetic fields as they change throughout the solar cycle. This paper ends by providing a glimpse into what the next solar cycle (#24) portends.

  19. Ovarian activity in beef and dairy cows with prolonged postpartum period and heifers that fail to conceive.

    PubMed

    Yimer, N; Rosnina, Y; Wahid, H; Saharee, A A; Yap, K C; Ganesamurthi, P

    2010-04-01

    The primary objectives of this study were to investigate incidence of abnormal ovarian cyclicity (AOC) and its type in dairy and beef cows with prolonged postpartum period (>90 days) and in heifers that fail to conceive. A total of 53 animals were included in the study: 17 Friesian crosses, 16 Braford crosses, eight Brangus crosses, and 12 local Kedah-Kelantan (KKX) crosses. These animals were initially checked for absence of pregnancy via palpation per rectum. Blood samples for progesterone analysis were obtained twice a week for 2 to 3 months following their spontaneous oestrous cycle, and all animals were rechecked for pregnancy at the end of the study. Progesterone analysis indicated that 33.9% of the total animals were having AOC: 18.9% with cessation of ovarian cyclicity, 9.4% with prolonged luteal phases (PLP), and 5.7% short luteal phases. The highest incidence was observed in Brangus crosses (62.5%), followed by Braford crosses (43.8%), and Friesian crosses (35.3%). In contrast, no AOC was observed in the local KKX breeds, and all of them were found to be pregnant at the end of the study. A significant difference (p < 0.05) in the incidence of AOC and its type was observed between Kedah-Kelantan crosses and the other breeds. Although not significant (p > 0.05), Friesian crosses showed a higher percentage incidence of AOC than beef cows (40% vs 36.4%), with major types being PLP (26.7%) in dairy and cessation of ovarian cycle (27.3%) in beef cows. Compared with beef heifers, beef cows showed a higher percentage of AOC (36.4% vs 28.6%) where again, cessation of cyclicity was the predominant abnormality. In conclusion, AOC reflected by abnormal endocrine pattern is a possible cause of reduction in fertility for dairy and beef cows beyond 90 days postpartum and heifers that fail to conceive. PMID:19809886

  20. Drug discovery in ovarian cancer.

    PubMed

    Chase, Dana M; Mathur, Nidhee; Tewari, Krishnansu S

    2010-11-01

    Drug discovery in the ovarian cancer arena has led to the activation of several important clinical trials. Many biologic agents have come down the pipeline and are being studied in phase II trials for recurrent disease. These agents include antivascular compounds that disrupt angiogenesis through a variety of mechanisms (e.g., prevention of ligand-binding to the vascular endothelial growth factor receptor-2 (VEGF-R2), high-affinity VEGF blockade, oral inhibitors of tyrosine kinases stimulated by VEGF, inhibition of alpha5beta1 integrin, neutralization of angioproteins, etc.). Other novel drugs include oral platinum compounds as well as those that antagonize the tumor proliferation genes in the Hedgehog pathway, and that target folic acid receptors which are expressed by ovarian cancer cells. In addition, studies are underway with oral agents that inhibit the tyrosine kinase activity associated with two oncogenes (epidermal growth factor receptor (EGFR) and HER-2/neu). Finally, emerging technologies in clinical trials include nanotechnology to enhance delivery of chemotherapy to ovarian tumors, drug resistance/sensitivity assays to guide therapy, and agents that mobilize and induce proliferation of hematopoetic progenitor cells to aid in red blood cell, white blood cell, and platelet recovery following chemotherapy. The relevant patents in drug discovery of ovarian cancer are discussed. PMID:20524931

  1. Stock price change rate prediction by utilizing social network activities.

    PubMed

    Deng, Shangkun; Mitsubuchi, Takashi; Sakurai, Akito

    2014-01-01

    Predicting stock price change rates for providing valuable information to investors is a challenging task. Individual participants may express their opinions in social network service (SNS) before or after their transactions in the market; we hypothesize that stock price change rate is better predicted by a function of social network service activities and technical indicators than by a function of just stock market activities. The hypothesis is tested by accuracy of predictions as well as performance of simulated trading because success or failure of prediction is better measured by profits or losses the investors gain or suffer. In this paper, we propose a hybrid model that combines multiple kernel learning (MKL) and genetic algorithm (GA). MKL is adopted to optimize the stock price change rate prediction models that are expressed in a multiple kernel linear function of different types of features extracted from different sources. GA is used to optimize the trading rules used in the simulated trading by fusing the return predictions and values of three well-known overbought and oversold technical indicators. Accumulated return and Sharpe ratio were used to test the goodness of performance of the simulated trading. Experimental results show that our proposed model performed better than other models including ones using state of the art techniques. PMID:24790586

  2. Stock Price Change Rate Prediction by Utilizing Social Network Activities

    PubMed Central

    Mitsubuchi, Takashi; Sakurai, Akito

    2014-01-01

    Predicting stock price change rates for providing valuable information to investors is a challenging task. Individual participants may express their opinions in social network service (SNS) before or after their transactions in the market; we hypothesize that stock price change rate is better predicted by a function of social network service activities and technical indicators than by a function of just stock market activities. The hypothesis is tested by accuracy of predictions as well as performance of simulated trading because success or failure of prediction is better measured by profits or losses the investors gain or suffer. In this paper, we propose a hybrid model that combines multiple kernel learning (MKL) and genetic algorithm (GA). MKL is adopted to optimize the stock price change rate prediction models that are expressed in a multiple kernel linear function of different types of features extracted from different sources. GA is used to optimize the trading rules used in the simulated trading by fusing the return predictions and values of three well-known overbought and oversold technical indicators. Accumulated return and Sharpe ratio were used to test the goodness of performance of the simulated trading. Experimental results show that our proposed model performed better than other models including ones using state of the art techniques. PMID:24790586

  3. Solar activity forecast: Spectral analysis and neurofuzzy prediction

    NASA Astrophysics Data System (ADS)

    Gholipour, Ali; Lucas, Caro; Araabi, Babak N.; Shafiee, Masoud

    2005-04-01

    Active research in the last two decades indicates that the physical precursor and solar dynamo techniques are preferred as practical tools for long-term prediction of solar activity. But why should we omit more than 23 cycles of solar activity history, and just use empirical methods or simple autoregressive methods on the basis of observations for the latest eight cycles? In this article, a method based on spectral analysis and neurofuzzy modeling is proposed that is capable of issuing very accurate long-term prediction of sunspot number time series. A locally linear neurofuzzy model is optimized for each of the principal components obtained from singular spectrum analysis, and the multi-step predicted values are recombined to make the sunspot number time series. The proposed method is used for solar cycles 22 and 23 and the results are remarkably good in comparison to the predictions made by solar dynamo and precursor methods. An early prediction of the maximum smoothed international sunspot number for cycle 24 is 145 in 2011 2012.

  4. Application of Avco data analysis and prediction techniques (ADAPT) to prediction of sunspot activity

    NASA Technical Reports Server (NTRS)

    Hunter, H. E.; Amato, R. A.

    1972-01-01

    The results are presented of the application of Avco Data Analysis and Prediction Techniques (ADAPT) to derivation of new algorithms for the prediction of future sunspot activity. The ADAPT derived algorithms show a factor of 2 to 3 reduction in the expected 2-sigma errors in the estimates of the 81-day running average of the Zurich sunspot numbers. The report presents: (1) the best estimates for sunspot cycles 20 and 21, (2) a comparison of the ADAPT performance with conventional techniques, and (3) specific approaches to further reduction in the errors of estimated sunspot activity and to recovery of earlier sunspot historical data. The ADAPT programs are used both to derive regression algorithm for prediction of the entire 11-year sunspot cycle from the preceding two cycles and to derive extrapolation algorithms for extrapolating a given sunspot cycle based on any available portion of the cycle.

  5. A new mathematical solution for predicting char activation reactions

    USGS Publications Warehouse

    Rafsanjani, H.H.; Jamshidi, E.; Rostam-Abadi, M.

    2002-01-01

    The differential conservation equations that describe typical gas-solid reactions, such as activation of coal chars, yield a set of coupled second-order partial differential equations. The solution of these coupled equations by exact analytical methods is impossible. In addition, an approximate or exact solution only provides predictions for either reaction- or diffusion-controlling cases. A new mathematical solution, the quantize method (QM), was applied to predict the gasification rates of coal char when both chemical reaction and diffusion through the porous char are present. Carbon conversion rates predicted by the QM were in closer agreement with the experimental data than those predicted by the random pore model and the simple particle model. ?? 2002 Elsevier Science Ltd. All rights reserved.

  6. Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy

    PubMed Central

    Podo, Franca; Paris, Luisa; Cecchetti, Serena; Spadaro, Francesca; Abalsamo, Laura; Ramoni, Carlo; Ricci, Alessandro; Pisanu, Maria Elena; Sardanelli, Francesco; Canese, Rossella; Iorio, Egidio

    2016-01-01

    Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20–50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods. PMID:27532027

  7. Activation of Phosphatidylcholine-Specific Phospholipase C in Breast and Ovarian Cancer: Impact on MRS-Detected Choline Metabolic Profile and Perspectives for Targeted Therapy.

    PubMed

    Podo, Franca; Paris, Luisa; Cecchetti, Serena; Spadaro, Francesca; Abalsamo, Laura; Ramoni, Carlo; Ricci, Alessandro; Pisanu, Maria Elena; Sardanelli, Francesco; Canese, Rossella; Iorio, Egidio

    2016-01-01

    Elucidation of molecular mechanisms underlying the aberrant phosphatidylcholine cycle in cancer cells plays in favor of the use of metabolic imaging in oncology and opens the way for designing new targeted therapies. The anomalous choline metabolic profile detected in cancer by magnetic resonance spectroscopy and spectroscopic imaging provides molecular signatures of tumor progression and response to therapy. The increased level of intracellular phosphocholine (PCho) typically detected in cancer cells is mainly attributed to upregulation of choline kinase, responsible for choline phosphorylation in the biosynthetic Kennedy pathway, but can also be partly produced by activation of phosphatidylcholine-specific phospholipase C (PC-PLC). This hydrolytic enzyme, known for implications in bacterial infection and in plant survival to hostile environmental conditions, is reported to be activated in mitogen- and oncogene-induced phosphatidylcholine cycles in mammalian cells, with effects on cell signaling, cell cycle regulation, and cell proliferation. Recent investigations showed that PC-PLC activation could account for 20-50% of the intracellular PCho production in ovarian and breast cancer cells of different subtypes. Enzyme activation was associated with PC-PLC protein overexpression and subcellular redistribution in these cancer cells compared with non-tumoral counterparts. Moreover, PC-PLC coimmunoprecipitated with the human epidermal growth factor receptor-2 (HER2) and EGFR in HER2-overexpressing breast and ovarian cancer cells, while pharmacological PC-PLC inhibition resulted into long-lasting HER2 downregulation, retarded receptor re-expression on plasma membrane and antiproliferative effects. This body of evidence points to PC-PLC as a potential target for newly designed therapies, whose effects can be preclinically and clinically monitored by metabolic imaging methods. PMID:27532027

  8. Predicting Physical Activity Promotion in Health Care Settings.

    ERIC Educational Resources Information Center

    Faulkner, Guy; Biddle, Stuart

    2001-01-01

    Tested the theory of planned behavior's (TPB) ability to predict stage of change for physical activity promotion among health professionals. Researchers measured attitudes, subjective norms, intentions, perceived behavioral control, and stage of change, then later reassessed stage of change. TPB variables of attitude, subjective norms, perceived…

  9. Predicting Work Activities with Divergent Thinking Tests: A Longitudinal Study

    ERIC Educational Resources Information Center

    Clapham, Maria M.; Cowdery, Edwina M.; King, Kelly E.; Montang, Melissa A.

    2005-01-01

    This study examined whether divergent thinking test scores obtained from engineering students during college predicted creative work activities fifteen years later. Results showed that a subscore of the "Owens Creativity Test", which assesses divergent thinking about mechanical objects, correlated significantly with self-ratings of creative work…

  10. Prediction of energy expenditure and physical activity in preschoolers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Accurate, nonintrusive, and feasible methods are needed to predict energy expenditure (EE) and physical activity (PA) levels in preschoolers. Herein, we validated cross-sectional time series (CSTS) and multivariate adaptive regression splines (MARS) models based on accelerometry and heart rate (HR) ...

  11. Combined TIM-3 blockade and CD137 activation affords the long-term protection in a murine model of ovarian cancer

    PubMed Central

    2013-01-01

    Background T-cell immunoglobulin and mucin domain 3 (TIM-3) is known as a negative immune regulator and emerging data have implicated TIM-3 a pivotal role in suppressing antitumor immunity. The co-stimulatory receptor CD137 is transiently upregulated on T-cells following activation and increases their proliferation and survival when engaged. Although antagonistic anti-TIM-3 or agonistic anti-CD137 antibodies can promote the rejection of several murine tumors, some poorly immunogenic tumors were refractory to this treatment. In this study, we sought to evaluate whether combined TIM-3 blockade and CD137 activation would significantly improve the immunotherapy in the murine ID8 ovarian cancer model. Methods Mice with established ID8 tumor were intraperitoneally injected with single or combined anti-TIM-3/CD137 monoclonal antibody (mAb); mice survival was recorded, the composition and gene expression of tumor-infiltrating immune cells in these mice was analyzed by flow cytometry and quantitative RT-PCR respectively, and the function of CD8+ cells was evaluated by ELISA and cytotoxicity assay. Results Either anti-TIM-3 or CD137 mAb alone, although effective in 3 days established tumor, was unable to prevent tumor progression in mice bearing 10 days established tumor, however, combined anti-TIM-3/CD137 mAb significantly inhibited the growth of these tumors with 60% of mice tumor free 90 days after tumor inoculation. Therapeutic efficacy was associated with a systemic immune response with memory and antigen specificity, required CD4+ cells and CD8+ cells. The 2 mAb combination increased CD4+ and CD8+ cells and decreased immunosuppressive CD4+FoxP3+ regulatory T (Treg) cells and CD11b+Gr-1+ myeloid suppressor cells (MDSC) at tumor sites, giving rise to significantly elevated ratios of CD4+ and CD8+ cells to Treg and MDSC; This is consistent with biasing local immune response towards an immunostimulatory Th1 type and is further supported by quantitative RT-PCR data

  12. Ovarian actions of resveratrol.

    PubMed

    Ortega, Israel; Duleba, Antoni J

    2015-08-01

    Resveratrol, a natural polyphenol found in grapes, berries, and medicinal plants, exhibits antioxidant and anti-inflammatory activities and has been proposed to be a longevity-prolonging agent. There is also growing evidence that resveratrol has cardioprotective properties and beneficial effects on both glucose and lipid metabolism. Recently, several studies have examined the use of resveratrol as a therapeutic agent to treat numerous pathological and metabolic disorders. Herein, we present insights into the mechanisms of action, biological effects, and current evidence of actions of resveratrol on the ovary. In vitro, resveratrol inhibits proliferation and androgen production by theca-interstitial cells. Resveratrol also exerts a cytostatic, but not cytotoxic, effect on granulosa cells, while decreasing aromatization and vascular endothelial growth factor expression. In vivo, resveratrol treatment reduced the size of adipocytes and improved estrus cyclicity in the previously acyclic rat model of polycystic ovary syndrome (PCOS). In addition, resveratrol increased the ovarian follicular reserve and prolonged the ovarian life span in rats. Taken together, resveratrol emerges as a potential therapeutic agent to treat conditions associated with androgen excess, such as PCOS. The efficacy of resveratrol in the treatment of gynecological conditions requires further investigation. PMID:26315293

  13. Resveratrol, Acetyl-Resveratrol, and Polydatin Exhibit Antigrowth Activity against 3D Cell Aggregates of the SKOV-3 and OVCAR-8 Ovarian Cancer Cell Lines

    PubMed Central

    Hogg, Simon J.; Chitcholtan, Kenny; Hassan, Wafaa; Sykes, Peter H.; Garrill, Ashley

    2015-01-01

    Resveratrol has aroused significant scientific interest as it has been claimed that it exhibits a spectrum of health benefits. These include effects as an anti-inflammatory and an antitumour compound. The purpose of this study was to investigate and compare any potential antigrowth effects of resveratrol and two of its derivatives, acetyl-resveratrol and polydatin, on 3D cell aggregates of the EGFR/Her-2 positive and negative ovarian cancer cell lines SKOV-3 and OVCAR-8, respectively. Results showed that resveratrol and acetyl-resveratrol reduced cell growth in the SKOV-3 and OVCAR-8 in a dose-dependant manner. The growth reduction was mediated by the induction of apoptosis via the cleavage of poly(ADP-ribose) polymerase (PARP-1). At lower concentrations, 5 and 10 µM, resveratrol, acetyl-resveratrol, and polydatin were less effective than higher concentrations, 50 and 100 µM. In SKOV-3 line, at higher concentrations, resveratrol and polydatin significantly reduced the phosphorylation of Her-2 and EGFR and the expression of Erk. Acetyl-resveratrol, on the other hand, did not change the activation of Her-2 and EGFR. Resveratrol, acetyl-resveratrol, and polydatin suppressed the secretion of VEGF in a dose-dependant fashion. In the OVCAR-8 cell line, resveratrol and acetyl-resveratrol at 5 and 10 µM increased the activation of Erk. Above these concentrations they decreased activation. Polydatin did not produce this effect. This study demonstrates that resveratrol and its derivatives may inhibit growth of 3D cell aggregates of ovarian cancer cell lines via different signalling molecules. Resveratrol and its derivatives, therefore, warrant further in vivo evaluation to assess their potential clinical utility. PMID:26617640

  14. Prediction of adolescents doing physical activity after completing secondary education.

    PubMed

    Moreno-Murcia, Juan Antonio; Huéscar, Elisa; Cervelló, Eduardo

    2012-03-01

    The purpose of this study, based on the self-determination theory (Ryan & Deci, 2000) was to test the prediction power of student's responsibility, psychological mediators, intrinsic motivation and the importance attached to physical education in the intention to continue to practice some form of physical activity and/or sport, and the possible relationships that exist between these variables. We used a sample of 482 adolescent students in physical education classes, with a mean age of 14.3 years, which were measured for responsibility, psychological mediators, sports motivation, the importance of physical education and intention to be physically active. We completed an analysis of structural equations modelling. The results showed that the responsibility positively predicted psychological mediators, and this predicted intrinsic motivation, which positively predicted the importance students attach to physical education, and this, finally, positively predicted the intention of the student to continue doing sport. Results are discussed in relation to the promotion of student's responsibility towards a greater commitment to the practice of physical exercise. PMID:22379700

  15. Activated T-cell Therapy, Low-Dose Aldesleukin, and Sargramostim in Treating Patients With Ovarian, Fallopian Tube, or Primary Peritoneal Cancer That is Stage III-IV, Refractory, or Recurrent

    ClinicalTrials.gov

    2016-02-15

    Malignant Ovarian Clear Cell Tumor; Malignant Ovarian Serous Tumor; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Stage IIIA Fallopian Tube Cancer; Stage IIIA Ovarian Cancer; Stage IIIA Primary Peritoneal Cancer; Stage IIIB Fallopian Tube Cancer; Stage IIIB Ovarian Cancer; Stage IIIB Primary Peritoneal Cancer; Stage IIIC Fallopian Tube Cancer; Stage IIIC Ovarian Cancer; Stage IIIC Primary Peritoneal Cancer; Stage IV Fallopian Tube Cancer; Stage IV Ovarian Cancer; Stage IV Primary Peritoneal Cancer

  16. Predicting Active Users' Personality Based on Micro-Blogging Behaviors

    PubMed Central

    Hao, Bibo; Guan, Zengda; Zhu, Tingshao

    2014-01-01

    Because of its richness and availability, micro-blogging has become an ideal platform for conducting psychological research. In this paper, we proposed to predict active users' personality traits through micro-blogging behaviors. 547 Chinese active users of micro-blogging participated in this study. Their personality traits were measured by the Big Five Inventory, and digital records of micro-blogging behaviors were collected via web crawlers. After extracting 845 micro-blogging behavioral features, we first trained classification models utilizing Support Vector Machine (SVM), differentiating participants with high and low scores on each dimension of the Big Five Inventory. The classification accuracy ranged from 84% to 92%. We also built regression models utilizing PaceRegression methods, predicting participants' scores on each dimension of the Big Five Inventory. The Pearson correlation coefficients between predicted scores and actual scores ranged from 0.48 to 0.54. Results indicated that active users' personality traits could be predicted by micro-blogging behaviors. PMID:24465462

  17. Predicting active users' personality based on micro-blogging behaviors.

    PubMed

    Li, Lin; Li, Ang; Hao, Bibo; Guan, Zengda; Zhu, Tingshao

    2014-01-01

    Because of its richness and availability, micro-blogging has become an ideal platform for conducting psychological research. In this paper, we proposed to predict active users' personality traits through micro-blogging behaviors. 547 Chinese active users of micro-blogging participated in this study. Their personality traits were measured by the Big Five Inventory, and digital records of micro-blogging behaviors were collected via web crawlers. After extracting 839 micro-blogging behavioral features, we first trained classification models utilizing Support Vector Machine (SVM), differentiating participants with high and low scores on each dimension of the Big Five Inventory [corrected]. The classification accuracy ranged from 84% to 92%. We also built regression models utilizing PaceRegression methods, predicting participants' scores on each dimension of the Big Five Inventory. The Pearson correlation coefficients between predicted scores and actual scores ranged from 0.48 to 0.54. Results indicated that active users' personality traits could be predicted by micro-blogging behaviors. PMID:24465462

  18. Ovarian cycle activity varies with respect to age and social status in free-ranging elephants in Addo Elephant National Park, South Africa

    PubMed Central

    Freeman, Elizabeth W.; Meyer, Jordana M.; Putman, Sarah B.; Schulte, Bruce A.; Brown, Janine L.

    2013-01-01

    Free-ranging African elephants live in a fission–fusion society, at the centre of which is the matriarch. Matriarchs are generally older females that guide their families to resources and co-ordinate group defense. While much is known about elephant society, knowledge is generally lacking about how age affects the physiology of wild elephants. Investigation of the ovarian activity of free-ranging elephants could provide insight into the reproductive ageing process, with implications for population management. Faecal samples were collected from 46 individuals ranging in age from 14 to 60 years for a 2-year period, and progestagen metabolite analyses were used to examine relationships between social status, age, season, and ovarian activity in female elephants in Addo Elephant National Park, South Africa. Social status was the strongest predictor of faecal progestagen metabolite concentrations in non-pregnant elephants, with grand matriarchs (n = 6) having the lowest values compared with matriarchs (n = 21) and non-matriarch females (n = 19). Likewise, social status and age were the strongest predictors of faecal progestagen metabolite concentrations in pregnant elephants (n = 27). The number of years since a non-pregnant female gave birth to her last calf (post-partum duration) was longer for older females with a higher social status, as well as during the dry season. Our results indicate that social standing and age of elephants are related to reproductive function, and that older females exhibit reductions in ovarian capacity. These results expand our understanding of reproduction and fertility throughout an elephant's lifespan, and the factors that impact gonadal function in free-ranging females. Given that possible over-abundance of elephants in areas such as Addo Elephant National Park is fuelling the debate over how best to manage these populations, knowledge about the reproductive potential of high-ranking females can provide managers with

  19. Combination Chemotherapy and Peripheral Stem Cell Transplantation in Treating Patients With Stage III Ovarian Cancer

    ClinicalTrials.gov

    2016-03-17

    Malignant Ovarian Mixed Epithelial Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  20. Australian Tropical Cyclone Activity: Interannual Prediction and Climate Change

    NASA Astrophysics Data System (ADS)

    Nicholls, N.

    2014-12-01

    It is 35 years since it was first demonstrated that interannual variations in seasonal Australian region tropical cyclone (TC) activity could be predicted using simple indices of the El Niño - Southern Oscillation (ENSO). That demonstration (Nicholls, 1979), which was surprising and unexpected at the time, relied on only 25 years of data (1950-1975), but its later confirmation eventually led to the introduction of operational seasonal tropical cyclone activity. It is worth examining how well the ENSO-TC relationship has performed, over the period since 1975. Changes in observational technology, and even how a tropical cyclone is defined, have affected the empirical relationships between ENSO and seasonal activity, and ways to overcome this in forecasting seasonal activity will be discussed. Such changes also complicate the investigation of long-term trends in cyclone activity. The early work linked cyclone activity to local sea surface temperature thereby leading to the expectation that global warming would result in an increase in cyclone activity. But studies in the 1990s (eg., Nicholls et al., 1998) suggested that such an increase in activity was not occurring, neither in the Australian region nor elsewhere. Trends in Australian tropical cyclone activity will be discussed, and the confounding influence of factors such as changes in observational technologies will be examined. Nicholls, N. 1979. A possible method for predicting seasonal tropical cyclone activity in the Australian region. Mon. Weath. Rev., 107, 1221-1224 Nicholls, N., Landsea, C., and Gill, J., 1998. Recent trends in Australian region tropical cyclone activity. Meteorology and Atmospheric Physics, 65, 197-205.

  1. Homologous recombination deficiency and ovarian cancer.

    PubMed

    Ledermann, Jonathan A; Drew, Yvette; Kristeleit, Rebecca S

    2016-06-01

    The discovery that PARP inhibitors block an essential pathway of DNA repair in cells harbouring a BRCA mutation has opened up a new therapeutic avenue for high-grade ovarian cancers. BRCA1 and BRCA2 proteins are essential for high-fidelity repair of double-strand breaks of DNA through the homologous recombination repair (HRR) pathway. Deficiency in HRR (HRD) is a target for PARP inhibitors. The first PARP inhibitor, olaparib, has now been licensed for BRCA-mutated ovarian cancers. While mutated BRCA genes are individually most commonly associated with HRD other essential HRR proteins may be mutated or functionally deficient potentially widening the therapeutic opportunities for PARP inhibitors. HRD is the first phenotypically defined predictive marker for therapy with PARP inhibitors in ovarian cancer. Several different PARP inhibitors are being trialled in ovarian cancer and this class of drugs has been shown to be a new selective therapy for high-grade ovarian cancer. Around 20% of high-grade serous ovarian cancers harbour germline or somatic BRCA mutations and testing for BRCA mutations should be incorporated into routine clinical practice. The expanded use of PARP inhibitors in HRD deficient (non-BRCA mutant) tumours using a signature of HRD in clinical practice requires validation. PMID:27065456

  2. Platelet Serotonin Transporter Function Predicts Default-Mode Network Activity

    PubMed Central

    Kasess, Christian H.; Meyer, Bernhard M.; Hofmaier, Tina; Diers, Kersten; Bartova, Lucie; Pail, Gerald; Huf, Wolfgang; Uzelac, Zeljko; Hartinger, Beate; Kalcher, Klaudius; Perkmann, Thomas; Haslacher, Helmuth; Meyer-Lindenberg, Andreas; Kasper, Siegfried; Freissmuth, Michael; Windischberger, Christian; Willeit, Matthäus; Lanzenberger, Rupert; Esterbauer, Harald; Brocke, Burkhard; Moser, Ewald; Sitte, Harald H.; Pezawas, Lukas

    2014-01-01

    Background The serotonin transporter (5-HTT) is abundantly expressed in humans by the serotonin transporter gene SLC6A4 and removes serotonin (5-HT) from extracellular space. A blood-brain relationship between platelet and synaptosomal 5-HT reuptake has been suggested, but it is unknown today, if platelet 5-HT uptake can predict neural activation of human brain networks that are known to be under serotonergic influence. Methods A functional magnetic resonance study was performed in 48 healthy subjects and maximal 5-HT uptake velocity (Vmax) was assessed in blood platelets. We used a mixed-effects multilevel analysis technique (MEMA) to test for linear relationships between whole-brain, blood-oxygen-level dependent (BOLD) activity and platelet Vmax. Results The present study demonstrates that increases in platelet Vmax significantly predict default-mode network (DMN) suppression in healthy subjects independent of genetic variation within SLC6A4. Furthermore, functional connectivity analyses indicate that platelet Vmax is related to global DMN activation and not intrinsic DMN connectivity. Conclusion This study provides evidence that platelet Vmax predicts global DMN activation changes in healthy subjects. Given previous reports on platelet-synaptosomal Vmax coupling, results further suggest an important role of neuronal 5-HT reuptake in DMN regulation. PMID:24667541

  3. Predicting activity approach based on new atoms similarity kernel function.

    PubMed

    Abu El-Atta, Ahmed H; Moussa, M I; Hassanien, Aboul Ella

    2015-07-01

    Drug design is a high cost and long term process. To reduce time and costs for drugs discoveries, new techniques are needed. Chemoinformatics field implements the informational techniques and computer science like machine learning and graph theory to discover the chemical compounds properties, such as toxicity or biological activity. This is done through analyzing their molecular structure (molecular graph). To overcome this problem there is an increasing need for algorithms to analyze and classify graph data to predict the activity of molecules. Kernels methods provide a powerful framework which combines machine learning with graph theory techniques. These kernels methods have led to impressive performance results in many several chemoinformatics problems like biological activity prediction. This paper presents a new approach based on kernel functions to solve activity prediction problem for chemical compounds. First we encode all atoms depending on their neighbors then we use these codes to find a relationship between those atoms each other. Then we use relation between different atoms to find similarity between chemical compounds. The proposed approach was compared with many other classification methods and the results show competitive accuracy with these methods. PMID:26117822

  4. Diagnostic Efficacy of Sonography for Diagnosis of Ovarian Torsion

    PubMed Central

    Rostamzadeh, Ayoob; Mirfendereski, Sam; Rezaie, Mohammad Jafar; Rezaei, Shohreh

    2014-01-01

    Objectives: Misdiagnosing ovarian torsion is now suggested as an important issue in clinical setting. The aim of this study was to determine the diagnostic accuracy of sonography for ovarian torsion. Methods : In this study 323 women with acute pelvic pain with highly suspected ovarian torsion signs and symptoms attending Imam Reza Medical Center in Kermanshah between 2011 through 2012 were included and underwent a transabdominal sonography (2-5 MHz probes). Then findings of sonography were compared with laparatomy. Results : The ultrasound correctly diagnosed 72.1% of ovarian torsion and missed 27.9% of them (false negatives). However, one free subject (0.4%) was misclassified as ovarian torsion (false positive). There was a strong correlation between sonography and laparatomy with a kappa value of 84.0%. The sensitivity and specificity of sonography were 72.1% and 99.6%, respectively. Sonography had a positive predictive value of 96.9%, a negative predictive value of 95.9%, and a total accuracy of 96.0% for detection of ovarian torsion. Conclusion: Sonography appears to be an excellent method to evaluate patients with suspected ovarian torsion. Abnormal blood flow detected by sonography is highly predictive of ovarian torsion and is therefore useful in the diagnosis of this phenomenon. PMID:24772154

  5. Prediction of Spatiotemporal Patterns of Neural Activity from Pairwise Correlations

    NASA Astrophysics Data System (ADS)

    Marre, O.; El Boustani, S.; Frégnac, Y.; Destexhe, A.

    2009-04-01

    We designed a model-based analysis to predict the occurrence of population patterns in distributed spiking activity. Using a maximum entropy principle with a Markovian assumption, we obtain a model that accounts for both spatial and temporal pairwise correlations among neurons. This model is tested on data generated with a Glauber spin-glass system and is shown to correctly predict the occurrence probabilities of spatiotemporal patterns significantly better than Ising models only based on spatial correlations. This increase of predictability was also observed on experimental data recorded in parietal cortex during slow-wave sleep. This approach can also be used to generate surrogates that reproduce the spatial and temporal correlations of a given data set.

  6. Prediction of Spatiotemporal Patterns of Neural Activity from Pairwise Correlations

    SciTech Connect

    Marre, O.; El Boustani, S.; Fregnac, Y.; Destexhe, A.

    2009-04-03

    We designed a model-based analysis to predict the occurrence of population patterns in distributed spiking activity. Using a maximum entropy principle with a Markovian assumption, we obtain a model that accounts for both spatial and temporal pairwise correlations among neurons. This model is tested on data generated with a Glauber spin-glass system and is shown to correctly predict the occurrence probabilities of spatiotemporal patterns significantly better than Ising models only based on spatial correlations. This increase of predictability was also observed on experimental data recorded in parietal cortex during slow-wave sleep. This approach can also be used to generate surrogates that reproduce the spatial and temporal correlations of a given data set.

  7. Ovarian tumors secreting insulin.

    PubMed

    Battocchio, Marialberta; Zatelli, Maria Chiara; Chiarelli, Silvia; Trento, Mariangela; Ambrosio, Maria Rosaria; Pasquali, Claudio; De Carlo, Eugenio; Dassie, Francesca; Mioni, Roberto; Rebellato, Andrea; Fallo, Francesco; Degli Uberti, Ettore; Martini, Chiara; Vettor, Roberto; Maffei, Pietro

    2015-08-01

    Combined ovarian germ cell and neuroendocrine tumors are rare. Only few cases of hyperinsulinism due to ovarian ectopic secretion have been hypothesized in the literature. An ovarian tumor was diagnosed in a 76-year-old woman, referred to our department for recurrent hypoglycemia with hyperinsulinism. In vivo tests, in particular fasting test, rapid calcium infusion test, and Octreotide test were performed. Ectopic hyperinsulinemic hypoglycemia was demonstrated in vivo and hypoglycemia disappeared after hysteroadnexectomy. Histological exam revealed an ovarian germ cell tumor with neuroendocrine and Yolk sac differentiation, while immunostaining showed insulin positivity in neuroendocrine cells. A cell culture was obtained by tumoral cells, testing Everolimus, and Pasireotide. Insulin was detected in cell culture medium and Everolimus and Pasireotide demonstrated their potentiality in reducing insulin secretion, more than controlling cell viability. Nine cases of hyperinsulinism due to ovarian ectopic secretion reported in literature have been reviewed. These data confirm the ovarian tissue potentiality to induce hyperinsulinemic hypoglycemic syndrome after neoplastic transformation. PMID:25896552

  8. [The molecular biology of epithelial ovarian cancer].

    PubMed

    Leary, Alexandra; Pautier, Patricia; Tazi, Youssef; Morice, Philippe; Duvillard, Pierre; Gouy, Sébastien; Uzan, Catherine; Gauthier, Hélène; Balleyguier, Corinne; Lhommé, Catherine

    2012-12-01

    Epithelial ovarian cancer frequently presents at an advanced stage where the cornerstone of management remains surgery and platinum-based chemotherapy. Unfortunately, despite sometimes dramatic initial responses, advanced ovarian cancer almost invariably relapses. Little progress has been made in the identification of effective targeted-therapies for ovarian cancer. The majority of clinical trials investigating novel agents have been negative and the only approved targeted-therapy is bevacizumab, for which reliable predictive biomarkers still elude us. Ovarian cancer is treated as a uniform disease. Yet, biological studies have highlighted the heterogeneity of this malignancy with marked differences in histology, oncogenesis, prognosis, chemo-responsiveness, and molecular profile. Recent high throughput molecular analyses have identified a huge number of genomic/phenotypic alterations. Broadly speaking, high grade serous carcinomas (type II) display significant genomic instability and numerous amplifications and losses; low grade (type I) tumors are genomically stable but display frequent mutations. Importantly, many of these genomic alterations relate to known oncogenes for which targeted-therapies are available or in development. There is today a real potential for personalized medicine in ovarian cancer. We will review the current literature regarding the molecular characterization of epithelial ovarian cancer and discuss the biological rationale for a number of targeted strategies. In order to translate these biological advances into meaningful clinical improvements for our patients, it is imperative to incorporate translational research in ovarian cancer trials, a number of strategies will be proposed such as the acquisition of quality tumor samples, including sequential pre- and post-treatment biopsies, the potential of liquid biopsies, and novel trial designs more adapted to the molecular era of ovarian cancer research. PMID:23238064

  9. Compulsivity predicts fronto striatal activation in severely anorectic individuals.

    PubMed

    Rothemund, Y; Buchwald, C; Georgiewa, P; Bohner, G; Bauknecht, H-C; Ballmaier, M; Klapp, B F; Klingebiel, R

    2011-12-01

    Anorexia nervosa is a severe illness and shows one of the highest death rates among psychiatric or psychosomatic diseases. However, despite several lines of research, the etiology of this disease is still unknown. One of those features is the rigidity of behaviors, for example, controlling of weight and pursuing of thinness, that often meets the criteria for obsessive-compulsive behavior. In this study, it was investigated whether the clinical feature of compulsivity in anorexia nervosa patients relates to regional brain activation. Using functional magnetic resonance imaging, 12 severely anorectic women were compared to 12 normal-weight female individuals following a cue-reactivity paradigm. Cues comprised food cues of high and low calorie content as well as eating-related utensils. Voxel-based morphometric analysis indicated significantly overall reduced gray matter volume and significantly increased cerebrospinal fluids in anorexia nervosa (AN) patients, which was controlled for in subsequent analyses. Following the high-calorie stimulation, AN patients activated the right caudate body and right precuneus, whereas control subjects did not show significant regional activations. In both other conditions, low-calorie foods and eating utensils, regional brain activations did not survive FDR thresholds. During the high-calorie condition, compulsivity, that is, the subscore "obsessive thoughts," predicted activation of the superior frontal gyrus [Brodmann areas (BA) 10], inferior frontal gyrus, anterior cingulate cortex (BA 32), cingulate gyrus (BA 24), caudate body, cuneus, pre- and postcentral gyrus. The subscore "compulsive acts" correlated with activation of the claustrum during the high-calorie condition and predicted a number of deactivations of frontal and temporal regions. We conclude that in severely anorectic individuals, the degree of compulsivity predicts activation and deactivation of the fronto-striatal pathway. PMID:21952129

  10. Anti-angiogenic agents in ovarian cancer: past, present, and future.

    PubMed

    Monk, B J; Minion, L E; Coleman, R L

    2016-04-01

    Angiogenesis plays a pivotal role in normal ovarian physiology as well as in the progression of ovarian cancer through ascites formation and metastatic spread. Bevacizumab (Avastin(®), Genentech; South San Francisco, CA, USA), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, is the most widely studied anti-angiogenesis agent both across tumor types and specifically in epithelial ovarian cancer. In 2005, single-agent bevacizumab at 15 mg/kg (IV) every 3 weeks was first reported to be active in a case of recurrent high-grade serous ovarian cancer after failing 11th line cytotoxic treatment. Since then, many case series, phase II and phase III trials have confirmed these results leading to regulatory approval in most countries including the US Food and Drug Administration in 2014. Guidelines now give clear recommendations as to when and how bevacizumab should be integrated into the ovarian cancer treatment paradigm. Other anti-VEGF agents such as the VEGF receptor (VEGFR) tyrosine kinase inhibitors have not shown increased activity or reduced toxicity relative to bevacizumab. However, anti-angiogenics other than anti-VEGF/VEGFR agents such as those targeting Angiopoietin-1 and -2 are in development as well as novel combinations with vascular disrupting agents (VDAs), PARP inhibitors and immune checkpoint inhibitors. Clearly, the benefits of anti-angiogenic agents such as bevacizumab must be carefully weighed against the cost and associated toxicities. Although almost all patients with ovarian cancer will receive an anti-angiogenic compound, cures are not increased. Predictive biomarkers are an urgent unmet need. PMID:27141068

  11. Toward the Prediction of FBPase Inhibitory Activity Using Chemoinformatic Methods

    PubMed Central

    Hao, Ming; Zhang, Shuwei; Qiu, Jieshan

    2012-01-01

    Currently, Chemoinformatic methods are used to perform the prediction for FBPase inhibitory activity. A genetic algorithm-random forest coupled method (GA-RF) was proposed to predict fructose 1,6-bisphosphatase (FBPase) inhibitors to treat type 2 diabetes mellitus using the Mold2 molecular descriptors. A data set of 126 oxazole and thiazole analogs was used to derive the GA-RF model, yielding the significant non-cross-validated correlation coefficient r2ncv and cross-validated r2cv values of 0.96 and 0.67 for the training set, respectively. The statistically significant model was validated by a test set of 64 compounds, producing the prediction correlation coefficient r2pred of 0.90. More importantly, the building GA-RF model also passed through various criteria suggested by Tropsha and Roy with r2o and r2m values of 0.90 and 0.83, respectively. In order to compare with the GA-RF model, a pure RF model developed based on the full descriptors was performed as well for the same data set. The resulting GA-RF model with significantly internal and external prediction capacities is beneficial to the prediction of potential oxazole and thiazole series of FBPase inhibitors prior to chemical synthesis in drug discovery programs. PMID:22837677

  12. Claudin and ovarian cancer

    PubMed Central

    Bose, Chinmoy K.; Mukhopadhyay, Ashis

    2010-01-01

    Claudins are a family of proteins and the most important component of the tight junction. They constitute a paracellular barrier that controls the flow of molecules in the intercellular space of an epithelium. Although it seems that claudin should be down regulated in cancer cell, some claudins are, in fact highly elevated in various human cancers, including ovarian cancer. Whereas the functional significance of claudin overexpression in ovarian carcinoma is unclear, these proteins are important for migration, invasion, and survival of ovarian cancer cells. They clearly represent a general pathway in tumorigenesis, are a novel marker for ovarian cancer and may become a target for therapy or diagnosis of this disease. PMID:24591894

  13. Claudin and ovarian cancer.

    PubMed

    Bose, Chinmoy K; Mukhopadhyay, Ashis

    2010-01-01

    Claudins are a family of proteins and the most important component of the tight junction. They constitute a paracellular barrier that controls the flow of molecules in the intercellular space of an epithelium. Although it seems that claudin should be down regulated in cancer cell, some claudins are, in fact highly elevated in various human cancers, including ovarian cancer. Whereas the functional significance of claudin overexpression in ovarian carcinoma is unclear, these proteins are important for migration, invasion, and survival of ovarian cancer cells. They clearly represent a general pathway in tumorigenesis, are a novel marker for ovarian cancer and may become a target for therapy or diagnosis of this disease. PMID:24591894

  14. Unbalanced estrogen metabolism in ovarian cancer.

    PubMed

    Zahid, Muhammad; Beseler, Cheryl L; Hall, James B; LeVan, Tricia; Cavalieri, Ercole L; Rogan, Eleanor G

    2014-05-15

    Greater exposure to estrogens is a risk factor for ovarian cancer. To investigate the role of estrogens in ovarian cancer, a spot urine sample and a saliva sample were obtained from 33 women with ovarian cancer and 34 age-matched controls. Thirty-eight estrogen metabolites, conjugates and DNA adducts were analyzed in the urine samples using ultraperformance liquid chromatography/tandem mass spectrometry, and the ratio of adducts to metabolites and conjugates was calculated for each sample. The ratio of depurinating estrogen-DNA adducts to estrogen metabolites and conjugates was significantly higher in cases compared to controls (p < 0.0001), demonstrating high specificity and sensitivity. DNA was purified from the saliva samples and analyzed for genetic polymorphisms in the genes for two estrogen-metabolizing enzymes. Women with two low-activity alleles of catechol-O-methyltransferase plus one or two high-activity alleles of cytochrome P450 1B1 had higher levels of estrogen-DNA adducts and were more likely to have ovarian cancer. These findings indicate that estrogen metabolism is unbalanced in ovarian cancer and suggest that formation of estrogen-DNA adducts plays a critical role in the initiation of ovarian cancer. PMID:24170413

  15. Erlotinib Plus Carboplatin and Paclitaxel in Ovarian Carcinoma

    ClinicalTrials.gov

    2015-10-29

    Brenner Tumor; Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  16. Predicting Activity Energy Expenditure Using the Actical[R] Activity Monitor

    ERIC Educational Resources Information Center

    Heil, Daniel P.

    2006-01-01

    This study developed algorithms for predicting activity energy expenditure (AEE) in children (n = 24) and adults (n = 24) from the Actical[R] activity monitor. Each participant performed 10 activities (supine resting, three sitting, three house cleaning, and three locomotion) while wearing monitors on the ankle, hip, and wrist; AEE was computed…

  17. Granulocyte colony-stimulating factor receptor signalling via Janus kinase 2/signal transducer and activator of transcription 3 in ovarian cancer

    PubMed Central

    Kumar, J; Fraser, F W; Riley, C; Ahmed, N; McCulloch, D R; Ward, A C

    2014-01-01

    Background: Ovarian cancer remains a major cause of cancer mortality in women, with only limited understanding of disease aetiology at the molecular level. Granulocyte colony-stimulating factor (G-CSF) is a key regulator of both normal and emergency haematopoiesis, and is used clinically to aid haematopoietic recovery following ablative therapies for a variety of solid tumours including ovarian cancer. Methods: The expression of G-CSF and its receptor, G-CSFR, was examined in primary ovarian cancer samples and a panel of ovarian cancer cell lines, and the effects of G-CSF treatment on proliferation, migration and survival were determined. Results: G-CSFR was predominantly expressed in high-grade serous ovarian epithelial tumour samples and a subset of ovarian cancer cell lines. Stimulation of G-CSFR-expressing ovarian epithelial cancer cells with G-CSF led to increased migration and survival, including against chemotherapy-induced apoptosis. The effects of G-CSF were mediated by signalling via the downstream JAK2/STAT3 pathway. Conclusion: This study suggests that G-CSF has the potential to impact on ovarian cancer pathogenesis, and that G-CSFR expression status should be considered in determining appropriate therapy. PMID:24220695

  18. Gonadotropin-dependent oocyte maturational competence requires activation of the protein kinase A pathway and synthesis of RNA and protein in ovarian follicles of Nibe, Nibea mitsukurii (Teleostei, Sciaenidae)

    USGS Publications Warehouse

    Yoshizaki, G.; Shusa, M.; Takeuchi, T.; Patino, R.

    2002-01-01

    Luteinizing hormone- (LH)-dependent ovarian follicle maturation has been recently described in two stages for teleost fishes. The oocyte's ability to respond to the steroidal maturation-inducing hormone (MIH), also known as oocyte maturational competence (OMC), is acquired during the first stage; whereas the MIH-dependent resumption of meiosis occurs during the second stage. However, studies directly addressing OMC have been performed with a limited number of species and therefore the general relevance of the two-stage model and its mechanisms remain uncertain. In this study, we examined the hormonal regulation of OMC and its basic transduction mechanisms in ovarian follicles of the sciaenid teleost, Nibe (Nibea mitsukurii). Exposure to MIH [17,20??-dihydroxy-4-pregnen-3-one or 17,20??,21-trihydroxy-4-pregnen-3-one] stimulated germinal vesicle breakdown (index of meiotic resumption) in full-grown follicles primed with human chorionic gonadotropin (HCG, an LH-like gonadotropin) but not in those pre-cultured in plain incubation medium. The induction of OMC by HCG was mimicked by protein kinase A (PKA) activators (forskolin and dibutyryl cyclic AMP), and blocked by specific inhibitors of PKA (H89 and H8) as well as inhibitors of RNA (actinomycin D) and protein (cycloheximide) synthesis. Forskolin-induced OMC was also inhibited by actinomycin D and cycloheximide. A strong activator of protein kinase C, PMA, inhibited HCG-dependent OMC. In conclusion, OMC in Nibe ovarian follicles is gonadotropin-dependent and requires activation of the PKA pathway followed by gene transcription and translation events. These observations are consistent with the two-stage model of ovarian follicle maturation proposed for other teleosts, and suggest that Nibe can be used as new model species for mechanistic studies of ovarian follicle differentiation and maturation in fishes.

  19. Prefrontal Activity Predicts Monkeys' Decisions During an Auditory Category Task

    PubMed Central

    Lee, Jung H.; Russ, Brian E.; Orr, Lauren E.; Cohen, Yale E.

    2009-01-01

    The neural correlates that relate auditory categorization to aspects of goal-directed behavior, such as decision-making, are not well understood. Since the prefrontal cortex (PFC) plays an important role in executive function and the categorization of auditory objects, we hypothesized that neural activity in the PFC should predict an animal's behavioral reports (decisions) during a category task. To test this hypothesis, we tested PFC activity that was recorded while monkeys categorized human spoken words (Russ et al., 2008b). We found that activity in the ventrolateral PFC, on average, correlated best with the monkeys' choices than with the auditory stimuli. This finding demonstrates a direct link between PFC activity and behavioral choices during a non-spatial auditory task. PMID:19587846

  20. New strategy to address DNA-methyl transferase activity in ovarian cancer cell cultures by monitoring the formation of 5-methylcytosine using HPLC-UV.

    PubMed

    Iglesias González, T; Blanco-González, E; Montes-Bayón, M

    2016-08-15

    Methylation of mammalian genomic DNA is catalyzed by DNA methyltransferases (DNMTs). Aberrant expression and activity of these enzymes has been reported to play an important role in the initiation and progression of tumors and its response to chemotherapy. Therefore, there is a great interest in developing strategies to detect human DNMTs activity. We propose a simple, antibody-free, label-free and non-radioactive analytical strategy in which methyltransferase activity is measured trough the determination of the 5-methylcytosine (5mC) content in DNA by a chromatographic method (HPLC-UV) previously developed. For this aim, a correlation between the enzyme activity and the concentration of 5mC obtained by HPLC-UV is previously obtained under optimized conditions using both, un-methylated and hemi-methylated DNA substrates and the prokaryotic methyltransferase M.SssI as model enzyme. The evaluation of the methylation yield in un-methylated known sequences (a 623bp PCR-amplicon) turned to be quantitative (110%) in experiments conducted in-vitro. Methylation of hemi-methylated and low-methylated sequences could be also detected with the proposed approach. The application of the methodology to the determination of the DNMTs activity in nuclear extracts from human ovarian cancer cells has revealed the presence of matrix effects (also confirmed by standard additions) that hampered quantitative enzyme recovery. The obtained results showed the high importance of adequate sample clean-up steps. PMID:27318640

  1. Gene bionetworks that regulate ovarian primordial follicle assembly

    PubMed Central

    2013-01-01

    Background Primordial follicle assembly is the process by which ovarian primordial follicles are formed. During follicle assembly oocyte nests break down and a layer of pre-granulosa cells surrounds individual oocytes to form primordial follicles. The pool of primordial follicles formed is the source of oocytes for ovulation during a female’s reproductive life. Results The current study utilized a systems approach to detect all genes that are differentially expressed in response to seven different growth factor and hormone treatments known to influence (increase or decrease) primordial follicle assembly in a neonatal rat ovary culture system. One novel factor, basic fibroblast growth factor (FGF2), was experimentally determined to inhibit follicle assembly. The different growth factor and hormone treatments were all found to affect similar physiological pathways, but each treatment affected a unique set of differentially expressed genes (signature gene set). A gene bionetwork analysis identified gene modules of coordinately expressed interconnected genes and it was found that different gene modules appear to accomplish distinct tasks during primordial follicle assembly. Predictions of physiological pathways important to follicle assembly were validated using ovary culture experiments in which ERK1/2 (MAPK1) activity was increased. Conclusions A number of the highly interconnected genes in these gene networks have previously been linked to primary ovarian insufficiency (POI) and polycystic ovarian disease syndrome (PCOS). Observations have identified novel factors and gene networks that regulate primordial follicle assembly. This systems biology approach has helped elucidate the molecular control of primordial follicle assembly and provided potential therapeutic targets for the treatment of ovarian disease. PMID:23875758

  2. Development of a Mouse Model of Menopausal Ovarian Cancer

    PubMed Central

    Smith, Elizabeth R.; Wang, Ying; Xu, Xiang-Xi

    2014-01-01

    Despite significant understanding of the genetic mutations involved in ovarian epithelial cancer and advances in genomic approaches for expression and mutation profiling of tumor tissues, several key questions in ovarian cancer biology remain enigmatic: the mechanism for the well-established impact of reproductive factors on ovarian cancer risk remains obscure; cell of origin of ovarian cancer continue to be debated; and the precursor lesion, sequence, or events in progression remain to be defined. Suitable mouse models should complement the analysis of human tumor tissues and may provide clues to these questions currently perplexing ovarian cancer biology. A potentially useful model is the germ cell-deficient Wv (white spotting variant) mutant mouse line, which may be used to study the impact of menopausal physiology on the increased risk of ovarian cancer. The Wv mice harbor a point mutation in c-Kit that reduces the receptor tyrosine kinase activity to about 1–5% (it is not a null mutation). Homozygous Wv mutant females have a reduced ovarian germ cell reservoir at birth and the follicles are rapidly depleted upon reaching reproductive maturity, but other biological phenotypes are minimal and the mice have a normal life span. The loss of ovarian function precipitates changes in hormonal and metabolic activity that model features of menopause in humans. As a consequence of follicle depletion, the Wv ovaries develop ovarian tubular adenomas, a benign epithelial tumor corresponding to surface epithelial invaginations and papillomatosis that mark human ovarian aging. Ongoing work will test the possibility of converting the benign epithelial tubular adenomas into neoplastic tumors by addition of an oncogenic mutation, such as of Tp53, to model the genotype and biology of serous ovarian cancer. Model based on the Wv mice may have the potential to gain biological and etiological insights into ovarian cancer development and prevention. PMID:24616881

  3. Resource assurance predicts specialist and generalist bee activity in drought

    PubMed Central

    Minckley, Robert L.; Roulston, T'ai H.; Williams, Neal M.

    2013-01-01

    Many short-lived desert organisms remain in diapause during drought. Theoretically, the cues desert species use to continue diapause through drought should differ depending on the availability of critical resources, but the unpredictability and infrequent occurrence of climate extremes and reduced insect activity during such events make empirical tests of this prediction difficult. An intensive study of a diverse bee–plant community through a drought event found that bee specialists of a drought-sensitive host plant were absent in the drought year in contrast to generalist bees and to specialist bees of a drought-insensitive host plant. Different responses of bee species to drought indicate that the diapause cues used by bee species allow them to reliably predict host availability. Species composition of the bee community in drought shifted towards mostly generalist species. However, we predict that more frequent and extended drought, predicted by climate change models for southwest North America, will result in bee communities that are species-poor and dominated by specialist species, as found today in the most arid desert region of North America. PMID:23536593

  4. HOXB13 promotes ovarian cancer progression

    PubMed Central

    Miao, Jiangyong; Wang, Zuncai; Provencher, Heather; Muir, Beth; Dahiya, Sonika; Carney, Erin; Leong, Chee-Onn; Sgroi, Dennis C.; Orsulic, Sandra

    2007-01-01

    Deregulated expression of HOXB13 in a subset of estrogen receptor-positive breast cancer patients treated with tamoxifen monotherapy is associated with an aggressive clinical course and poor outcome. Because the ovary is another hormone-responsive organ, we investigated whether HOXB13 plays a role in ovarian cancer progression. We show that HOXB13 is expressed in multiple human ovarian cancer cell lines and tumors and that knockdown of endogenous HOXB13 by RNA interference in human ovarian cancer cell lines is associated with reduced cell proliferation. Ectopic expression of HOXB13 is capable of transforming p53−/− mouse embryonic fibroblasts and promotes cell proliferation and anchorage-independent growth in mouse ovarian cancer cell lines that contain genetic alterations in p53, myc, and ras. In this genetically defined cell line model of ovarian cancer, we demonstrate that HOXB13 collaborates with activated ras to markedly promote tumor growth in vivo and that HOXB13 confers resistance to tamoxifen-mediated apoptosis. Taken together, our results support a pro-proliferative and pro-survival role for HOXB13 in ovarian cancer. PMID:17942676

  5. Ovarian Cancer Stage IV

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IV Add to My Pictures View /Download : ... 1200x1335 View Download Large: 2400x2670 View Download Title: Ovarian Cancer Stage IV Description: Drawing of stage IV shows ...

  6. Ovarian Cancer Stage IIIC

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage IIIC Add to My Pictures View /Download : ... 1530x1350 View Download Large: 3060x2700 View Download Title: Ovarian Cancer Stage IIIC Description: Drawing of stage IIIC shows ...

  7. Ovarian Cancer Stage II

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage II Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage II Description: Three-panel drawing of stage ...

  8. Ovarian Cancer Stage I

    MedlinePlus

    ... hyphen, e.g. -historical Searches are case-insensitive Ovarian Cancer Stage I Add to My Pictures View /Download : ... 1650x675 View Download Large: 3300x1350 View Download Title: Ovarian Cancer Stage I Description: Three-panel drawing of stage ...

  9. Ovarian Cancer Fact Sheet

    MedlinePlus

    ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Around one in every 60 ... States, ovarian cancer is the eighth most common cancer and the fifth leading cause of cancer death. Are some women more at ...

  10. Conventional Chemotherapy and Oncogenic Pathway Targeting in Ovarian Carcinosarcoma Using a Patient-Derived Tumorgraft

    PubMed Central

    Becker, Marc A.; Hou, Xiaonan; Enderica-Gonzalez, Sergio; Harrington, Sean C.; Haluska, Paul

    2015-01-01

    Ovarian carcinosarcoma is a rare subtype of ovarian cancer with poor clinical outcomes. The low incidence of this disease makes accrual to large clinical trials challenging. However, studies have shown that treatment responses in patient-derived xenograft (PDX) models correlate with matched-patient responses in the clinic, supporting their use for preclinical testing of standard and novel therapies. An ovarian carcinosarcoma PDX is presented herein and showed resistance to carboplatin and paclitaxel (similar to the patient) but exhibited significant sensitivity to ifosfamide and paclitaxel. The PDX demonstrated overexpression of EGFR mRNA and gene amplification by array comparative genomic hybridization (log2 ratio 0.399). EGFR phosphorylation was also detected. Angiogensis and insulin-like growth factor pathways were also implicated by overexpression of VEGFC and IRS1. In order to improve response to chemotherapy, the PDX was treated with carboplatin/paclitaxel with or without a pan-HER and VEGF inhibitor (BMS-690514) but there was no tumor growth inhibition or improved animal survival, which may be explained by a KRAS mutation. Resistance was also observed when the IGF-1R inhibitor BMS-754807 was combined with carboplatin/paclitaxel. Because poly (ADP-ribose) polymerase inhibitors have activity in ovarian cancer patients, with and without BRCA mutations, ABT-888 was also tested but found to have no activity. Pathogenic mutations were also detected in TP53 and PIK3CA. In conclusion, ifosfamide/paclitaxel was superior to carboplatin/paclitaxel in this ovarian carcinosarcoma PDX and gene overexpression or amplification alone was not sufficient to predict response to targeted therapy. Better predictive markers of response are needed. PMID:25962155

  11. Prediction of antifungal activity of gemini imidazolium compounds.

    PubMed

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  12. Prediction of Antifungal Activity of Gemini Imidazolium Compounds

    PubMed Central

    Pałkowski, Łukasz; Błaszczyński, Jerzy; Skrzypczak, Andrzej; Błaszczak, Jan; Nowaczyk, Alicja; Wróblewska, Joanna; Kożuszko, Sylwia; Gospodarek, Eugenia; Słowiński, Roman; Krysiński, Jerzy

    2015-01-01

    The progress of antimicrobial therapy contributes to the development of strains of fungi resistant to antimicrobial drugs. Since cationic surfactants have been described as good antifungals, we present a SAR study of a novel homologous series of 140 bis-quaternary imidazolium chlorides and analyze them with respect to their biological activity against Candida albicans as one of the major opportunistic pathogens causing a wide spectrum of diseases in human beings. We characterize a set of features of these compounds, concerning their structure, molecular descriptors, and surface active properties. SAR study was conducted with the help of the Dominance-Based Rough Set Approach (DRSA), which involves identification of relevant features and relevant combinations of features being in strong relationship with a high antifungal activity of the compounds. The SAR study shows, moreover, that the antifungal activity is dependent on the type of substituents and their position at the chloride moiety, as well as on the surface active properties of the compounds. We also show that molecular descriptors MlogP, HOMO-LUMO gap, total structure connectivity index, and Wiener index may be useful in prediction of antifungal activity of new chemical compounds. PMID:25961015

  13. Anti-Proliferative and Apoptotic Activities of Müllerian Inhibiting Substance Combined with Calcitriol in Ovarian Cancer Cell Lines

    PubMed Central

    Jung, Yeon Soo; Kim, Hee Jung; Seo, Seok Kyo; Choi, Young Sik; Nam, Eun Ji; Kim, Sunghoon; Kim, Sang Wun; Han, Hyuck Dong; Kim, Jae Wook

    2016-01-01

    Purpose This study aimed to investigate whether Müllerian inhibiting substance (MIS) in combination with calcitriol modulates proliferation and apoptosis of human ovarian cancer (OCa) cell lines (SKOV3, OVCAR3, and OVCA433) and identify the signaling pathway by which MIS mediates apoptosis. Materials and Methods OCa cell lines were treated with MIS in the absence or presence of calcitriol. Cell viability and proliferation were evaluated using the Cell Counting Kit-8 assay and apoptosis was evaluated by DNA fragmentation assay. Western blot and enzyme-linked immunosorbent assay were used to determine the signaling pathway. Results The cells showed specific staining for the MIS type II receptor. Treatment of OCa cells with MIS and calcitriol led to dose- and time-dependent inhibition of cell growth and survival. The combination treatment significantly suppressed cell growth, down-regulated the expression of B-cell lymphoma 2 (Bcl-2), and up-regulated the expressions of Bcl-2 associated X protein, caspase-3, and caspase-9 through the extracellular signal-regulated kinase signaling pathway. Conclusion These results, coupled with a much-needed decrease in the toxic side effects of currently employed therapeutic agents, provide a strong rationale for testing the therapeutic potential of MIS, alone or in combination with calcitriol, in the treatment of OCa. PMID:26632380

  14. Baseline Brain Activity Predicts Response to Neuromodulatory Pain Treatment

    PubMed Central

    Jensen, Mark P.; Sherlin, Leslie H.; Fregni, Felipe; Gianas, Ann; Howe, Jon D.; Hakimian, Shahin

    2015-01-01

    Objectives The objective of this study was to examine the associations between baseline electroencephalogram (EEG)-assessed brain oscillations and subsequent response to four neuromodulatory treatments. Based on available research, we hypothesized that baseline theta oscillations would prospectively predict response to hypnotic analgesia. Analyses involving other oscillations and the other treatments (meditation, neurofeedback, and both active and sham transcranial direct current stimulation) were viewed as exploratory, given the lack of previous research examining brain oscillations as predictors of response to these other treatments. Design Randomized controlled study of single sessions of four neuromodulatory pain treatments and a control procedure. Methods Thirty individuals with spinal cord injury and chronic pain had their EEG recorded before each session of four active treatments (hypnosis, meditation, EEG biofeedback, transcranial direct current stimulation) and a control procedure (sham transcranial direct stimulation). Results As hypothesized, more presession theta power was associated with greater response to hypnotic analgesia. In exploratory analyses, we found that less baseline alpha power predicted pain reduction with meditation. Conclusions The findings support the idea that different patients respond to different pain treatments and that between-person treatment response differences are related to brain states as measured by EEG. The results have implications for the possibility of enhancing pain treatment response by either 1) better patient/treatment matching or 2) influencing brain activity before treatment is initiated in order to prepare patients to respond. Research is needed to replicate and confirm the findings in additional samples of individuals with chronic pain. PMID:25287554

  15. Epithelial ovarian cancer: An overview

    PubMed Central

    Desai, Arpita; Xu, Jingyao; Aysola, Kartik; Qin, Yunlong; Okoli, Chika; Hariprasad, Ravipati; Chinemerem, Ugorji; Gates, Candace; Reddy, Avinash; Danner, Omar; Franklin, Geary; Ngozi, Anachebe; Cantuaria, Guilherme; Singh, Karan; Grizzle, William; Landen, Charles; Partridge, Edward E; Rice, Valerie Montgomery; Reddy, E Shyam P; Rao, Veena N

    2014-01-01

    Ovarian cancer is the second most common gynecological cancer and the leading cause of death in the United States. In this article we review the diagnosis and current management of epithelial ovarian cancer which accounts for over 95 percent of the ovarian malignancies. We will present various theories about the potential origin of ovarian malignancies. We will discuss the genetic anomalies and syndromes that may cause ovarian cancers with emphasis on Breast cancer type 1/2 mutations. The pathology and pathogenesis of ovarian carcinoma will also be presented. Lastly, we provide a comprehensive overview of treatment strategies and staging of ovarian cancer, conclusions and future directions. PMID:25525571

  16. Prediction of Active-Region CME Productivity from Magnetograms

    NASA Technical Reports Server (NTRS)

    Falconer, D. A.; Moore, R. L.; Gary, G. A.

    2004-01-01

    We report results of an expanded evaluation of whole-active-region magnetic measures as predictors of active-region coronal mass ejection (CME) productivity. Previously, in a sample of 17 vector magnetograms of 12 bipolar active regions observed by the Marshall Space Flight Center (MSFC) vector magnetograph, from each magnetogram we extracted a measure of the size of the active region (the active region s total magnetic flux a) and four measures of the nonpotentiality of the active region: the strong-shear length L(sub SS), the strong-gradient length L(sub SG), the net vertical electric current I(sub N), and the net-current magnetic twist parameter alpha (sub IN). This sample size allowed us to show that each of the four nonpotentiality measures was statistically significantly correlated with active-region CME productivity in time windows of a few days centered on the day of the magnetogram. We have now added a fifth measure of active-region nonpotentiality (the best-constant-alpha magnetic twist parameter (alpha sub BC)), and have expanded the sample to 36 MSFC vector magnetograms of 31 bipolar active regions. This larger sample allows us to demonstrate statistically significant correlations of each of the five nonpotentiality measures with future CME productivity, in time windows of a few days starting from the day of the magnetogram. The two magnetic twist parameters (alpha (sub 1N) and alpha (sub BC)) are normalized measures of an active region s nonpotentially in that they do not depend directly on the size of the active region, while the other three nonpotentiality measures (L(sub SS), L(sub SG), and I(sub N)) are non-normalized measures in that they do depend directly on active-region size. We find (1) Each of the five nonpotentiality measures is statistically significantly correlated (correlation confidence level greater than 95%) with future CME productivity and has a CME prediction success rate of approximately 80%. (2) None of the nonpotentiality

  17. Ovarian torsion: opportunities to improve clinical management.

    PubMed

    Bharathan, R; Ramsawak, L; Kelly, A

    2012-10-01

    Ovarian torsion is an uncommon condition which may affect women of any age. In a significant number of women, it may be associated with a concomitant pathology such as a cyst. Presently, there is no single diagnostic tool with significant predictive value. Multimodal diagnostic tools hold promise of early accurate diagnosis; prospective studies are required to assess the validity of such tools. This would enable wider application of ovarian function preserving procedures. Further, an assessment of the psychological impact of oophorectomy should be studied in order to facilitate the optimal tailored care. PMID:22943718

  18. Real-time Neural Network predictions of geomagnetic activity indices

    NASA Astrophysics Data System (ADS)

    Bala, R.; Reiff, P. H.

    2009-12-01

    The Boyle potential or the Boyle Index (BI), Φ (kV)=10-4 (V/(km/s))2 + 11.7 (B/nT) sin3(θ/2), is an empirically-derived formula that can characterize the Earth's polar cap potential, which is readily derivable in real time using the solar wind data from ACE (Advanced Composition Explorer). The BI has a simplistic form that utilizes a non-magnetic "viscous" and a magnetic "merging" component to characterize the magnetospheric behavior in response to the solar wind. We have investigated its correlation with two of conventional geomagnetic activity indices in Kp and the AE index. We have shown that the logarithms of both 3-hr and 1-hr averages of the BI correlate well with the subsequent Kp: Kp = 8.93 log10(BI) - 12.55 along with 1-hr BI correlating with the subsequent log10(AE): log10(AE) = 1.78 log10(BI) - 3.6. We have developed a new set of algorithms based on Artificial Neural Networks (ANNs) suitable for short term space weather forecasts with an enhanced lead-time and better accuracy in predicting Kp and AE over some leading models; the algorithms omit the time history of its targets to utilize only the solar wind data. Inputs to our ANN models benefit from the BI and its proven record as a forecasting parameter since its initiation in October, 2003. We have also performed time-sensitivity tests using cross-correlation analysis to demonstrate that our models are as efficient as those that incorporates the time history of the target indices in their inputs. Our algorithms can predict the upcoming full 3-hr Kp, purely from the solar wind data and achieve a linear correlation coefficient of 0.840, which means that it predicts the upcoming Kp value on average to within 1.3 step, which is approximately the resolution of the real-time Kp estimate. Our success in predicting Kp during a recent unexpected event (22 July ’09) is shown in the figure. Also, when predicting an equivalent "one hour Kp'', the correlation coefficient is 0.86, meaning on average a prediction

  19. Insights from HuR biology point to potential improvement for second-line ovarian cancer therapy

    PubMed Central

    Huang, Yu-Hung; Peng, Weidan; Furuuchi, Narumi; DuHadaway, James B.; Jimbo, Masaya; Pirritano, Andrea; Dunton, Charles J.; Daum, Gary S.; Leiby, Benjamin E.; Brody, Jonathan R.; Sawicki, Janet A.

    2016-01-01

    This retrospective study aimed to investigate the role that an RNA-binding protein, HuR, plays in the response of high-grade serous ovarian tumors to chemotherapeutics. We immunohistochemically stained sections of 31 surgically-debulked chemo-naïve ovarian tumors for HuR and scored the degree of HuR cytoplasmic staining. We found no correlation between HuR intracellular localization in tumor sections and progression free survival (PFS) of these patients, 29 of whom underwent second-line gemcitabine/platin combination therapy for recurrent disease. Ribonucleoprotein immunoprecipitation (RNP-IP) analysis of ovarian cancer cells in culture showed that cytoplasmic HuR increases deoxycytidine kinase (dCK), a metabolic enzyme that activates gemcitabine. The effects of carboplatin treatment on HuR and WEE1 (a mitotic inhibitor) expression, and on cell cycle kinetics, were also examined. Treatment of ovarian cancer cells with carboplatin results in increased HuR cytoplasmic expression and elevated WEE1 expression, arresting cell cycle G2/M transition. This may explain why HuR cytoplasmic localization in chemo-naïve tumors is not predictive of therapeutic response and PFS following second-line gemcitabine/platin combination therapy. These results suggest treatment of recurrent ovarian tumors with a combination of gemcitabine, carboplatin, and a WEE1 inhibitor may be potentially advantageous as compared to current clinical practices. PMID:26943573

  20. Long-Range Solar Activity Predictions: A Reprieve from Cycle #24's Activity

    NASA Technical Reports Server (NTRS)

    Richon, K.; Schatten, K.

    2003-01-01

    We discuss the field of long-range solar activity predictions and provide an outlook into future solar activity. Orbital predictions for satellites in Low Earth Orbit (LEO) depend strongly on exospheric densities. Solar activity forecasting is important in this regard, as the solar ultra-violet (UV) and extreme ultraviolet (EUV) radiations inflate the upper atmospheric layers of the Earth, forming the exosphere in which satellites orbit. Rather than concentrate on statistical, or numerical methods, we utilize a class of techniques (precursor methods) which is founded in physical theory. The geomagnetic precursor method was originally developed by the Russian geophysicist, Ohl, using geomagnetic observations to predict future solar activity. It was later extended to solar observations, and placed within the context of physical theory, namely the workings of the Sun s Babcock dynamo. We later expanded the prediction methods with a SOlar Dynamo Amplitude (SODA) index. The SODA index is a measure of the buried solar magnetic flux, using toroidal and poloidal field components. It allows one to predict future solar activity during any phase of the solar cycle, whereas previously, one was restricted to making predictions only at solar minimum. We are encouraged that solar cycle #23's behavior fell closely along our predicted curve, peaking near 192, comparable to the Schatten, Myers and Sofia (1996) forecast of 182+/-30. Cycle #23 extends from 1996 through approximately 2006 or 2007, with cycle #24 starting thereafter. We discuss the current forecast of solar cycle #24, (2006-2016), with a predicted smoothed F10.7 radio flux of 142+/-28 (1-sigma errors). This, we believe, represents a reprieve, in terms of reduced fuel costs, etc., for new satellites to be launched or old satellites (requiring reboosting) which have been placed in LEO. By monitoring the Sun s most deeply rooted magnetic fields; long-range solar activity can be predicted. Although a degree of uncertainty

  1. MV-NIS Infected Mesenchymal Stem Cells in Treating Patients With Recurrent Ovarian Cancer

    ClinicalTrials.gov

    2016-07-08

    Malignant Ovarian Brenner Tumor; Ovarian Clear Cell Adenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Adenocarcinoma; Ovarian Transitional Cell Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  2. Polyglutamate Paclitaxel and Carboplatin in Treating Patients With Ovarian Epithelial, Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2015-05-07

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Stage III Ovarian Cancer; Stage IV Ovarian Cancer; Undifferentiated Ovarian Carcinoma

  3. Solar Activity Predictions Based on Solar Dynamo Theories

    NASA Astrophysics Data System (ADS)

    Schatten, Kenneth H.

    2009-05-01

    We review solar activity prediction methods, statistical, precursor, and recently the Dikpati and the Choudhury groups’ use of numerical flux-dynamo methods. Outlining various methods, we compare precursor techniques with weather forecasting. Precursors involve events prior to a solar cycle. First started by the Russian geomagnetician Ohl, and then Brown and Williams; the Earth's field variations near solar minimum was used to predict the next solar cycle, with a correlation of 0.95. From the standpoint of causality, as well as energetically, these relationships were somewhat bizarre. One index used was the "number of anomalous quiet days,” an antiquated, subjective index. Scientific progress cannot be made without some suspension of disbelief; otherwise old paradigms become tautologies. So, with youthful naïveté, Svalgaard, Scherrer, Wilcox and I viewed the results through rose-colored glasses and pressed ahead searching for understanding. We eventually fumbled our way to explaining how the Sun could broadcast the state of its internal dynamo to Earth. We noted one key aspect of the Babcock-Leighton Flux Dynamo theory: the polar field at the end of a cycle serves as a seed for the next cycle's growth. Near solar minimum this field usually bathes the Earth, and thereby affects geomagnetic indices then. We found support by examining 8 previous solar cycles. Using our solar precursor technique we successfully predicted cycles 21, 22 and 23 using WSO and MWSO data. Pesnell and I improved the method using a SODA (SOlar Dynamo Amplitude) Index. In 2005, nearing cycle 23's minimum, Svalgaard and I noted an unusually weak polar field, and forecasted a small cycle 24. We discuss future advances: the flux-dynamo methods. As far as future solar activity, I shall let the Sun decide; it will do so anyhow.

  4. Predictive Analysis of Landslide Activity Using Remote Sensing Data

    NASA Astrophysics Data System (ADS)

    Markuzon, N.; Regan, J.; Slesnick, C.

    2012-12-01

    Landslides are historically one of the most damaging geohazard phenomena in terms of death tolls and socio-economic losses. Therefore, understanding the underlying causes of landslides and how environmental phenomena affect their frequency and severity is of critical importance. Of specific importance for mitigating future damage is increasing our understanding of how climate change will affect landslide severity, occurrence rates, and damage. We are developing data driven models aimed at predicting landslide activity. The models learn multi-dimensional weather and geophysical patterns associated with historical landslides and estimate location-dependent probabilities for landslides under current or future weather and geophysical conditions. Our approach uses machine learning algorithms capable of determining non-linear associations between dependent variables and landslide occurrence without requiring detailed knowledge of geomorphology. Our primary goal in year one of the project is to evaluate the predictive capabilities of data mining models in application to landslide activity, and to analyze if the approach will discover previously unknown variables and/or relationships important to landslide occurrence, frequency or severity. The models include remote sensing and ground-based data, including weather, landcover, slope, elevation and drainage information as well as urbanization data. The historical landslide dataset we used to build our preliminary models was compiled from City of Seattle landslide files, United States Geological Survey reports, newspaper articles, and a verified subset of the Seattle Landslide Database that consists of all reported landslides within Seattle, WA, between 1948 and 1999. Most of the landslides analyzed to-date are shallow. Using statistical analysis and unsupervised clustering methods we have thus far identified subsets of weather conditions that lead to a significantly higher landslide probability, and have developed

  5. Absence of Activation of DNA Repair Genes and Excellent Efficacy of Phosphaplatins against Human Ovarian Cancers: Implications To Treat Resistant Cancers.

    PubMed

    Bose, Rathindra N; Moghaddas, Shadi; Belkacemi, Louiza; Tripathi, Swarnendu; Adams, Nyssa R; Majmudar, Pooja; McCall, Kelly; Dezvareh, Homa; Nislow, Corey

    2015-11-12

    Phosphaplatins, platinum(II) and platinum(IV) complexes coordinated to a pyrophosphate moiety, exhibit excellent antitumor activities against a variety of cancers. To determine whether phosphaplatins trigger resistance to treatment by engaging DNA damage repair genes, a yeast genome-wide fitness assay was used. Treatment of yeast cells with pyrodach-2 (D2) or pyrodach-4 (D4) revealed no particular sensitivity to nucleotide excision repair, homologous recombination repair, or postreplication repair when compared with platin control compounds. Also, TNF receptor superfamily member 6 (FAS) protein was overexpressed in phosphaplatin-treated ovarian tumor cells, and platinum colocalized with FAS protein in lipid rafts. An overactivation of sphingomyelinase (ASMase) was noted in the treated cells, indicating participation of an extrinsic apoptotic mechanism due to increased ceramide release. Our results indicate that DNA is not the target of phosphaplatins and accordingly, that phosphaplatins might not cause resistance to treatment. Activation of ASMase and FAS along with the colocalization of platinum with FAS in lipid rafts support an extrinsic apoptotic signaling mechanism that is mediated by phosphaplatins. PMID:26455832

  6. Luteinizing Hormone Reduces the Activity of the NPR2 Guanylyl Cyclase in Mouse Ovarian Follicles, Contributing to the Cyclic GMP Decrease that Promotes Resumption of Meiosis in Oocytes

    PubMed Central

    Robinson, Jerid W.; Zhang, Meijia; Shuhaibar, Leia C.; Norris, Rachael P.; Geerts, Andreas; Wunder, Frank; Eppig, John J.; Potter, Lincoln R.; Jaffe, Laurinda A.

    2012-01-01

    In preovulatory ovarian follicles of mice, meiotic prophase arrest in the oocyte is maintained by cyclic GMP from the surrounding granulosa cells that diffuses into the oocyte through gap junctions. The cGMP is synthesized in the granulosa cells by the transmembrane guanylyl cyclase natriuretic peptide receptor 2 (NPR2) in response to the agonist C-type natriuretic peptide (CNP). In response to luteinizing hormone (LH), cGMP in the granulosa cells decreases, and as a consequence, oocyte cGMP decreases and meiosis resumes. Here we report that within 20 minutes, LH treatment results in decreased guanylyl cyclase activity of NPR2, as determined in the presence of a maximally activating concentration of CNP. This occurs by a process that does not reduce the amount of NPR2 protein. We also show that by a slower process, first detected at 2 hours, LH decreases the amount of CNP available to bind to the receptor. Both of these LH actions contribute to decreasing cGMP in the follicle, thus signaling meiotic resumption in the oocyte. PMID:22546688

  7. COL11A1 confers chemoresistance on ovarian cancer cells through the activation of Akt/c/EBPβ pathway and PDK1 stabilization

    PubMed Central

    Wu, Yi-Hui; Chang, Tzu-Hao; Huang, Yu-Fang; Chen, Chien-Chin; Chou, Cheng-Yang

    2015-01-01

    Chemoresistance to anticancer drugs substantially reduces survival in epithelial ovarian carcinoma (EOC). Here, microarray analysis showed that collagen type XI alpha 1 (COL11A1) is a chemotherapy response-associated gene. Chemoresistant cells expressed higher COL11A1 and c/EBPβ than chemosensitive cells. COL11A1 or c/EBPβ downregulation suppressed chemoresistance, whereas COL11A1 overexpression attenuated sensitivity to cisplatin and paclitaxel. The c/EBPβ binding site in the COL11A1 promoter was identified as the major determinant of cisplatin- and paclitaxel-induced COL11A1 expression. Immunoprecipitation and immunofluorescence showed that in resistant cells, Akt and PDK1 were highly expressed and that anticancer drugs enhanced binding activity between COL11A1 and PDK1 binding and attenuated PDK1 ubiquitination and degradation. Conversely, chemosensitive cells showed decreased activity of COL11A1 binding to PDK1 and increased PDK1 ubiquitination, which were reversed by COL11A1 overexpression. Analysis of 104 EOC patients showed that high COL11A1 mRNA levels are significantly associated with poor chemoresponse and clinical outcome. PMID:26087191

  8. Monitoring ovarian cycle activity via progestagens in urine and feces of female mountain gorillas: A comparison of EIA and LC-MS measurements.

    PubMed

    Habumuremyi, Sosthene; Robbins, Martha M; Fawcett, Katie A; Deschner, Tobias

    2014-02-01

    Understanding the reproductive biology of endangered mountain gorillas (Gorilla beringei beringei) is essential for optimizing conservation strategies, determining any demographic impact of socioecological changes, and providing information for comparative studies of primates. Non-invasive techniques have been used to assess the reproductive function of many primates and the importance of validating the measurements of hormones metabolites is widely recognized because they may vary even within closely related species. To determine if it is possible to non-invasively monitor ovarian activity in wild mountain gorillas, we used enzyme immunoassays (EIA) to quantify both urinary and fecal excretion of immunoreactive pregnanediol-3-glucuronide (iPdG), defined as all metabolites detected by a pregnanediol-3-glucuronide immunoassay (PdG EIA). Simultaneously, we performed the liquid chromatography mass spectrometry (LC-MS) to quantify the excretion of pregnanediol in urine and feces. Samples were analyzed over nine cycles of five females from the habituated gorillas monitored by Karisoke Research Center, Rwanda. As an additional indicator for ovulation timing, estrone conjugates (E1C) were measured in a subset of urine samples. The concentrations of iPdG and pregnanediol measured in the same samples were significantly correlated. Urinary concentrations of iPdG and pregnanediol fluctuated over the menstrual cycle but did not reveal any cyclic pattern, whereas a typical preovulatory urinary E1C surge and postovulatory increases of fecal iPdG and pregnanediol were detected. The luteal peaks of iPdG and pregnanediol levels in feces were on average 2.8 and 7.6 times higher, respectively, than averaged levels in the corresponding follicular phase. The relative number of days with observed matings was higher within the presumed fertile window than in the preceding period. Overall, the results indicate that fecal analysis of iPdG and pregnanediol is suitable for detecting

  9. The sequential structure of brain activation predicts skill.

    PubMed

    Anderson, John R; Bothell, Daniel; Fincham, Jon M; Moon, Jungaa

    2016-01-29

    In an fMRI study, participants were trained to play a complex video game. They were scanned early and then again after substantial practice. While better players showed greater activation in one region (right dorsal striatum) their relative skill was better diagnosed by considering the sequential structure of whole brain activation. Using a cognitive model that played this game, we extracted a characterization of the mental states that are involved in playing a game and the statistical structure of the transitions among these states. There was a strong correspondence between this measure of sequential structure and the skill of different players. Using multi-voxel pattern analysis, it was possible to recognize, with relatively high accuracy, the cognitive states participants were in during particular scans. We used the sequential structure of these activation-recognized states to predict the skill of individual players. These findings indicate that important features about information-processing strategies can be identified from a model-based analysis of the sequential structure of brain activation. PMID:26707716

  10. Cortical alpha activity predicts the confidence in an impending action

    PubMed Central

    Kubanek, Jan; Hill, N. Jeremy; Snyder, Lawrence H.; Schalk, Gerwin

    2015-01-01

    When we make a decision, we experience a degree of confidence that our choice may lead to a desirable outcome. Recent studies in animals have probed the subjective aspects of the choice confidence using confidence-reporting tasks. These studies showed that estimates of the choice confidence substantially modulate neural activity in multiple regions of the brain. Building on these findings, we investigated the neural representation of the confidence in a choice in humans who explicitly reported the confidence in their choice. Subjects performed a perceptual decision task in which they decided between choosing a button press or a saccade while we recorded EEG activity. Following each choice, subjects indicated whether they were sure or unsure about the choice. We found that alpha activity strongly encodes a subject's confidence level in a forthcoming button press choice. The neural effect of the subjects' confidence was independent of the reaction time and independent of the sensory input modeled as a decision variable. Furthermore, the effect is not due to a general cognitive state, such as reward expectation, because the effect was specifically observed during button press choices and not during saccade choices. The neural effect of the confidence in the ensuing button press choice was strong enough that we could predict, from independent single trial neural signals, whether a subject was going to be sure or unsure of an ensuing button press choice. In sum, alpha activity in human cortex provides a window into the commitment to make a hand movement. PMID:26283892

  11. Prediction of Antibacterial Activity from Physicochemical Properties of Antimicrobial Peptides

    PubMed Central

    Melo, Manuel N.; Ferre, Rafael; Feliu, Lídia; Bardají, Eduard; Planas, Marta; Castanho, Miguel A. R. B.

    2011-01-01

    Consensus is gathering that antimicrobial peptides that exert their antibacterial action at the membrane level must reach a local concentration threshold to become active. Studies of peptide interaction with model membranes do identify such disruptive thresholds but demonstrations of the possible correlation of these with the in vivo onset of activity have only recently been proposed. In addition, such thresholds observed in model membranes occur at local peptide concentrations close to full membrane coverage. In this work we fully develop an interaction model of antimicrobial peptides with biological membranes; by exploring the consequences of the underlying partition formalism we arrive at a relationship that provides antibacterial activity prediction from two biophysical parameters: the affinity of the peptide to the membrane and the critical bound peptide to lipid ratio. A straightforward and robust method to implement this relationship, with potential application to high-throughput screening approaches, is presented and tested. In addition, disruptive thresholds in model membranes and the onset of antibacterial peptide activity are shown to occur over the same range of locally bound peptide concentrations (10 to 100 mM), which conciliates the two types of observations. PMID:22194847

  12. Active targeting using HER-2-affibody-conjugated nanoparticles enabled sensitive and specific imaging of orthotopic HER-2 positive ovarian tumors.

    PubMed

    Satpathy, Minati; Wang, Liya; Zielinski, Rafal; Qian, Weiping; Lipowska, Malgorzata; Capala, Jacek; Lee, Gee Young; Xu, Hong; Wang, Y Andrew; Mao, Hui; Yang, Lily

    2014-02-12

    Despite advances in cancer diagnosis and treatment, ovarian cancer remains one of the most fatal cancer types. The development of targeted nanoparticle imaging probes and therapeutics offers promising approaches for early detection and effective treatment of ovarian cancer. In this study, HER-2 targeted magnetic iron oxide nanoparticles (IONPs) are developed by conjugating a high affinity and small size HER-2 affibody that is labeled with a unique near infrared dye (NIR-830) to the nanoparticles. Using a clinically relevant orthotopic human ovarian tumor xenograft model, it is shown that HER-2 targeted IONPs are selectively delivered into both primary and disseminated ovarian tumors, enabling non-invasive optical and MR imaging of the tumors as small as 1 mm in the peritoneal cavity. It is determined that HER-2 targeted delivery of the IONPs is essential for specific and sensitive imaging of the HER-2 positive tumor since we are unable to detect the imaging signal in the tumors following systemic delivery of non-targeted IONPs into the mice bearing HER-2 positive SKOV3 tumors. Furthermore, imaging signals and the IONPs are not detected in HER-2 low expressing OVCAR3 tumors after systemic delivery of HER-2 targeted-IONPs. Since HER-2 is expressed in a high percentage of ovarian cancers, the HER-2 targeted dual imaging modality IONPs have potential for the development of novel targeted imaging and therapeutic nanoparticles for ovarian cancer detection, targeted drug delivery, and image-guided therapy and surgery. PMID:24038985

  13. L1 Cell Adhesion Molecule-Specific Chimeric Antigen Receptor-Redirected Human T Cells Exhibit Specific and Efficient Antitumor Activity against Human Ovarian Cancer in Mice.

    PubMed

    Hong, Hao; Brown, Christine E; Ostberg, Julie R; Priceman, Saul J; Chang, Wen-Chung; Weng, Lihong; Lin, Paul; Wakabayashi, Mark T; Jensen, Michael C; Forman, Stephen J

    2016-01-01

    New therapeutic modalities are needed for ovarian cancer, the most lethal gynecologic malignancy. Recent clinical trials have demonstrated the impressive therapeutic potential of adoptive therapy using chimeric antigen receptor (CAR)-redirected T cells to target hematological cancers, and emerging studies suggest a similar impact may be achieved for solid cancers. We sought determine whether genetically-modified T cells targeting the CE7-epitope of L1-CAM, a cell adhesion molecule aberrantly expressed in several cancers, have promise as an immunotherapy for ovarian cancer, first demonstrating that L1-CAM was highly over-expressed on a panel of ovarian cancer cell lines, primary ovarian tumor tissue specimens, and ascites-derived primary cancer cells. Human central memory derived T cells (TCM) were then genetically modified to express an anti-L1-CAM CAR (CE7R), which directed effector function upon tumor antigen stimulation as assessed by in vitro cytokine secretion and cytotoxicity assays. We also found that CE7R+ T cells were able to target primary ovarian cancer cells. Intraperitoneal (i.p.) administration of CE7R+ TCM induced a significant regression of i.p. established SK-OV-3 xenograft tumors in mice, inhibited ascites formation, and conferred a significant survival advantage compared with control-treated animals. Taken together, these studies indicate that adoptive transfer of L1-CAM-specific CE7R+ T cells may offer a novel and effective immunotherapy strategy for advanced ovarian cancer. PMID:26761817

  14. Can Ovarian Cancer Be Found Early?

    MedlinePlus

    ... Topic Signs and symptoms of ovarian cancer Can ovarian cancer be found early? About 20% of ovarian cancers ... cancer in its earliest stage. Ways to find ovarian cancer early Regular women's health exams During a pelvic ...

  15. Ovarian Folliculogenesis.

    PubMed

    Rimon-Dahari, Nitzan; Yerushalmi-Heinemann, Lia; Alyagor, Liat; Dekel, Nava

    2016-01-01

    The ovary, the female gonad, serves as the source for the germ cells as well as the major supplier of steroid sex hormones. During embryonic development, the primordial germ cells (PGCs) are specified, migrate to the site of the future gonad, and proliferate, forming structures of germ cells nests, which will eventually break down to generate the primordial follicles (PMFs). Each PMF contains an oocyte arrested at the first prophase of meiosis, surrounded by a flattened layer of somatic pre-granulosa cells. Most of the PMFs are kept dormant and only a selected population is activated to join the growing pool of follicles in a process regulated by both intra- and extra-oocyte factors. The PMFs will further develop into secondary pre-antral follicles, a stage which depends on bidirectional communication between the oocyte and the surrounding somatic cells. Many of the signaling molecules involved in this dialog belong to the transforming growth factor β (TGF-β) superfamily. As the follicle continues to develop, a cavity called antrum is formed. The resulting antral follicles relay on the pituitary gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) for their development. Most of the follicles undergo atretic degeneration and only a subset of the antral follicles, known as the dominant follicles, will reach the preovulatory stage at each reproductive cycle, respond to LH, and subsequently ovulate, releasing a fertilizable oocyte. The remaining somatic cells in the raptured follicle will undergo terminal differentiation and form the corpus luteum, which secretes progesterone necessary to maintain pregnancy. PMID:27300179

  16. Tumor infiltrating lymphocytes in ovarian cancer

    PubMed Central

    Santoiemma, Phillip P; Powell, Daniel J

    2015-01-01

    The accumulation of tumor infiltrating lymphocytes (TILs) in ovarian cancer is prognostic for increased survival while increases in immunosuppressive regulatory T-cells (Tregs) are associated with poor outcomes. Approaches that bolster tumor-reactive TILs may limit tumor progression. However, identifying tumor-reactive TILs in ovarian cancer has been challenging, though adoptive TIL therapy in patients has been encouraging. Other forms of TIL immunomodulation remain under investigation including Treg depletion, antibody-based checkpoint modification, activation and amplification using dendritic cells, antigen presenting cells or IL-2 cytokine culture, adjuvant cytokine injections, and gene-engineered T-cells. Many approaches to TIL manipulation inhibit ovarian cancer progression in preclinical or clinical studies as monotherapy. Here, we review the impact of TILs in ovarian cancer and attempts to mobilize TILs to halt tumor progression. We conclude that effective TIL therapy for ovarian cancer is at the brink of translation and optimal TIL activity may require combined methodologies to deliver clinically-relevant treatment. PMID:25894333

  17. [Immunological analogies between ovarian cancer and pregnancy].

    PubMed

    Hanssen, S; Collinet, P; Leblanc, E; Salzet, M; Vinatier, D

    2013-05-01

    During pregnancy an environment allowing installation of tolerance toward the fetus is set up locally at the materno-fetal interface. Numerous effectors of immunity are involved in this tolerance (NK cell, T cell, Macrophages, dendritic cell). Specific mechanisms during pregnancy attract locally these immunological cells. In the decidua, they are educated toward tolerance. These mechanisms evolve during the pregnancy because at the end of the pregnancy, tolerance is broken to prepare and activate the labor. Ovarian tumors, after having surmounted the immunosurveillance, like trophoblast, chair the installation of a tolerance of their host facilitating the development of the disease. The blocking of these mechanisms of tolerance coupled with activation of mechanisms of defenses offer new perspectives in the treatment of the ovarian cancer. The authors suggest showing the analogies of the tolerance observed during ovarian cancer and pregnancy. The knowledge of the orchestration of the physiological mechanisms observed during pregnancy will offer new therapeutic targets. PMID:23182791

  18. Solubility Prediction of Active Pharmaceutical Compounds with the UNIFAC Model

    NASA Astrophysics Data System (ADS)

    Nouar, Abderrahim; Benmessaoud, Ibtissem; Koutchoukali, Ouahiba; Koutchoukali, Mohamed Salah

    2016-03-01

    The crystallization from solution of an active pharmaceutical ingredient requires the knowledge of the solubility in the entire temperature range investigated during the process. However, during the development of a new active ingredient, these data are missing. Its experimental determination is possible, but tedious. UNIFAC Group contribution method Fredenslund et al. (Vapor-liquid equilibria using UNIFAC: a group contribution method, 1977; AIChE J 21:1086, 1975) can be used to predict this physical property. Several modifications on this model have been proposed since its development in 1977, modified UNIFAC of Dortmund Weidlich et al. (Ind Eng Chem Res 26:1372, 1987), Gmehling et al. (Ind Eng Chem Res 32:178, 1993), Pharma-modified UNIFAC Diedrichs et al. (Evaluation und Erweiterung thermodynamischer Modelle zur Vorhersage von Wirkstofflöslichkeiten, PhD Thesis, 2010), KT-UNIFAC Kang et al. (Ind Eng Chem Res 41:3260, 2002), ldots In this study, we used UNIFAC model by considering the linear temperature dependence of interaction parameters as in Pharma-modified UNIFAC and structural groups as defined by KT-UNIFAC first-order model. More than 100 binary datasets were involved in the estimation of interaction parameters. These new parameters were then used to calculate activity coefficient and solubility of some molecules in various solvents at different temperatures. The model gives better results than those from the original UNIFAC and shows good agreement between the experimental solubility and the calculated one.

  19. Autonomic activity during sleep predicts memory consolidation in humans.

    PubMed

    Whitehurst, Lauren N; Cellini, Nicola; McDevitt, Elizabeth A; Duggan, Katherine A; Mednick, Sara C

    2016-06-28

    Throughout history, psychologists and philosophers have proposed that good sleep benefits memory, yet current studies focusing on the relationship between traditionally reported sleep features (e.g., minutes in sleep stages) and changes in memory performance show contradictory findings. This discrepancy suggests that there are events occurring during sleep that have not yet been considered. The autonomic nervous system (ANS) shows strong variation across sleep stages. Also, increases in ANS activity during waking, as measured by heart rate variability (HRV), have been correlated with memory improvement. However, the role of ANS in sleep-dependent memory consolidation has never been examined. Here, we examined whether changes in cardiac ANS activity (HRV) during a daytime nap were related to performance on two memory conditions (Primed and Repeated) and a nonmemory control condition on the Remote Associates Test. In line with prior studies, we found sleep-dependent improvement in the Primed condition compared with the Quiet Wake control condition. Using regression analyses, we compared the proportion of variance in performance associated with traditionally reported sleep features (model 1) vs. sleep features and HRV during sleep (model 2). For both the Primed and Repeated conditions, model 2 (sleep + HRV) predicted performance significantly better (73% and 58% of variance explained, respectively) compared with model 1 (sleep only, 46% and 26% of variance explained, respectively). These findings present the first evidence, to our knowledge, that ANS activity may be one potential mechanism driving sleep-dependent plasticity. PMID:27298366

  20. Decreased dopamine activity predicts relapse in methamphetamine abusers

    SciTech Connect

    Wang G. J.; Wang, G.-J.; Smith, L.; Volkow, N.D.; Telang, F.; Logan, J.; Tomasi, D.; Wong, C.T.; Hoffman, W.; Jayne, M.; Alia-Klein, N.; Thanos, P.; Fowler, J.S.

    2011-01-20

    Studies in methamphetamine (METH) abusers showed that the decreases in brain dopamine (DA) function might recover with protracted detoxification. However, the extent to which striatal DA function in METH predicts recovery has not been evaluated. Here we assessed whether striatal DA activity in METH abusers is associated with clinical outcomes. Brain DA D2 receptor (D2R) availability was measured with positron emission tomography and [{sup 11}C]raclopride in 16 METH abusers, both after placebo and after challenge with 60 mg oral methylphenidate (MPH) (to measure DA release) to assess whether it predicted clinical outcomes. For this purpose, METH abusers were tested within 6 months of last METH use and then followed up for 9 months of abstinence. In parallel, 15 healthy controls were tested. METH abusers had lower D2R availability in caudate than in controls. Both METH abusers and controls showed decreased striatal D2R availability after MPH and these decreases were smaller in METH than in controls in left putamen. The six METH abusers who relapsed during the follow-up period had lower D2R availability in dorsal striatum than in controls, and had no D2R changes after MPH challenge. The 10 METH abusers who completed detoxification did not differ from controls neither in striatal D2R availability nor in MPH-induced striatal DA changes. These results provide preliminary evidence that low striatal DA function in METH abusers is associated with a greater likelihood of relapse during treatment. Detection of the extent of DA dysfunction may be helpful in predicting therapeutic outcomes.

  1. Multiplexed model predictive control for active vehicle suspensions

    NASA Astrophysics Data System (ADS)

    Hu, Yinlong; Chen, Michael Z. Q.; Hou, Zhongsheng

    2015-02-01

    Multiplexed model predictive control (MMPC) is a recently proposed efficient model predictive control (MPC) algorithm, which can effectively reduce the computational burden of the online optimisation in MPC implementation by updating the control inputs in an asynchronous manner. This paper investigates the application of MMPC in active vehicle suspension design. An MMPC controller integrated with soft constraints and a Kalman filter is proposed based on a full-car model. Ride comfort, roadholding and suspension deflection are considered in this paper, where ride comfort and roadholding are formulated as a quadratic cost function in terms of sprung mass accelerations and tyre deflections, while suspension deflection performance is formulated as a hard constraint. The saturation of the actuator force is also considered and formulated as a hard constraint as well. Numerical simulation is performed with respect to different choices of weighting factors, vehicle speeds and control horizons. The results show that the overall performance of ride comfort and roadholding can be improved significantly by employing MMPC and the average time taken by MMPC to solve the individual quadratic programming problem is considerably smaller than that of the conventional MPC, which effectively demonstrate the effectiveness of the proposed method.

  2. Target of rapamycin activation predicts lifespan in fruit flies

    PubMed Central

    Scialò, Filippo; Sriram, Ashwin; Naudí, Alba; Ayala, Victoria; Jové, Mariona; Pamplona, Reinald; Sanz, Alberto

    2015-01-01

    Aging and age-related diseases are one of the most important health issues that the world will confront during the 21st century. Only by understanding the proximal causes will we be able to find treatments to reduce or delay the onset of degenerative diseases associated with aging. Currently, the prevalent paradigm in the field is the accumulation of damage. However, a new theory that proposes an alternative explanation is gaining momentum. The hyperfunction theory proposes that aging is not a consequence of a wear and tear process, but a result of the continuation of developmental programs during adulthood. Here we use Drosophila melanogaster, where evidence supporting both paradigms has been reported, to identify which parameters that have been previously related with lifespan best predict the rate of aging in wild type flies cultured at different temperatures. We find that mitochondrial function and mitochondrial reactive oxygen species (mtROS) generation correlates with metabolic rate, but not with the rate of aging. Importantly, we find that activation of nutrient sensing pathways (i.e. insulin-PI3K/Target of rapamycin (Tor) pathway) correlates with lifespan, but not with metabolic rate. Our results, dissociate metabolic rate and lifespan in wild type flies and instead link nutrient sensing signaling with longevity as predicted by the hyperfunction theory. PMID:26259964

  3. Ovarian hyperstimulation syndrome

    MedlinePlus

    ... 3 to 6% of women who go through in vitro fertilization . Other risk factors for OHSS include: Being younger than age 35 Having a very high estrogen level during fertility treatments Having polycystic ovarian syndrome

  4. National Ovarian Cancer Coalition

    MedlinePlus

    ... ovarian cancer Read More View More News Upcoming Events Fabric Extravaganza! September 09, 2016 @ 12:00PM Hosted ... Roxy and Dukes Roadhouse View All Our Upcoming Events Latest from the Blog: Hailey's Story How her ...

  5. Ovarian metabolism of xenobiotics.

    PubMed

    Bhattacharya, Poulomi; Keating, Aileen F

    2011-07-01

    At birth, the mammalian ovary contains a finite number of primordial follicles, which once depleted, cannot be replaced. Xenobiotic exposures can destroy primordial follicles resulting in premature ovarian failure and, consequently, early entry into menopause. A number of chemical classes can induce premature ovarian failure, including environmental, chemotherapeutic and industrial exposures. While our knowledge on the mechanistic events that occur in the ovary with chemical exposures is increasing, our understanding of the ovary's capacity to metabolize such compounds is less established. This review will focus on three chemicals for which information on ovarian metabolism is known: trichloroethylene, 7,12-dimethylbenz[a]anthracene and 4-vinylcyclohexene. The current state of understanding of ovarian bioactivation and detoxification processes for each will be described. PMID:21616964

  6. Ovarian metabolism of xenobiotics

    PubMed Central

    Bhattacharya, Poulomi; Keating, Aileen F

    2013-01-01

    At birth, the mammalian ovary contains a finite number of primordial follicles, which once depleted, cannot be replaced. Xenobiotic exposures can destroy primordial follicles resulting in premature ovarian failure and, consequently, early entry into menopause. A number of chemical classes can induce premature ovarian failure, including environmental, chemotherapeutic and industrial exposures. While our knowledge on the mechanistic events that occur in the ovary with chemical exposures is increasing, our understanding of the ovary's capacity to metabolize such compounds is less established. This review will focus on three chemicals for which information on ovarian metabolism is known: trichloroethylene, 7,12-dimethylbenz[a]anthracene and 4-vinylcyclohexene. The current state of understanding of ovarian bioactivation and detoxification processes for each will be described. PMID:21616964

  7. Prediction Activities at NASA's Global Modeling and Assimilation Office

    NASA Technical Reports Server (NTRS)

    Schubert, Siegfried

    2010-01-01

    The Global Modeling and Assimilation Office (GMAO) is a core NASA resource for the development and use of satellite observations through the integrating tools of models and assimilation systems. Global ocean, atmosphere and land surface models are developed as components of assimilation and forecast systems that are used for addressing the weather and climate research questions identified in NASA's science mission. In fact, the GMAO is actively engaged in addressing one of NASA's science mission s key questions concerning how well transient climate variations can be understood and predicted. At weather time scales the GMAO is developing ultra-high resolution global climate models capable of resolving high impact weather systems such as hurricanes. The ability to resolve the detailed characteristics of weather systems within a global framework greatly facilitates addressing fundamental questions concerning the link between weather and climate variability. At sub-seasonal time scales, the GMAO is engaged in research and development to improve the use of land information (especially soil moisture), and in the improved representation and initialization of various sub-seasonal atmospheric variability (such as the MJO) that evolves on time scales longer than weather and involves exchanges with both the land and ocean The GMAO has a long history of development for advancing the seasonal-to-interannual (S-I) prediction problem using an older version of the coupled atmosphere-ocean general circulation model (AOGCM). This includes the development of an Ensemble Kalman Filter (EnKF) to facilitate the multivariate assimilation of ocean surface altimetry, and an EnKF developed for the highly inhomogeneous nature of the errors in land surface models, as well as the multivariate assimilation needed to take advantage of surface soil moisture and snow observations. The importance of decadal variability, especially that associated with long-term droughts is well recognized by the

  8. Predicting eruptions from precursory activity using remote sensing data hybridization

    NASA Astrophysics Data System (ADS)

    Reath, K. A.; Ramsey, M. S.; Dehn, J.; Webley, P. W.

    2016-07-01

    Many volcanoes produce some level of precursory activity prior to an eruption. This activity may or may not be detected depending on the available monitoring technology. In certain cases, precursors such as thermal output can be interpreted to make forecasts about the time and magnitude of the impending eruption. Kamchatka (Russia) provides an ideal natural laboratory to study a wide variety of eruption styles and precursory activity prior to an eruption. At Bezymianny volcano for example, a clear increase in thermal activity commonly occurs before an eruption, which has allowed predictions to be made months ahead of time. Conversely, the eruption of Tolbachik volcano in 2012 produced no discernable thermal precursors before the large scale effusive eruption. However, most volcanoes fall between the extremes of consistently behaved and completely undetectable, which is the case with neighboring Kliuchevskoi volcano. This study tests the effectiveness of using thermal infrared (TIR) remote sensing to track volcanic thermal precursors using data from both the Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) and Advanced Very High Resolution Radiometer (AVHRR) sensors. It focuses on three large eruptions that produced different levels and durations of effusive and explosive behavior at Kliuchevskoi. Before each of these eruptions, TIR spaceborne sensors detected thermal anomalies (i.e., pixels with brightness temperatures > 2 °C above the background temperature). High-temporal, low-spatial resolution (i.e., ~ hours and 1 km) AVHRR data are ideal for detecting large thermal events occurring over shorter time scales, such as the hot material ejected following strombolian eruptions. In contrast, high-spatial, low-temporal resolution (i.e., days to weeks and 90 m) ASTER data enables the detection of much lower thermal activity; however, activity with a shorter duration will commonly be missed. ASTER and AVHRR data are combined to track low

  9. Prediction of Energy Expenditure and Physical Activity in Preschoolers

    PubMed Central

    Butte, Nancy F.; Wong, William W.; Lee, Jong Soo; Adolph, Anne L.; Puyau, Maurice R.; Zakeri, Issa F.

    2013-01-01

    Purpose Accurate, nonintrusive and feasible methods are needed to predict energy expenditure (EE) and physical activity (PA) levels in preschoolers. Herein, we validated cross-sectional time series (CSTS) and multivariate adaptive regression splines (MARS) models based on accelerometry and heart rate (HR) for prediction of EE using room calorimetry and doubly labeled water (DLW), and established accelerometry cut-points for PA levels. Methods Fifty preschoolers, mean±SD age 4.5±0.8 y, participated in room calorimetry for minute-by-minute measurements of EE, accelerometer counts (AC) (Actiheart and ActiGraph GT3X+) and HR (Actiheart). Free-living, 105 children, aged 4.6±0.9 years, completed the 7-d DLW procedure while wearing the devices. AC cut-points for PA levels were established using smoothing splines and receiver operating characteristic curves. Results Based on calorimetry, mean percent errors for EE were -2.9±10.8% and -1.1±7.4% for CSTS models, and -1.9±9.6 and 1.3±8.1% for MARS models using the Actiheart and ActiGraph+HR devices, respectively. Based on DLW, mean percent errors were -0.5±9.7% and 4.1±8.5% for CSTS models and 3.2±10.1% and 7.5±10.0% for MARS models using the Actiheart and ActiGraph+HR devices, respectively. Applying activity EE thresholds, final accelerometer cut-points were determined: 41, 449, and 1,297 cpm for Actiheart x-axis; 820, 3,908, and 6,112 cpm for ActiGraph vector magnitude; and 240, 2,120, and 4,450 cpm for ActiGraph x-axis for sedentary/light, light/moderate, and moderate/vigorous PA (MVPA). Based on confusion matrices, correctly classified rates were 81–83% for sedentary PA, 58–64% for light PA and 62–73% for MVPA. Conclusion The lack of bias and acceptable limits of agreement affirm the validity of the CSTS and MARS models for the prediction of EE in preschool-aged children. Accelerometer cut-points are satisfactory for classification of sedentary, light and moderate-vigorous levels of PA in preschoolers

  10. Hypodontia and ovarian cancer: A systematic review

    PubMed Central

    Iavazzo, Christos; Papakiritsis, Matthaios; Gkegkes, Ioannis D.

    2016-01-01

    Hypodontia can be defined as the non-formation of one or more teeth during the developmental period. Mutation in several genes related to tooth formation has previously been correlated with cancer. Regarding the ovarian cancer, there are few studies that associate the presence of hypodontia with ovarian cancer. A systematic literature search was performed in PubMed and Scopus. In total, 385 patients were included in this study. Control group was present in 3 out of 4 studies (340 patients). Hypodontia was present in 56 out of 290 patients (incidence of 19.3%). Only in 2 out of 4 studies, the number of missing teeth was mentioned (47 teeth), while the majority of them were either maxillary second premolars or maxillary lateral incisors. Unilateral distribution of the missing teeth was present in 28 out of 46 patients, while bilateral distribution of the missing teeth was present in 18 out of 46 patients. The presence of ovarian cancer in the family medical history occurred in 12 out of 33 patients. Only 1 out of 4 studies examined the presence of genes with mutations in the included patients. Based on our findings, the lack of clinical studies was the principal obstacle to clarify the possible predictive value of hypodontia in the early prediction of patients with higher risk of ovarian cancer. PMID:27026778

  11. Brain monoamine oxidase A activity predicts trait aggression.

    PubMed

    Alia-Klein, Nelly; Goldstein, Rita Z; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D; Fowler, Joanna S

    2008-05-01

    The genetic deletion of monoamine oxidase A (MAO A), an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, Mendelian Inheritance in Men database number 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in vivo in healthy nonsmoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the multidimensional personality questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions, the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than one-third of the variability. Because trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

  12. Brain Monoamine Oxidase-A Activity Predicts Trait Aggression

    PubMed Central

    Alia-Klein, Nelly; Goldstein, Rita Z.; Kriplani, Aarti; Logan, Jean; Tomasi, Dardo; Williams, Benjamin; Telang, Frank; Shumay, Elena; Biegon, Anat; Craig, Ian W.; Henn, Fritz; Wang, Gene-Jack; Volkow, Nora D.; Fowler, Joanna S.

    2008-01-01

    The genetic deletion of monoamine oxidase A (MAO A, an enzyme which breaks down the monoamine neurotransmitters norepinephrine, serotonin and dopamine) produces aggressive phenotypes across species. Therefore, a common polymorphism in the MAO A gene (MAOA, MIM 309850, referred to as high or low based on transcription in non-neuronal cells) has been investigated in a number of externalizing behavioral and clinical phenotypes. These studies provide evidence linking the low MAOA genotype and violent behavior but only through interaction with severe environmental stressors during childhood. Here, we hypothesized that in healthy adult males the gene product of MAO A in the brain, rather than the gene per se, would be associated with regulating the concentration of brain amines involved in trait aggression. Brain MAO A activity was measured in-vivo in healthy non-smoking men with positron emission tomography using a radioligand specific for MAO A (clorgyline labeled with carbon 11). Trait aggression was measured with the Multidimensional Personality Questionnaire (MPQ). Here we report for the first time that brain MAO A correlates inversely with the MPQ trait measure of aggression (but not with other personality traits) such that the lower the MAO A activity in cortical and subcortical brain regions the higher the self-reported aggression (in both MAOA genotype groups) contributing to more than a third of the variability. Since trait aggression is a measure used to predict antisocial behavior, these results underscore the relevance of MAO A as a neurochemical substrate of aberrant aggression. PMID:18463263

  13. Cortical activity patterns predict robust speech discrimination ability in noise

    PubMed Central

    Shetake, Jai A.; Wolf, Jordan T.; Cheung, Ryan J.; Engineer, Crystal T.; Ram, Satyananda K.; Kilgard, Michael P.

    2012-01-01

    The neural mechanisms that support speech discrimination in noisy conditions are poorly understood. In quiet conditions, spike timing information appears to be used in the discrimination of speech sounds. In this study, we evaluated the hypothesis that spike timing is also used to distinguish between speech sounds in noisy conditions that significantly degrade neural responses to speech sounds. We tested speech sound discrimination in rats and recorded primary auditory cortex (A1) responses to speech sounds in background noise of different intensities and spectral compositions. Our behavioral results indicate that rats, like humans, are able to accurately discriminate consonant sounds even in the presence of background noise that is as loud as the speech signal. Our neural recordings confirm that speech sounds evoke degraded but detectable responses in noise. Finally, we developed a novel neural classifier that mimics behavioral discrimination. The classifier discriminates between speech sounds by comparing the A1 spatiotemporal activity patterns evoked on single trials with the average spatiotemporal patterns evoked by known sounds. Unlike classifiers in most previous studies, this classifier is not provided with the stimulus onset time. Neural activity analyzed with the use of relative spike timing was well correlated with behavioral speech discrimination in quiet and in noise. Spike timing information integrated over longer intervals was required to accurately predict rat behavioral speech discrimination in noisy conditions. The similarity of neural and behavioral discrimination of speech in noise suggests that humans and rats may employ similar brain mechanisms to solve this problem. PMID:22098331

  14. Bi-Directional SIFT Predicts a Subset of Activating Mutations

    PubMed Central

    Lee, William; Lazarus, Robert A.; Zhang, Zemin

    2009-01-01

    Advancements in sequencing technologies have empowered recent efforts to identify polymorphisms and mutations on a global scale. The large number of variations and mutations found in these projects requires high-throughput tools to identify those that are most likely to have an impact on function. Numerous computational tools exist for predicting which mutations are likely to be functional, but none that specifically attempt to identify mutations that result in hyperactivation or gain-of-function. Here we present a modified version of the SIFT (Sorting Intolerant from Tolerant) algorithm that utilizes protein sequence alignments with homologous sequences to identify functional mutations based on evolutionary fitness. We show that this bi-directional SIFT (B-SIFT) is capable of identifying experimentally verified activating mutants from multiple datasets. B-SIFT analysis of large-scale cancer genotyping data identified potential activating mutations, some of which we have provided detailed structural evidence to support. B-SIFT could prove to be a valuable tool for efforts in protein engineering as well as in identification of functional mutations in cancer. PMID:20011534

  15. An update on primary ovarian insufficiency.

    PubMed

    Jin, Min; Yu, YiQi; Huang, HeFeng

    2012-08-01

    Primary ovarian insufficiency (POI) occurs in about 1% of female population under the age of 40, leading to reproductive problems, an earlier encounter with menopausal symptoms, and complicated diseases. There are three presumable mechanisms involved in the development of POI, namely apoptosis acceleration, follicular maturation blocking and premature follicle activation, through the following studied causes: (i) chromosomal abnormalities or gene mutations: mostly involve X chromosome, such as FMR1 premutation; more and more potentially causal genes have been screened recently; (ii) metabolic disorders such as classic galactosaemia and 17-OH deficiency; (iii) autoimmune mediated ovarian damage: observed alone or with some certain autoimmune disorders and syndromes; but the specificity and sensitivity of antibodies towards ovary are still questionable; (iv) iatrogenic: radiotherapy or chemotherapy used in cancer treatment, as well as pelvic surgery with potential threat to ovaries' blood supply can directly damage ovarian function; (v) virus infection such as HIV and mumps; (vi) toxins and other environmental/lifestyle factors: cigarette smoking, toxins (e.g., 4-vinylcyclohexene diepoxide), and other environmental factors are associated with the development of POI. The etiology of a majority of POI cases is not identified, and is believed to be multifactorial. Strategies to POI include hormone replacement and infertility treatment. Assisted conception with donated oocytes has been proven to achieve pregnancy in POI women. Embryo cryopreservation, ovarian tissue cryopreservation and oocyte cryopreservation have been used to preserve ovarian reserve in women undergoing cancer treatments. PMID:22932883

  16. Gamma-glutamyltransferase activity in mammary gland of pregnant rats and its regulation by ovarian hormones, prolactin and placental lactogen.

    PubMed Central

    Bussmann, L E; Deis, R P

    1984-01-01

    Ovariectomy and ovariectomy plus hysterectomy on day 18 of pregnancy increased gamma-glutamyltransferase activity in the mammary gland. The withdrawal of progesterone and the subsequent release of prolactin are responsible for the rise in enzyme activity. Rat placental lactogen in the absence of prolactin and progesterone is able to induce gamma-glutamyltransferase activity. PMID:6149746

  17. Global cortical activity predicts shape of hand during grasping.

    PubMed

    Agashe, Harshavardhan A; Paek, Andrew Y; Zhang, Yuhang; Contreras-Vidal, José L

    2015-01-01

    Recent studies show that the amplitude of cortical field potentials is modulated in the time domain by grasping kinematics. However, it is unknown if these low frequency modulations persist and contain enough information to decode grasp kinematics in macro-scale activity measured at the scalp via electroencephalography (EEG). Further, it is unclear as to whether joint angle velocities or movement synergies are the optimal kinematics spaces to decode. In this offline decoding study, we infer from human EEG, hand joint angular velocities as well as synergistic trajectories as subjects perform natural reach-to-grasp movements. Decoding accuracy, measured as the correlation coefficient (r) between the predicted and actual movement kinematics, was r = 0.49 ± 0.02 across 15 hand joints. Across the first three kinematic synergies, decoding accuracies were r = 0.59 ± 0.04, 0.47 ± 0.06, and 0.32 ± 0.05. The spatial-temporal pattern of EEG channel recruitment showed early involvement of contralateral frontal-central scalp areas followed by later activation of central electrodes over primary sensorimotor cortical areas. Information content in EEG about the grasp type peaked at 250 ms after movement onset. The high decoding accuracies in this study are significant not only as evidence for time-domain modulation in macro-scale brain activity, but for the field of brain-machine interfaces as well. Our decoding strategy, which harnesses the neural "symphony" as opposed to local members of the neural ensemble (as in intracranial approaches), may provide a means of extracting information about motor intent for grasping without the need for penetrating electrodes and suggests that it may be soon possible to develop non-invasive neural interfaces for the control of prosthetic limbs. PMID:25914616

  18. Predicting Monoamine Oxidase Inhibitory Activity through Ligand-Based Models

    PubMed Central

    Vilar, Santiago; Ferino, Giulio; Quezada, Elias; Santana, Lourdes; Friedman, Carol

    2013-01-01

    The evolution of bio- and cheminformatics associated with the development of specialized software and increasing computer power has produced a great interest in theoretical in silico methods applied in drug rational design. These techniques apply the concept that “similar molecules have similar biological properties” that has been exploited in Medicinal Chemistry for years to design new molecules with desirable pharmacological profiles. Ligand-based methods are not dependent on receptor structural data and take into account two and three-dimensional molecular properties to assess similarity of new compounds in regards to the set of molecules with the biological property under study. Depending on the complexity of the calculation, there are different types of ligand-based methods, such as QSAR (Quantitative Structure-Activity Relationship) with 2D and 3D descriptors, CoMFA (Comparative Molecular Field Analysis) or pharmacophoric approaches. This work provides a description of a series of ligand-based models applied in the prediction of the inhibitory activity of monoamine oxidase (MAO) enzymes. The controlled regulation of the enzymes’ function through the use of MAO inhibitors is used as a treatment in many psychiatric and neurological disorders, such as depression, anxiety, Alzheimer’s and Parkinson’s disease. For this reason, multiple scaffolds, such as substituted coumarins, indolylmethylamine or pyridazine derivatives were synthesized and assayed toward MAO-A and MAO-B inhibition. Our intention is to focus on the description of ligand-based models to provide new insights in the relationship between the MAO inhibitory activity and the molecular structure of the different inhibitors, and further study enzyme selectivity and possible mechanisms of action. PMID:23231398

  19. Global cortical activity predicts shape of hand during grasping

    PubMed Central

    Agashe, Harshavardhan A.; Paek, Andrew Y.; Zhang, Yuhang; Contreras-Vidal, José L.

    2015-01-01

    Recent studies show that the amplitude of cortical field potentials is modulated in the time domain by grasping kinematics. However, it is unknown if these low frequency modulations persist and contain enough information to decode grasp kinematics in macro-scale activity measured at the scalp via electroencephalography (EEG). Further, it is unclear as to whether joint angle velocities or movement synergies are the optimal kinematics spaces to decode. In this offline decoding study, we infer from human EEG, hand joint angular velocities as well as synergistic trajectories as subjects perform natural reach-to-grasp movements. Decoding accuracy, measured as the correlation coefficient (r) between the predicted and actual movement kinematics, was r = 0.49 ± 0.02 across 15 hand joints. Across the first three kinematic synergies, decoding accuracies were r = 0.59 ± 0.04, 0.47 ± 0.06, and 0.32 ± 0.05. The spatial-temporal pattern of EEG channel recruitment showed early involvement of contralateral frontal-central scalp areas followed by later activation of central electrodes over primary sensorimotor cortical areas. Information content in EEG about the grasp type peaked at 250 ms after movement onset. The high decoding accuracies in this study are significant not only as evidence for time-domain modulation in macro-scale brain activity, but for the field of brain-machine interfaces as well. Our decoding strategy, which harnesses the neural “symphony” as opposed to local members of the neural ensemble (as in intracranial approaches), may provide a means of extracting information about motor intent for grasping without the need for penetrating electrodes and suggests that it may be soon possible to develop non-invasive neural interfaces for the control of prosthetic limbs. PMID:25914616

  20. R-Ketorolac Targets Cdc42 and Rac1 and Alters Ovarian Cancer Cell Behaviors Critical for Invasion and Metastasis.

    PubMed

    Guo, Yuna; Kenney, S Ray; Muller, Carolyn Y; Adams, Sarah; Rutledge, Teresa; Romero, Elsa; Murray-Krezan, Cristina; Prekeris, Rytis; Sklar, Larry A; Hudson, Laurie G; Wandinger-Ness, Angela

    2015-10-01

    Cdc42 (cell division control protein 42) and Rac1 (Ras-related C3 botulinum toxin substrate 1) are attractive therapeutic targets in ovarian cancer based on established importance in tumor cell migration, adhesion, and invasion. Despite a predicted benefit, targeting GTPases has not yet been translated to clinical practice. We previously established that Cdc42 and constitutively active Rac1b are overexpressed in primary ovarian tumor tissues. Through high-throughput screening and computational shape homology approaches, we identified R-ketorolac as a Cdc42 and Rac1 inhibitor, distinct from the anti-inflammatory, cyclooxygenase inhibitory activity of S-ketorolac. In the present study, we establish R-ketorolac as an allosteric inhibitor of Cdc42 and Rac1. Cell-based assays validate R-ketorolac activity against Cdc42 and Rac1. Studies on immortalized human ovarian adenocarcinoma cells (SKOV3ip) and primary patient-derived ovarian cancer cells show that R-ketorolac is a robust inhibitor of growth factor or serum-dependent Cdc42 and Rac1 activation with a potency and cellular efficacy similar to small-molecule inhibitors of Cdc42 (CID2950007/ML141) and Rac1 (NSC23766). Furthermore, GTPase inhibition by R-ketorolac reduces downstream p21-activated kinases (PAK1/PAK2) effector activation by >80%. Multiple assays of cell behavior using SKOV3ip and primary patient-derived ovarian cancer cells show that R-ketorolac significantly inhibits cell adhesion, migration, and invasion. In summary, we provide evidence for R-ketorolac as a direct inhibitor of Cdc42 and Rac1 that is capable of modulating downstream GTPase-dependent, physiologic responses, which are critical to tumor metastasis. Our findings demonstrate the selective inhibition of Cdc42 and Rac1 GTPases by an FDA-approved drug, racemic ketorolac, that can be used in humans. PMID:26206334

  1. Ultrasonography for early detection of ovarian carcinoma.

    PubMed

    Andolf, E; Svalenius, E; Astedt, B

    1986-12-01

    Ultrasound scan for detection of ovarian enlargements was performed in a target group of out-patients attending the clinic for various reasons in the 40-70 years range. Overall 805 women were examined, in 99% of whom the ovaries and/or their vessels could be identified. Pathological findings were suspected in 83 patients at the first scan, and were confirmed in 50 after a repeat scan, 39 of whom subsequently underwent surgery. Various ovarian lesions were found in 35 women, including five mucinous and serous cystadenomas, one carcinoma, two borderline tumours, and a cancer of the caecum. None of the borderline or malignant ovarian lesions were found by manual pelvic examination. Ultrasound screening appears to be a useful diagnostic aid, though its usefulness might be further improved if other risk factors such as heredity and period of ovulatory activity are taken into consideration. PMID:3542015

  2. Recent and Past Musical Activity Predicts Cognitive Aging Variability: Direct Comparison with General Lifestyle Activities

    PubMed Central

    Hanna-Pladdy, Brenda; Gajewski, Byron

    2012-01-01

    Studies evaluating the impact of modifiable lifestyle factors on cognition offer potential insights into sources of cognitive aging variability. Recently, we reported an association between extent of musical instrumental practice throughout the life span (greater than 10 years) on preserved cognitive functioning in advanced age. These findings raise the question of whether there are training-induced brain changes in musicians that can transfer to non-musical cognitive abilities to allow for compensation of age-related cognitive declines. However, because of the relationship between engagement in general lifestyle activities and preserved cognition, it remains unclear whether these findings are specifically driven by musical training or the types of individuals likely to engage in greater activities in general. The current study controlled for general activity level in evaluating cognition between musicians and nomusicians. Also, the timing of engagement (age of acquisition, past versus recent) was assessed in predictive models of successful cognitive aging. Seventy age and education matched older musicians (>10 years) and non-musicians (ages 59–80) were evaluated on neuropsychological tests and general lifestyle activities. Musicians scored higher on tests of phonemic fluency, verbal working memory, verbal immediate recall, visuospatial judgment, and motor dexterity, but did not differ in other general leisure activities. Partition analyses were conducted on significant cognitive measures to determine aspects of musical training predictive of enhanced cognition. The first partition analysis revealed education best predicted visuospatial functions in musicians, followed by recent musical engagement which offset low education. In the second partition analysis, early age of musical acquisition (<9 years) predicted enhanced verbal working memory in musicians, while analyses for other measures were not predictive. Recent and past musical activity, but not

  3. Is androgen production in association with immune system activation potential evidence for existence of a functional adrenal/ovarian autoimmune system in women?

    PubMed Central

    2013-01-01

    Background Low functional ovarian reserve (FOR) is at all ages associated with low testosterone (T) levels. Causes are, however, unknown. We, therefore, investigate whether androgens with low FOR are associated with non-specific immune system activation. Methods 322 infertile women with low and normal FOR (controls) were assessed with a broadly based immune profile, which in previous studies has proven effective in differentiating infertile patients with and without immune system activation. Patients were either immune-positive (greater than or equal to one positive tested parameter) or immune negative (no positive test). 135 suffered from prematurely diminished FOR (POA/OPOI; < age 38), 155 from physiologic diminished FOR due to age (DOR; > age 40), and 32 were controls (< age 38 with normal age-specific FOR). Prevalence of immune-positive vs. negative was assessed in all 3 patient groups. Results Women with immune abnormalities, overall, demonstrated higher total T (TT, P = 0.004) and free T (FT, P < 0.001) levels than those without. The three clinical and two immunologic-defined patient groups demonstrated significant statistical interaction in mean TT (P = 0.008), with mean TT and FT in women with positive immune findings being significantly higher in control than in POA/OPOI and physiologic DOR patients (all 4 differences P < 0.001). No such differences between the three groups were seen in women without immune abnormalities. Conclusions In this study we used a definition of immune-positivity, which favors sensitivity over specificity, resulting in significant numbers of false-positives but likely only few false-negatives. The study allows suggesting the possibility of an immune system-derived androgen-production factor (APF), which maintains normal androgen levels but is deficient in women with low FOR and immune system inactivity. Existence of such an APF would suggest the presence of a still unknown functional adrenal autoimmune system

  4. Administered activity and metastatic cure probability during radioimmunotherapy of ovarian cancer in nude mice with {sup 211}At-MX35 F(ab'){sub 2}

    SciTech Connect

    Elgqvist, Joergen . E-mail: jorgen.elgqvist@radfys.gu.se; Andersson, Hakan; Bernhardt, Peter; Baeck, Tom; Claesson, Ingela; Hultborn, Ragnar; Jensen, Holger; Johansson, Bengt R.; Lindegren, Sture; Olsson, Marita; Palm, Stig; Warnhammar, Elisabet; Jacobsson, Lars

    2006-11-15

    Purpose: To elucidate the therapeutic efficacy of {alpha}-radioimmunotherapy of ovarian cancer in mice. This study: (i) estimated the minimum required activity (MRA), giving a reasonable high therapeutic efficacy; and (ii) calculated the specific energy to tumor cell nuclei and the metastatic cure probability (MCP) using various assumptions regarding monoclonal-antibody (mAb) distribution in measured tumors. The study was performed using the {alpha}-particle emitter Astatine-211 ({sup 211}At) labeled to the mAb MX35 F(ab'){sub 2}. Methods and Materials: Animals were inoculated intraperitoneally with {approx}1 x 10{sup 7} cells of the cell line NIH:OVCAR-3. Four weeks later animals were treated with 25, 50, 100, or 200 kBq {sup 211}At-MX35 F(ab'){sub 2} (n = 74). Another group of animals was treated with a nonspecific mAb: 100 kBq {sup 211}At-Rituximab F(ab'){sub 2} (n = 18). Eight weeks after treatment the animals were sacrificed and presence of macro- and microscopic tumors and ascites was determined. An MCP model was developed and compared with the experimentally determined tumor-free fraction (TFF). Results: When treatment was given 4 weeks after cell inoculation, the TFFs were 25%, 22%, 50%, and 61% after treatment with 25, 50, 100, or 200 kBq {sup 211}At-MX35 F(ab'){sub 2}, respectively, the specific energy to irradiated cell nuclei varying between {approx}2 and {approx}400 Gy. Conclusion: As a significant increase in the therapeutic efficacy was observed between the activity levels of 50 and 100 kBq (TFF increase from 22% to 50%), the conclusion was that the MRA is {approx}100 kBq {sup 211}At-MX35 F(ab'){sub 2}. MCP was most consistent with the TFF when assuming a diffusion depth of 30 {mu}m of the mAbs in the tumors.

  5. Subgenual cingulate cortical activity predicts the efficacy of electroconvulsive therapy.

    PubMed

    Argyelan, M; Lencz, T; Kaliora, S; Sarpal, D K; Weissman, N; Kingsley, P B; Malhotra, A K; Petrides, G

    2016-01-01

    Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its mechanism of action is unknown. Our goal was to investigate the neurobiological underpinnings of ECT response using longitudinally collected resting-state functional magnetic resonance imaging (rs-fMRI) in 16 patients with treatment-resistant depression and 10 healthy controls. Patients received bifrontal ECT 3 times a week under general anesthesia. We acquired rs-fMRI at three time points: at baseline, after the 1st ECT administration and after the course of the ECT treatment; depression was assessed with the Hamilton Depression Rating Scale (HAM-D). The primary measure derived from rs-fMRI was fractional amplitude of low frequency fluctuation (fALFF), which provides an unbiased voxel-wise estimation of brain activity. We also conducted seed-based functional connectivity analysis based on our primary findings. We compared treatment-related changes in HAM-D scores with pre- and post-treatment fALFF and connectivity measures. Subcallosal cingulate cortex (SCC) demonstrated higher BOLD signal fluctuations (fALFF) at baseline in depressed patients, and SCC fALFF decreased over the course of treatment. The baseline level of fALFF of SCC predicted response to ECT. In addition, connectivity of SCC with bilateral hippocampus, bilateral temporal pole, and ventromedial prefrontal cortex was significantly reduced over the course of treatment. These results suggest that the antidepressant effect of ECT may be mediated by downregulation of SCC activity and connectivity. SCC function may serve as an important biomarker of target engagement in the development of novel therapies for depression that is resistant to treatment with standard medications. PMID:27115120

  6. Subgenual cingulate cortical activity predicts the efficacy of electroconvulsive therapy

    PubMed Central

    Argyelan, M; Lencz, T; Kaliora, S; Sarpal, D K; Weissman, N; Kingsley, P B; Malhotra, A K; Petrides, G

    2016-01-01

    Electroconvulsive therapy (ECT) is the most effective treatment for depression, yet its mechanism of action is unknown. Our goal was to investigate the neurobiological underpinnings of ECT response using longitudinally collected resting-state functional magnetic resonance imaging (rs-fMRI) in 16 patients with treatment-resistant depression and 10 healthy controls. Patients received bifrontal ECT 3 times a week under general anesthesia. We acquired rs-fMRI at three time points: at baseline, after the 1st ECT administration and after the course of the ECT treatment; depression was assessed with the Hamilton Depression Rating Scale (HAM-D). The primary measure derived from rs-fMRI was fractional amplitude of low frequency fluctuation (fALFF), which provides an unbiased voxel-wise estimation of brain activity. We also conducted seed-based functional connectivity analysis based on our primary findings. We compared treatment-related changes in HAM-D scores with pre- and post-treatment fALFF and connectivity measures. Subcallosal cingulate cortex (SCC) demonstrated higher BOLD signal fluctuations (fALFF) at baseline in depressed patients, and SCC fALFF decreased over the course of treatment. The baseline level of fALFF of SCC predicted response to ECT. In addition, connectivity of SCC with bilateral hippocampus, bilateral temporal pole, and ventromedial prefrontal cortex was significantly reduced over the course of treatment. These results suggest that the antidepressant effect of ECT may be mediated by downregulation of SCC activity and connectivity. SCC function may serve as an important biomarker of target engagement in the development of novel therapies for depression that is resistant to treatment with standard medications. PMID:27115120

  7. Predicting Water Activity for Complex Wastes with Solvation Cluster Equilibria (SCE) - 12042

    SciTech Connect

    Agnew, S.F.; Reynolds, J.G.; Johnston, C.T.

    2012-07-01

    Predicting an electrolyte mixture's water activity, i.e. the ratio of water vapor pressure over a solution with that of pure water, in principle reveals both boiling point and solubilities for that mixture. Better predictions of these properties helps support the ongoing missions to concentrate complex nuclear waste mixtures in order to conserve tank space and improved predictions of water activity will help. A new approach for predicting water activity, the solvation cluster equilibria (SCE) model, uses pure electrolyte water activities to predict water activity for a complex mixture of those electrolytes. An SCE function based on electrolyte hydration free energy and a standard Debye- Hueckel (DH) charge compression fits each pure electrolyte's water activity with three parameters. Given these pure electrolyte water activities, the SCE predicts any mixture water activity over a large range of concentration with an additional parameter for each mixture vector, the multinarity. In contrast to ionic strength, which scales with concentration, multinarity is related to the relative proportion of electrolytes in a mixture and can either increase or decrease the water activity prediction over a broad range of concentration for that mixture. The SCE model predicts water activity for complex electrolyte mixtures based on the water activities of pure electrolytes. Three parameter SCE functions fit the water activities of pure electrolytes and along with a single multinarity parameter for each mixture vector then predict the mixture water activity. Predictions of water activity can in principle predict solution electrolyte activity and this relationship will be explored in the future. Predicting electrolyte activities for complex mixtures provides a means of determining solubilities for each electrolyte. Although there are a number of reports [9, 10, 11] of water activity models for pure and binary mixtures of electrolytes, none of them compare measured versus calculated

  8. Predictive active disturbance rejection control for processes with time delay.

    PubMed

    Zheng, Qinling; Gao, Zhiqiang

    2014-07-01

    Active disturbance rejection control (ADRC) has been shown to be an effective tool in dealing with real world problems of dynamic uncertainties, disturbances, nonlinearities, etc. This paper addresses its existing limitations with plants that have a large transport delay. In particular, to overcome the delay, the extended state observer (ESO) in ADRC is modified to form a predictive ADRC, leading to significant improvements in the transient response and stability characteristics, as shown in extensive simulation studies and hardware-in-the-loop tests, as well as in the frequency response analysis. In this research, it is assumed that the amount of delay is approximately known, as is the approximated model of the plant. Even with such uncharacteristic assumptions for ADRC, the proposed method still exhibits significant improvements in both performance and robustness over the existing methods such as the dead-time compensator based on disturbance observer and the Filtered Smith Predictor, in the context of some well-known problems of chemical reactor and boiler control problems. PMID:24182516

  9. Traction force dynamics predict gap formation in activated endothelium.

    PubMed

    Valent, Erik T; van Nieuw Amerongen, Geerten P; van Hinsbergh, Victor W M; Hordijk, Peter L

    2016-09-10

    In many pathological conditions the endothelium becomes activated and dysfunctional, resulting in hyperpermeability and plasma leakage. No specific therapies are available yet to control endothelial barrier function, which is regulated by inter-endothelial junctions and the generation of acto-myosin-based contractile forces in the context of cell-cell and cell-matrix interactions. However, the spatiotemporal distribution and stimulus-induced reorganization of these integral forces remain largely unknown. Traction force microscopy of human endothelial monolayers was used to visualize contractile forces in resting cells and during thrombin-induced hyperpermeability. Simultaneously, information about endothelial monolayer integrity, adherens junctions and cytoskeletal proteins (F-actin) were captured. This revealed a heterogeneous distribution of traction forces, with nuclear areas showing lower and cell-cell junctions higher traction forces than the whole-monolayer average. Moreover, junctional forces were asymmetrically distributed among neighboring cells. Force vector orientation analysis showed a good correlation with the alignment of F-actin and revealed contractile forces in newly formed filopodia and lamellipodia-like protrusions within the monolayer. Finally, unstable areas, showing high force fluctuations within the monolayer were prone to form inter-endothelial gaps upon stimulation with thrombin. To conclude, contractile traction forces are heterogeneously distributed within endothelial monolayers and force instability, rather than force magnitude, predicts the stimulus-induced formation of intercellular gaps. PMID:27498166

  10. Predicting Activation of Experiments Inside the Annular Core Research Reactor

    SciTech Connect

    Greenberg, Joseph Isaac

    2015-11-01

    The objective of this thesis is to create a program to quickly estimate the radioactivity and decay of experiments conducted inside of the Annular Core Research Reactor at Sandia National Laboratories and eliminate the need for users to write code. This is achieved by model the neutron fluxes in the reactor’s central cavity where experiments are conducted for 4 different neutron spectra using MCNP. The desired neutron spectrum, experiment material composition, and reactor power level are then input into CINDER2008 burnup code to obtain activation and decay information for every isotope generated. DREAD creates all of the files required for CINDER2008 through user selected inputs in a graphical user interface and executes the program for the user and displays the resulting estimation for dose rate at various distances. The DREAD program was validated by weighing and measuring various experiments in the different spectra and then collecting dose rate information after they were irradiated and comparing it to the dose rates that DREAD predicted. The program provides results with an average of 17% higher estimates than the actual values and takes seconds to execute.

  11. Why have ovarian cancer mortality rates declined? Part I. Incidence.

    PubMed

    Sopik, Victoria; Iqbal, Javaid; Rosen, Barry; Narod, Steven A

    2015-09-01

    The age-adjusted mortality rate from ovarian cancer in the United States has declined over the past several decades. The decline in mortality might be the consequence of a reduced number of cases (incidence) or a reduction in the proportion of patients who die from their cancer (case-fatality). In part I of this three-part series, we examine rates of ovarian cancer incidence and mortality from the Surveillance Epidemiology and End Results (SEER) registry database and we explore to what extent the observed decline in mortality can be explained by a downward shift in the stage distribution of ovarian cancer (i.e. due to early detection) or by fewer cases of ovarian cancer (i.e. due to a change in risk factors). The proportion of localized ovarian cancers did not increase, suggesting that a stage-shift did not contribute to the decline in mortality. The observed decline in mortality paralleled a decline in incidence. The trends in ovarian cancer incidence coincided with temporal changes in the exposure of women from different birth cohorts to various reproductive risk factors, in particular, to changes in the use of the oral contraceptive pill and to declining parity. Based on recent changes in risk factor propensity, we predict that the trend of the declining age-adjusted incidence rate of ovarian cancer in the United States will reverse and rates will increase in coming years. PMID:26080287

  12. Luteinizing Hormone Causes Phosphorylation and Activation of the cGMP Phosphodiesterase PDE5 in Rat Ovarian Follicles, Contributing, Together with PDE1 Activity, to the Resumption of Meiosis.

    PubMed

    Egbert, Jeremy R; Uliasz, Tracy F; Shuhaibar, Leia C; Geerts, Andreas; Wunder, Frank; Kleiman, Robin J; Humphrey, John M; Lampe, Paul D; Artemyev, Nikolai O; Rybalkin, Sergei D; Beavo, Joseph A; Movsesian, Matthew A; Jaffe, Laurinda A

    2016-05-01

    The meiotic cell cycle of mammalian oocytes in preovulatory follicles is held in prophase arrest by diffusion of cGMP from the surrounding granulosa cells into the oocyte. Luteinizing hormone (LH) then releases meiotic arrest by lowering cGMP in the granulosa cells. The LH-induced reduction of cGMP is caused in part by a decrease in guanylyl cyclase activity, but the observation that the cGMP phosphodiesterase PDE5 is phosphorylated during LH signaling suggests that an increase in PDE5 activity could also contribute. To investigate this idea, we measured cGMP-hydrolytic activity in rat ovarian follicles. Basal activity was due primarily to PDE1A and PDE5, and LH increased PDE5 activity. The increase in PDE5 activity was accompanied by phosphorylation of PDE5 at serine 92, a protein kinase A/G consensus site. Both the phosphorylation and the increase in activity were promoted by elevating cAMP and opposed by inhibiting protein kinase A, supporting the hypothesis that LH activates PDE5 by stimulating its phosphorylation by protein kinase A. Inhibition of PDE5 activity partially suppressed LH-induced meiotic resumption as indicated by nuclear envelope breakdown, but inhibition of both PDE5 and PDE1 activities was needed to completely inhibit this response. These results show that activities of both PDE5 and PDE1 contribute to the LH-induced resumption of meiosis in rat oocytes, and that phosphorylation and activation of PDE5 is a regulatory mechanism. PMID:27009040

  13. Up-regulation of DNAM-1 and NKp30, associated with improvement of NK cells activation after long-term culture of mononuclear cells from patients with ovarian neoplasia.

    PubMed

    da Silva, Rodrigo Fernandes; Petta, Carlos Alberto; Derchain, Sophie Françoise; Alici, Evren; Guimarães, Fernando

    2014-08-01

    This study aimed at evaluating the functional activation and activating receptors expression on resting, short- and long-term NK and NK-like T cells from blood of ovarian neoplasia patients. Blood from patients with adnexal benign alterations (n = 10) and ovarian cancer (grade I-IV n = 14) were collected after signed consent. Effector cells activation was evaluated by the expression of the CD107a molecule. Short-term culture was conducted overnight with IL-2 and long-term culture for 21 days, by a method designed to expand CD56(+) lymphocytes. Short-term culture significantly increased NK cells activation compared to resting NK cells (p<0.05), however, the long-term procedure supported an even higher increase (p<0.001). Resting NK-like T cells showed poor activation, which was not altered by the culture procedures. The long-term culture effectively increased the expression of the activating receptors on NK and NK-like T cells, either by increasing the number of cells expressing a given receptor and/or by up-regulating their expression intensity. As a conclusion, the long-term culture system employed, resulted in a high number of functional NK cells. The culture system was particularly efficient on the up-regulation of NKp30 and DNAM-1 receptors on NK cells. PMID:24882570

  14. Circulating concentrations of leptin, ovarian follicle number, and oocyte lipid content and active mitochondria, in Zebu crossbred cows maintained on standard or improved nutrition.

    PubMed

    Castaneda, C A; Kaye, P; Pantaleon, M; Phillips, N; Fry, R; D'Occhio, M J

    2013-07-01

    Zebu (Bos indicus) crossbred beef cows (Droughtmaster) were maintained long-term (16 months) on standard nutrition (SN) or improved nutrition (IN). Cows on IN had better body condition and greater (P<0.05) circulating concentrations of leptin than cows on SN (0.7±0.1n/ml and 1.7±0.1n/ml, respectively). There were no outstanding differences between SN and IN cows in basal number of ovarian follicles (≤4mm, 5-8mm, and ≥9mm) and there were also no differences in number of oocytes recovered by oocyte pick-up. Cows on IN had a greater (P<0.05) number of total follicles after stimulation with FSH than cows on SN. Oocytes from cows on IN had greater (P<0.05) lipid content than cows on SN (-0.23±0.16 and 0.20±0.18 arbitrary units, respectively) and oocytes of the former cows also tended to have more active mitochondria, although this was not significant. Cows on IN showed a positive relationship (R(2)=0.31, P<0.05) between plasma leptin and oocyte lipid content. Lipids are utilized by oocytes during high energy consumptive processes including fertilization and early cleavage. The greater lipid content of oocytes from IN cows could therefore confer a reproductive advantage. The present study has shown relationships between nutrition, body condition, circulating leptin, and oocyte lipid content, but a clear cause-and-effect requires further investigation in the cow. PMID:23735657

  15. Effect of pre-partum feed supplementation on post-partum ovarian activity, milk production and calf growth of small holder dairy Cattle in Cameroon.

    PubMed

    Bayemi, Pougue Henri; Nsongka, Munji Victorine; Leinyuy, Isabelle; Webb, Edward Cottington; Nchadji, Justin Mbanya; Cavestany, Daniel; Bryant, Mike

    2015-01-01

    Seventy-two cows were selected for an on-farm study on the effect of feed supplementation before calving on milk production, ovarian activity and calf growth of Holstein, indigenous Red Fulani cows and their crosses. Pre-partum feed supplementation was done using cotton seed cake (80%), maize (18%), bone meal (1%) and kitchen salt (1% NaCl). Supplementation levels consisted of a low supplementation fed at 1 kg per animal per day and high supplementation fed at 2 kg per animal per day. In addition, Red Fulani cows received the supplements in two different ways namely a pre-partum supplementation consisting of 1 kg per cow per day and pre- and post-partum supplementation consisting of 1 kg per cow per day before calving and 1 kg per cow per day post-partum up to 30 days after calving. Blood samples were analysed using ELISA Progesterone kits to determine the length of post-partum anoestrus. Results show that pre-partum levels of feeding did not have any effect (P > 0.05) on body condition score (BCS) at 12 weeks after calving, calf birth weight, average daily weight gain of calves, milk production and post-partum anoestrus. High BCS at calving was shown to influence BCS at 12 weeks of lactation. Holstein cows had bigger calves (P < 0.01) at birth (45 kg) compared to traditional cows (36 kg) and crosses (34 kg). There was little benefit of pre-partum supplementation on the parameters investigated in this study. Consequently, low income farmers are advised to concentrate their efforts of supplementation early in lactation. PMID:25339431

  16. MicroRNA Expression and Regulation in Human Ovarian Carcinoma Cells by Luteinizing Hormone

    PubMed Central

    Cui, Juan; Eldredge, Joanna B.; Xu, Ying; Puett, David

    2011-01-01

    Background MicroRNAs have been widely-studied with regard to their aberrant expression and high correlation with tumorigenesis and progression in various solid tumors. With the major goal of assessing gonadotropin (luteinizing hormone, LH) contributions to LH receptor (LHR)-positive ovarian cancer cells, we have conducted a genome-wide transcriptomic analysis on human epithelial ovarian cancer cells to identify the microRNA-associated cellular response to LH-mediated activation of LHR. Methods Human ovarian cancer cells (SKOV3) were chosen as negative control (LHR−) and stably transfected to express functional LHR (LHR+), followed by incubation with LH (0–20 h). At different times of LH-mediated activation of LHR the cancer cells were analyzed by a high-density Ovarian Cancer Disease-Specific-Array (DSA, ALMAC™), which profiled ∼100,000 transcripts with ∼400 non-coding microRNAs. Findings In total, 65 microRNAs were identified to exhibit differential expression in either LHR expressing SKOV3 cells or LH-treated cells, a few of which have been found in the genomic fragile regions that are associated with abnormal deletion or amplification in cancer, such as miR-21, miR-101-1, miR-210 and miR-301a. By incorporating the dramatic expression changes observed in mRNAs, strong microRNA/mRNA regulatory pairs were predicted through statistical analyses coupled with collective computational prediction. The role of each microRNA was then determined through a functional analysis based on the highly-confident microRNA/mRNA pairs. Conclusion The overall impact on the transcriptome-level expression indicates that LH may regulate apoptosis and cell growth of LHR+ SKOV3 cells, particularly by reducing cancer cell proliferation, with some microRNAs involved in regulatory roles. PMID:21765906

  17. MicroRNAs in Ovarian Cancer.

    PubMed

    Katz, Betina; Tropé, Claes G; Reich, Reuven; Davidson, Ben

    2015-09-01

    Ovarian cancer, consisting predominantly of ovarian carcinoma, is the eighth most common cancer in women and the most lethal gynecologic malignancy. Efforts focus on identifying biomarkers which may aid in early diagnosis and reduce mortality, as well as on characterizing therapeutic targets with the aim of circumventing chemoresistance and prolonging survival at advanced-stage disease. MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression, and have been found to play an important role in ovarian carcinoma. Recent research has identified multiple miRNAs involved in the biology and progression of the disease, and supports a role for miRNAs as potential biomarkers, predictive markers and prognostic factors. Many of the studies published to date nevertheless suffer from critical weaknesses which affect data quality and reproducibility, including the comparison of normal ovaries to tumor tissue without compensation for the highly discrepant target cell fraction in these two specimen types and the inclusion of carcinomas of different histotypes, non-epithelial tumors or tumors of non-specified histology. These shortcomings highlight the critical role of pathologists as part of the team in the setting of such research. This review summarizes current knowledge in this area and discusses the potential clinical relevance of miRNAs in ovarian carcinoma, with focus on studies of clinical specimens in which tissue selection has been deemed adequate. PMID:26216350

  18. Methoxychlor induces atresia by altering Bcl2 factors and inducing caspase activity in mouse ovarian antral follicles in vitro

    PubMed Central

    Basavarajappa, Mallikarjuna S.; Karman, Bethany N.; Wang, Wei; Gupta, Rupesh K.; Flaws, Jodi A.

    2012-01-01

    Methoxychlor (MXC) is an organochlorine pesticide widely used in many countries against various species of insects that attack crops and domestic animals. MXC reduces fertility by increasing atresia (death) of antral follicles in vivo. MXC also induces atresia of antral follicles after 96 h in vitro. The current work tested the hypothesis that MXC induces morphological atresia at early time points (24 and 48 h) by altering pro-apoptotic (Bax, Bok, Casp3, and caspase activity) and anti-apoptotic (Bcl2 and Bcl-xL) factors in the follicles. The results indicate that at 24 h, MXC increased Bcl-xL and Bax mRNA levels and increased the ratio of Bax/Bcl2. At 48–96 h, MXC induced morphological atresia. At 24–96 h, MXC increased caspase activities. These data suggest that MXC may induce atresia by altering Bcl2 factors and inducing caspase activities in antral follicles. PMID:23000595

  19. STRUCTURE-ACTIVITY RELATIONSHIP STUIDES AND THEIR ROLE IN PREDICTING AND INVESTIGATING CHEMICAL TOXICITY

    EPA Science Inventory

    Structure-Activity Relationship Studies and their Role in Predicting and Investigating Chemical Toxicity

    Structure-activity relationships (SAR) represent attempts to generalize chemical information relative to biological activity for the twin purposes of generating insigh...

  20. CONSIDERATION OF REACTION INTERMEDIATES IN STRUCTURE-ACTIVITY RELATIONSHIPS: A KEY TO UNDERSTANDING AND PREDICTION

    EPA Science Inventory

    Consideration of Reaction Intermediates in Structure- Activity Relationships: A Key to Understanding and Prediction

    A structure-activity relationship (SAR) represents an empirical means for generalizing chemical information relative to biological activity, and is frequent...

  1. Predicting the unpredictable: critical analysis and practical implications of predictive anticipatory activity

    PubMed Central

    Mossbridge, Julia A.; Tressoldi, Patrizio; Utts, Jessica; Ives, John A.; Radin, Dean; Jonas, Wayne B.

    2014-01-01

    A recent meta-analysis of experiments from seven independent laboratories (n = 26) indicates that the human body can apparently detect randomly delivered stimuli occurring 1–10 s in the future (Mossbridge etal., 2012). The key observation in these studies is that human physiology appears to be able to distinguish between unpredictable dichotomous future stimuli, such as emotional vs. neutral images or sound vs. silence. This phenomenon has been called presentiment (as in “feeling the future”). In this paper we call it predictive anticipatory activity (PAA). The phenomenon is “predictive” because it can distinguish between upcoming stimuli; it is “anticipatory” because the physiological changes occur before a future event; and it is an “activity” because it involves changes in the cardiopulmonary, skin, and/or nervous systems. PAA is an unconscious phenomenon that seems to be a time-reversed reflection of the usual physiological response to a stimulus. It appears to resemble precognition (consciously knowing something is going to happen before it does), but PAA specifically refers to unconscious physiological reactions as opposed to conscious premonitions. Though it is possible that PAA underlies the conscious experience of precognition, experiments testing this idea have not produced clear results. The first part of this paper reviews the evidence for PAA and examines the two most difficult challenges for obtaining valid evidence for it: expectation bias and multiple analyses. The second part speculates on possible mechanisms and the theoretical implications of PAA for understanding physiology and consciousness. The third part examines potential practical applications. PMID:24723870

  2. Ovarian vein thrombosis

    PubMed Central

    Jenayah, Amel Achour; Saoudi, Sarra; Boudaya, Fethia; Bouriel, Ines; Sfar, Ezzeddine; Chelli, Dalenda

    2015-01-01

    Ovarian vein thrombosis (OVT) is a rare cause of abdominal pain that may mimic a surgical abdomen. It is most often diagnosed during the postpartum period. In this report, we present four cases of postoperative ovarian vein thrombosis. The complications of OVT can be significant, and the diagnosis relies on a careful examination of the radiographic findings. It can occur with lower quadrant abdominal pain, especially in the setting of recent pregnancy, abdominal surgery, pelvic inflammatory disease, or malignancy. Diagnosis can be made with confidence using ultrasound, computed tomography or magnetic resonance imaging. Treatment of ovarian vein thrombosis is particularly important in the post-partum patients, with anticoagulation therapy being the current recommendation. PMID:26526119

  3. Immunotherapy in ovarian cancer

    PubMed Central

    Mantia-Smaldone, Gina M.; Corr, Bradley; Chu, Christina S.

    2012-01-01

    Ovarian cancer is the most deadly gynecologic malignancy, with more than 15,000 deaths anticipated in 2012.1 While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years.1,2 Host anti-tumor immune responses are associated with a significant improvement in overall survival for women with ovarian cancer.3,4 By bolstering these responses, it may therefore be possible to significantly influence the prognosis of women with this lethal disease. In this review, we will focus on innovative immune-based strategies which are currently being investigated in the treatment of ovarian cancer. PMID:22906947

  4. Blood cell mitochondrial DNA content and premature ovarian aging.

    PubMed

    Bonomi, Marco; Somigliana, Edgardo; Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  5. Blood Cell Mitochondrial DNA Content and Premature Ovarian Aging

    PubMed Central

    Cacciatore, Chiara; Busnelli, Marta; Rossetti, Raffaella; Bonetti, Silvia; Paffoni, Alessio; Mari, Daniela; Ragni, Guido; Persani, Luca; Arosio, M.; Beck-Peccoz, P.; Biondi, M.; Bione, S.; Bruni, V.; Brigante, C.; Cannavo`, S.; Cavallo, L.; Cisternino, M.; Colombo, I.; Corbetta, S.; Crosignani, P.G.; D'Avanzo, M.G.; Dalpra, L.; Danesino, C.; Di Battista, E.; Di Prospero, F.; Donti, E.; Einaudi, S.; Falorni, A.; Foresta, C.; Fusi, F.; Garofalo, N.; Giotti, I.; Lanzi, R.; Larizza, D.; Locatelli, N.; Loli, P.; Madaschi, S.; Maghnie, M.; Maiore, S.; Mantero, F.; Marozzi, A.; Marzotti, S.; Migone, N.; Nappi, R.; Palli, D.; Patricelli, M.G.; Pisani, C.; Prontera, P.; Petraglia, F.; Radetti, G.; Renieri, A.; Ricca, I.; Ripamonti, A.; Rossetti, R.; Russo, G.; Russo, S.; Tonacchera, M.; Toniolo, D.; Torricelli, F.; Vegetti, W.; Villa, N.; Vineis, P.; Wasniewsk, M.; Zuffardi, O.

    2012-01-01

    Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase γ (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. PMID:22879975

  6. Can vesicle size distributions predict eruption intensity during volcanic activity?

    NASA Astrophysics Data System (ADS)

    LaRue, A.; Baker, D. R.; Polacci, M.; Allard, P.; Sodini, N.

    2013-06-01

    We studied three-dimensional (3-D) vesicle size distributions by X-ray microtomography in scoria collected during the relatively quiescent Phase II of the 2010 eruption at Eyjafjallajökull volcano, Iceland. Our goal was to compare the vesicle size distributions (VSDs) measured in these samples with those found in Stromboli volcano, Italy. Stromboli was chosen because its VSDs are well-characterized and show a correlation with eruption intensity: typical Strombolian activity produces VSDs with power-law exponents near 1, whereas larger and more energetic Vulcanian-type explosions and Plinian eruptions produce VSDs with power-law exponents near 1.5. The hypothesis to be tested was whether or not the samples studied in this work would contain VSDs similar to normal Strombolian products, display higher power-law exponents, or be described by exponential functions. Before making this comparison we tested the hypothesis that the phreatomagmatic nature of the Eyjafjallajökull eruption might have a significant effect on the VSDs. We performed 1 atm bubble-growth experiments in which the samples were inundated with water and compared them to similar, control, experiments without water inundation. No significant differences between the VSDs of the two sets of experiments were found, and the hypothesis is not supported by the experimental evidence; therefore, VSDs of magmatic and phreatomagmatic eruptions can be directly compared. The Phase II Eyjafjallajökull VSDs are described by power law exponents of ~ 0.8, typical of normal Strombolian eruptions. The comparable VSDs and behavior of Phase II of the Eyjafjallajökull 2010 eruption to Stromboli are interpreted to be a reflection of similar conduit systems in both volcanoes that are being constantly fed by the ascent of deep magma that mixes with resident magma at shallow depths. Such behavior implies that continued activity during Phase II of the Eyjafjallajökull eruption could be expected and would have been predicted

  7. Synergistic effects of Pten loss and WNT/CTNNB1 signaling pathway activation in ovarian granulosa cell tumor development and progression

    PubMed Central

    Laguë, Marie-Noëlle; Paquet, Marilène; Fan, Heng-Yu; Kaartinen, M. Johanna; Chu, Simon; Jamin, Soazik P.; Behringer, Richard R.; Fuller, Peter J.; Mitchell, Andrew; Doré, Monique; Huneault, Louis M.; Richards, JoAnne S.; Boerboom, Derek

    2008-01-01

    The mechanisms of granulosa cell tumor (GCT) development may involve the dysregulation of signaling pathways downstream of follicle-stimulating hormone, including the phosphoinosite-3 kinase (PI3K)/AKT pathway. To test this hypothesis, a genetically engineered mouse model was created to derepress the PI3K/AKT pathway in granulosa cells by conditional targeting of the PI3K antagonist gene Pten (Ptenflox/flox;Amhr2cre/+). The majority of Ptenflox/flox;Amhr2cre/+ mice featured no ovarian anomalies, but occasionally (∼7%) developed aggressive, anaplastic GCT with pulmonary metastases. The expression of the PI3K/AKT downstream effector FOXO1 was abrogated in Ptenflox/flox;Amhr2cre/+ GCT, indicating a mechanism by which GCT cells may increase proliferation and evade apoptosis. To relate these findings to spontaneously occurring GCT, analyses of PTEN and phospho-AKT expression were performed on human and equine tumors. Although PTEN loss was not detected, many GCT (2/5 human, 7/17 equine) featured abnormal nuclear or perinuclear localization of phospho-AKT, suggestive of altered PI3K/AKT activity. As inappropriate activation of WNT/CTNNB1 signaling causes late-onset GCT development and cross talk between the PI3K/AKT and WNT/CTNNB1 pathways has been reported, we tested whether these pathways could synergize in GCT. Activation of both the PI3K/AKT and WNT/CTNNB1 pathways in the granulosa cells of a mouse model (Ptenflox/flox;Ctnnb1flox(ex3)/+;Amhr2cre/+) resulted in the development of GCT similar to those observed in Ptenflox/flox;Amhr2cre/+ mice, but with 100% penetrance, perinatal onset, extremely rapid growth and the ability to spread by seeding into the abdominal cavity. These data indicate a synergistic effect of dysregulated PI3K/AKT and WNT/CTNNB1 signaling in the development and progression of GCT and provide the first animal models for metastatic GCT. PMID:18687666

  8. Retropancreatic Ovarian Tumor.

    PubMed

    Acharya, Soumyo Ranjan; Dasgupta, Prosenjit; Das, Subhobroto; Halder, Sandip; Panda, Nilanjan

    2016-06-01

    Retroperitoneal mucinous cystadenomas are rare lesions (less than 50 reported) characterized by presence of ovary like stroma of unknown origin. However, germinal component of ovary has never been found in them. The pancreas occasionally gives rise to mucinous cystadenomas, but they are always intrapancreatic. We report a unique case of a rare retroperitoneal mucinous cystadenomas with presence of ovarian follicles in a 45-year-old lady who presented with an abdominal mass. This was successfully excised. Though retroperitoneal mucinous cystadenomas are rare, presence of ovarian follicle (germ cell) in them has never been reported before. PMID:27358520

  9. MicroRNA signatures characterizing caste-independent ovarian activity in queen and worker honeybees (Apis mellifera L.).

    PubMed

    Macedo, L M F; Nunes, F M F; Freitas, F C P; Pires, C V; Tanaka, E D; Martins, J R; Piulachs, M-D; Cristino, A S; Pinheiro, D G; Simões, Z L P

    2016-06-01

    Queen and worker honeybees differ profoundly in reproductive capacity. The queen of this complex society, with 200 highly active ovarioles in each ovary, is the fertile caste, whereas the workers have approximately 20 ovarioles as a result of receiving a different diet during larval development. In a regular queenright colony, the workers have inactive ovaries and do not reproduce. However, if the queen is sensed to be absent, some of the workers activate their ovaries, producing viable haploid eggs that develop into males. Here, a deep-sequenced ovary transcriptome library of reproductive workers was used as supporting data to assess the dynamic expression of the regulatory molecules and microRNAs (miRNAs) of reproductive and nonreproductive honeybee females. In this library, most of the differentially expressed miRNAs are related to ovary physiology or oogenesis. When we quantified the dynamic expression of 19 miRNAs in the active and inactive worker ovaries and compared their expression in the ovaries of virgin and mated queens, we noted that some miRNAs (miR-1, miR-31a, miR-13b, miR-125, let-7 RNA, miR-100, miR-276, miR-12, miR-263a, miR-306, miR-317, miR-92a and miR-9a) could be used to identify reproductive and nonreproductive statuses independent of caste. Furthermore, integrative gene networks suggested that some candidate miRNAs function in the process of ovary activation in worker bees. PMID:26853694

  10. Inhibitory Effect of Baicalin and Baicalein on Ovarian Cancer Cells

    PubMed Central

    Chen, Jianchu; Li, Zhaoliang; Chen, Allen Y.; Ye, Xingqian; Luo, Haitao; Rankin, Gary O.; Chen, Yi Charlie

    2013-01-01

    Ovarian cancer is one of the primary causes of death for women all through the Western world. Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants and are thought to have antioxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45–55 μM for baicalin and 25–40 μM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 μM for baicalin and 68 μM for baicalein. Baicalin decreased expression of VEGF (20 μM), cMyc (80 μM), and NFkB (20 μM); baicalein decreased expression of VEGF (10 μM), HIF-1α (20 μM), cMyc (20 μM), and NFkB (40 μM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB. Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers. PMID:23502466

  11. Denileukin Diftitox Used in Treating Patients With Advanced Refractory Ovarian Cancer, Primary Peritoneal Carcinoma, or Epithelial Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-05-02

    Fallopian Tube Cancer; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mixed Epithelial Carcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Undifferentiated Adenocarcinoma; Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer

  12. Predicting Classroom Achievement from Active Responding on a Computer-Based Groupware System.

    ERIC Educational Resources Information Center

    Shin, Jongho; Deno, Stanley L.; Robinson, Steven L.; Marston, Douglas

    2000-01-01

    The predictive validity of active responding on a computer-based groupware system was examined with 48 second graders. Results showed that active responding correlated highly with initial and final performance measures and that active responding contributed significantly to predicting final performance when initial performance was controlled.…

  13. An Activity for Predicting Performances in the 1984 Summer Olympics.

    ERIC Educational Resources Information Center

    Henningsen, Jacqueline

    1984-01-01

    Techniques that students can use to make predictions about performances in the Olympics include point estimation. This is used to estimate a single value using a set of data. A worksheet for students is included. (MNS)

  14. Predictive motor control of sensory dynamics in auditory active sensing.

    PubMed

    Morillon, Benjamin; Hackett, Troy A; Kajikawa, Yoshinao; Schroeder, Charles E

    2015-04-01

    Neuronal oscillations present potential physiological substrates for brain operations that require temporal prediction. We review this idea in the context of auditory perception. Using speech as an exemplar, we illustrate how hierarchically organized oscillations can be used to parse and encode complex input streams. We then consider the motor system as a major source of rhythms (temporal priors) in auditory processing, that act in concert with attention to sharpen sensory representations and link them across areas. We discuss the circuits that could mediate this audio-motor interaction, notably the potential role of the somatosensory system. Finally, we reposition temporal predictions in the context of internal models, discussing how they interact with feature-based or spatial predictions. We argue that complementary predictions interact synergistically according to the organizational principles of each sensory system, forming multidimensional filters crucial to perception. PMID:25594376

  15. New developments in treatment of ovarian carcinoma: focus on trabectedin

    PubMed Central

    Cassier, Philippe A; Duret, Aude; Trédan, Olivier; Carrabin, Nicolas; Méeus, Pierre; Treilleux, Isabelle; Guastalla, Jean-Paul; Ray-Coquard, Isabelle

    2010-01-01

    Trabectedin is a new marine-derived compound that binds the DNA minor groove and interacts with proteins of the DNA repair machinery. Trabectedin has shown promising single-agent activity in pretreated patients with soft tissue sarcoma, and ovarian and breast cancer, and combination with various other chemotherapeutic drugs seems feasible. Toxicities are mainly hematologic and hepatic, with Grade 3–4 neutropenia and thrombocytopenia observed in approximately 50% and 20% of patients, respectively, and Grade 3–4 elevation of liver enzymes observed in 35%–50% of patients treated with trabectedin. The recently reported results of a large Phase III trial comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer showed improved progression-free survival with the combination of trabectedin and PLD, albeit at the price of increased toxicity. Current research focuses on the identification of predictive factors for patients treated with trabectedin, as well as the development of other combinations. PMID:21188115

  16. Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.

    PubMed

    Mo, Lihong; Pospichalova, Vendula; Huang, Zhiqing; Murphy, Susan K; Payne, Sturgis; Wang, Fang; Kennedy, Margaret; Cianciolo, George J; Bryja, Vitezslav; Pizzo, Salvatore V; Bachelder, Robin E

    2015-01-01

    Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance. PMID:26148191

  17. Physiology and Endocrinology of the Ovarian Cycle in Macaques

    PubMed Central

    Weinbauer, Gerhard F.; Niehoff, Marc; Niehaus, Michael; Srivastav, Shiela; Fuchs, Antje; Van Esch, Eric; Cline, J. Mark

    2009-01-01

    Macaques provide excellent models for preclinical testing and safety assessment of female reproductive toxicants. Currently, cynomolgus monkeys are the predominant species for (reproductive) toxicity testing. Marmosets and rhesus monkeys are being used occasionally. The authors provide a brief review on physiology and endocrinology of the cynomolgus monkey ovarian cycle, practical guidance on assessment and monitoring of ovarian cyclicity, and new data on effects of social housing on ovarian cyclicity in toxicological studies. In macaques, cycle monitoring is achieved using daily vaginal smears for menstruation combined with cycle-timed frequent sampling for steroid and peptide hormone analysis. Owing to requirements of frequent and timed blood sampling, it is not recommended to incorporate these special evaluations into a general toxicity study design. Marmosets lack external signs of ovarian cyclicity, and cycle monitoring is done by regular determinations of progesterone. Cynomolgus and marmoset monkeys do not exhibit seasonal variations in ovarian activity, whereas such annual rhythm is pronounced in rhesus monkeys. Studies on pair- and group-housed cynomolgus monkeys revealed transient alterations in the duration and endocrinology of the ovarian cycle followed by return to normal cyclicity after approximately six months. This effect is avoided if the animals had contact with each other prior to mingling. These experiments also demonstrated that synchronization of ovarian cycles did not occur. PMID:20852722

  18. Effect of benzene extract of Hibiscus rosa sinensis on the estrous cycle and ovarian activity in albino mice.

    PubMed

    Murthy, D R; Reddy, C M; Patil, S B

    1997-07-01

    The benzene extract of Hibiscus rosa sinensis flowers was administered intraperitoneally at the dose levels of 125 and 250 mg/kg body weight to adult mice and resulted in an irregular estrous cycle with prolonged estrus and metestrus. An increase in the atretic follicles and the absence of corpora lutea indicate the antiovulatory effect of the extract. The extract also showed estrogenic activity in immature mice by early opening of the vagina, premature cornification of the vaginal epithelium and an increase in uterine weight. Therefore the antiovulatory effect may be due to an imbalance in the hormonal environment, as there may be an increase in the endogenous secretion of estrogen by atretic follicles, and also to the estrogenicity of the flower extract. PMID:9255415

  19. Non-ovarian aromatization is required to activate female sexual motivation in testosterone-treated ovariectomized quail.

    PubMed

    de Bournonville, Catherine; Balthazart, Jacques; Ball, Gregory F; Cornil, Charlotte A

    2016-07-01

    Although aromatase is expressed in both male and female brains, its functional significance in females remains poorly understood. In female quail, sexual receptivity is activated by estrogens. However it is not known whether sexual motivation is similarly estrogen-dependent and whether estrogens locally produced in the brain contribute to these behavioral responses. Four main experiments were designed to address these questions. In Experiment 1 chronic treatment of females with the anti-estrogen tamoxifen decreased their receptivity, confirming that this response is under the control of estrogens. In Experiment 2 chronic treatment with tamoxifen significantly decreased sexual motivation as treated females no longer approached a sexual partner. In Experiment 3 (a) ovariectomy (OVX) induced a significant decrease of time spent near the male and a significantly decreased receptivity compared to gonadally intact females, (b) treatment with testosterone (OVX+T) partially restored these responses and (c) this effect of T was prevented when estradiol synthesis was inhibited by the potent aromatase inhibitor Vorozole (OVX+T+VOR). Serum estradiol concentration was significantly higher in OVX+T than in OVX or OVX+T+VOR females. Together these data demonstrate that treatment of OVX females with T increases sexual motivation and that these effects are mediated at least in part by non-gonadal aromatization of the androgen. Finally, assays of aromatase activity on brain and peripheral tissues (Experiment 4) strongly suggest that brain aromatization contributes to behavioral effects observed here following T treatment but alternative sources of estrogens (e.g. liver) should also be considered. PMID:27189762

  20. Borderline ovarian tumours.

    PubMed

    Tropé, Claes Göran; Kaern, Janne; Davidson, Ben

    2012-06-01

    Borderline ovarian tumours account for 10-20% of all epithelial ovarian cancer. Historically, standard primary surgery has included borderline ovarian tumours, omentectomy, peritoneal washing and multiple biopsies. As one-third of borderline ovarian tumours are diagnosed in women under the age of 40 years, fertility-sparing treatment has been more frequently used in the past 10 years. Fertility drugs are well tolerated in women with infertility after fertility-sparing surgery. Careful selection of candidates is necessary. Laparoscopic techniques can be used, but should be reserved for oncologic surgeons. This conservative treatment increases the rate of recurrence, albeit with no effect on survival. The pregnancy rate is nearly 50%, and most are achieved spontaneously. These women should be closely followed up. The question is whether this is acceptable from a gynaecologic oncologic point of view. For this reason, we will discuss recently published studies and gynaecologic oncologic concerns about the mode of fertility-sparing surgery and its consequences. PMID:22321906

  1. Childhood ovarian malignancy.

    PubMed

    Mahadik, Kalpana; Ghorpade, Kanchanmala

    2014-04-01

    Objective of this article is to appraise diagnostic aspects and treatment modalities in childhood ovarian tumor in background of available evidence. Literature search on Pubmed revealed various aspects of epidemiology, histopathological diagnosis, and treatment of pediatric ovarian tumor. 85 % of childhood tumors are germ cell tumors. The varied histopathological picture in germ cell tumors poses a diagnostic and therapeutic challenge. Immunohistochemistry and newer genetic markers like SALL4 and karyopherin-2 (KPNA2) have been helpful in differentiating ovarian yolk sac tumor from dysgerminoma, teratomas, and other pictures of hepatoid, endometrioid, clear cell carcinomatous, and adenocarcinomatous tissues with varied malignant potential. Before platinum therapy, these tumors were almost fatal in children. Fertility-conserving surgery with bleomycin, etoposide, and cisplatin has dramatically changed the survival rates in these patients. This modality gives cancer cure with healthy offspring to female patients with childhood ovarian tumor. Evidence also supports this protocol resulting in successful pregnancy rates and safety of cytotoxic drugs in children born to these patients. PMID:24757335

  2. Ovarian Cancer Statistics

    MedlinePlus

    ... at a Glance Show More At a Glance Estimated New Cases in 2016 22,280 % of All New Cancer Cases 1.3% Estimated Deaths in 2016 14,240 % of All Cancer ... of This Cancer : In 2013, there were an estimated 195,767 women living with ovarian cancer in ...

  3. Ovarian cavernous hemangioma.

    PubMed

    Alvarez, M; Cerezo, L

    1986-01-01

    Vascular tumors of the female genital tract are rare, especially those of the ovary. Most cases are small lesions that are discovered incidentally. We describe a 68-year-old woman with a benign hemangioma that presented clinically as a very large ovarian mass. PMID:3753575

  4. Ovarian hyperstimulation syndrome

    MedlinePlus

    ... 3 to 6% of women who go through in vitro fertilization . Other risk factors for OHSS include: Being younger ... A.M. Editorial team. Related MedlinePlus Health Topics Assisted Reproductive Technology Ovarian Disorders Browse the Encyclopedia A.D.A. ...

  5. Solar activity prediction of sunspot numbers (verification). Predicted solar radio flux; predicted geomagnetic indices Ap and Kp. [space shuttle program: satellite orbital lifetime

    NASA Technical Reports Server (NTRS)

    Newman, S. R.

    1980-01-01

    Efforts to further verify a previously reported technique for predicting monthly sunspot numbers over a period of years (1979 to 1989) involved the application of the technique over the period for the maximum epoch of solar cycle 19. Results obtained are presented. Methods and results for predicting solar flux (F10.7 cm) based on flux/sunspot number models, ascent and descent, and geomagnetic activity indices as a function of sunspot number and solar cycle phase classes are included.

  6. Nestling activity levels during begging behaviour predicts activity level and body mass in adulthood

    PubMed Central

    Griffith, Simon C.

    2014-01-01

    Across a range of species including humans, personality traits, or differences in behaviour between individuals that are consistent over time, have been demonstrated. However, few studies have measured whether these consistent differences are evident in very young animals, and whether they persist over an individual’s entire lifespan. Here we investigated the begging behaviour of very young cross-fostered zebra finch nestlings and the relationship between that and adult activity levels. We found a link between the nestling activity behaviour head movements during begging, measured at just five and seven days after hatching, and adult activity levels, measured when individuals were between three and three and a half years old. Moreover, body mass was found to be negatively correlated with both nestling and adult activity levels, suggesting that individuals which carry less body fat as adults are less active both as adults and during begging as nestlings. Our work suggests that the personality traits identified here in both very young nestlings and adults may be linked to physiological factors such as metabolism or environmental sources of variation. Moreover, our work suggests it may be possible to predict an individual’s future adult personality at a very young age, opening up new avenues for future work to explore the relationship between personality and a number of aspects of individual life history and survival. PMID:25279258

  7. Nestling activity levels during begging behaviour predicts activity level and body mass in adulthood.

    PubMed

    McCowan, Luke S C; Griffith, Simon C

    2014-01-01

    Across a range of species including humans, personality traits, or differences in behaviour between individuals that are consistent over time, have been demonstrated. However, few studies have measured whether these consistent differences are evident in very young animals, and whether they persist over an individual's entire lifespan. Here we investigated the begging behaviour of very young cross-fostered zebra finch nestlings and the relationship between that and adult activity levels. We found a link between the nestling activity behaviour head movements during begging, measured at just five and seven days after hatching, and adult activity levels, measured when individuals were between three and three and a half years old. Moreover, body mass was found to be negatively correlated with both nestling and adult activity levels, suggesting that individuals which carry less body fat as adults are less active both as adults and during begging as nestlings. Our work suggests that the personality traits identified here in both very young nestlings and adults may be linked to physiological factors such as metabolism or environmental sources of variation. Moreover, our work suggests it may be possible to predict an individual's future adult personality at a very young age, opening up new avenues for future work to explore the relationship between personality and a number of aspects of individual life history and survival. PMID:25279258

  8. Gene expression profiling analysis of ovarian cancer

    PubMed Central

    YIN, JI-GANG; LIU, XIAN-YING; WANG, BIN; WANG, DAN-YANG; WEI, MAN; FANG, HUA; XIANG, MEI

    2016-01-01

    As a gynecological oncology, ovarian cancer has high incidence and mortality. To study the mechanisms of ovarian cancer, the present study analyzed the GSE37582 microarray. GSE37582 was downloaded from Gene Expression Omnibus and included data from 74 ovarian cancer cases and 47 healthy controls. The differentially-expressed genes (DEGs) were screened using linear models for microarray data package in R and were further screened for functional annotation. Next, Gene Ontology and pathway enrichment analysis of the DEGs was conducted. The interaction associations of the proteins encoded by the DEGs were searched using the Search Tool for the Retrieval of Interacting Genes, and the protein-protein interaction (PPI) network was visualized by Cytoscape. Moreover, module analysis of the PPI network was performed using the BioNet analysis tool in R. A total of 284 DEGs were screened, consisting of 145 upregulated genes and 139 downregulated genes. In particular, downregulated FBJ murine osteosarcoma viral oncogene homolog (FOS) was an oncogene, while downregulated cyclin-dependent kinase inhibitor 1A (CDKN1A) was a tumor suppressor gene and upregulated cluster of differentiation 44 (CD44) was classed as an ‘other’ gene. The enriched functions included collagen catabolic process, stress-activated mitogen-activated protein kinases cascade and insulin receptor signaling pathway. Meanwhile, FOS (degree, 15), CD44 (degree, 9), B-cell CLL/lymphoma 2 (BCL2; degree, 7), CDKN1A (degree, 7) and matrix metallopeptidase 3 (MMP3; degree, 6) had higher connectivity degrees in the PPI network for the DEGs. These genes may be involved in ovarian cancer by interacting with other genes in the module of the PPI network (e.g., BCL2-FOS, BCL2-CDKN1A, FOS-CDKN1A, FOS-CD44, MMP3-MMP7 and MMP7-CD44). Overall, BCL2, FOS, CDKN1A, CD44, MMP3 and MMP7 may be correlated with ovarian cancer. PMID:27347159

  9. PTN signaling: Components and mechanistic insights in human ovarian cancer.

    PubMed

    Sethi, Geetika; Kwon, Youngjoo; Burkhalter, Rebecca J; Pathak, Harsh B; Madan, Rashna; McHugh, Sarah; Atay, Safinur; Murthy, Smruthi; Tawfik, Ossama W; Godwin, Andrew K

    2015-12-01

    Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian

  10. Comparing two different superovulation protocols on ovarian activity and fecal glucocorticoid levels in the brown brocket deer (Mazama gouazoubira)

    PubMed Central

    2014-01-01

    Background Stress is a limiting factor in assisted reproduction in wild animals maintained in captivity. However, the knowledge of assisted reproduction techniques for wild animals is useful for future in situ and ex situ conservation programs. Thus, this study evaluated the ovulation rate, presence of functional corpora lutea and fecal glucocorticoid levels following treatments promoting superovulation in captive brown brocket deer. Methods The crossover design used six hinds, allocated to two groups (n = 6): eCG Treatment, CIDR for 8 days, followed by 0.25 mg of EB on day 0, 700 IU of eCG on day 4 following device insertion and 265 mug of PGF2alfa on day 8; and FSH Treatment, CIDR for 7.5 days, followed by 0.25 mg of EB on day 0, 130 mg of FSH in 8 equal doses and 265 mug of PGF2alfa on day 7.5. Induced adrenal activity and treatment efficacy were evaluated by corpora lutea (CL) counts and fecal glucocorticoid and progestin concentration (ng/g feces) analyses for five different phases: Pre, two days before treatment; Early, first four days of treatment; Late, last four days of treatment; Total, entire treatment period; and Post, five days posttreatment. Results eCG Treatment resulted in the highest number of CL (P lower than 0.05). There was no significant difference for fecal glucocorticoid concentrations in five different time periods between the treatments; however Pre fecal glucocorticoid concentrations (90.06+/−19.64) were significantly different from Late (200.76+/−26.39) within FSH Treatment. The mean fecal progestin concentration and mean ovulation rate were higher in eCG Treatment (4293.69+/−769.47, 7.0+/−1.8) than in FSH Treatment (1571.26+/−240.28, 2.6+/−0.8) (P lower than or equal to 0.05). Conclusions Although the eCG Treatment induced a good superovulatory response, with the formation of functional corpora lutea, we cannot yet affirm that we have established a suitable protocol for induction of SOV in the species M

  11. Do We Know What Causes Ovarian Cancer?

    MedlinePlus

    ... ovarian cancer be prevented? Do we know what causes ovarian cancer? We don’t yet know exactly what causes ... Another theory is that male hormones (androgens) can cause ovarian cancer. Researchers have made great progress in understanding how ...

  12. ARHGAP10, downregulated in ovarian cancer, suppresses tumorigenicity of ovarian cancer cells

    PubMed Central

    Luo, N; Guo, J; Chen, L; Yang, W; Qu, X; Cheng, Z

    2016-01-01

    Rho GTPase-activating proteins (RhoGAPs) are implicated in the development and progression of ovarian cancer. ARHGAP10 is a member of RhoGAP proteins and inactivates Cdc42 by converting GTP-bound form to GDP-bound form. Here, we aimed to evaluate ARHGAP10 expression profile and functions in ovarian cancer. The decreased expression of ARHGAP10 was found in 77.3% (58/75) of ovarian cancer tissues, compared with their non-tumorous counterparts. Furthermore, overall survival in ovarian cancer patients with higher expression of ARHGAP10 was longer than those with lower expression. Ectopic expression of ARHGAP10 in two ovarian cancer cell lines with lower expression of ARHGAP10 (A2780 and HO-8910) dramatically suppressed cell proliferation in vitro. In nude mice, its stable overexpression significantly inhibited the tumorigenicity of A2780 cells. We further demonstrated that overexpression of ARHGAP10 significantly inhibited cell adhesion, migration and invasion, resulted in cell arrest in G1 phase of cell cycle and a significant increase of apoptosis. Moreover, ARHGAP10 interacted with Cdc42 and overexpression of ARHGAP10 inhibited the activity of Cdc42 in A2780 cells. Gene set enrichment analysis on The Cancer Genome Atlas dataset showed that KEGG cell cycle, replication and base excision repair (BER) pathways were correlatively with the ARHGAP10 expression, which was further confirmed in ovarian cancer cells by western blotting. Hence, ARHGAP10 may serve as a tumor suppressor through inactivating Cdc42, as well as inhibiting cell cycle, replication and BER pathways. Our data suggest an important role of ARHGAP10 in the molecular etiology of cancer and implicate the potential application of ARHGAP10 in cancer therapy. PMID:27010858

  13. Prediction of Pathway Activation by Xenobiotic-Responsive Transcription Factors in the Mouse Liver

    EPA Science Inventory

    Many drugs and environmentally-relevant chemicals activate xenobioticresponsive transcription factors (TF). Identification of target genes of these factors would be useful in predicting pathway activation in in vitro chemical screening. Starting with a large compendium of Affymet...

  14. Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

    ClinicalTrials.gov

    2016-07-12

    Ovarian Brenner Tumor; Ovarian Carcinosarcoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Serous Surface Papillary Adenocarcinoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Undifferentiated Ovarian Carcinoma

  15. Review of ovarian tumors in children and adolescents: radiologic-pathologic correlation.

    PubMed

    Heo, Suk Hee; Kim, Jin Woong; Shin, Sang Soo; Jeong, Seo In; Lim, Hyo Soon; Choi, Yoo Duk; Lee, Kyoung Hwa; Kang, Woo Dae; Jeong, Yong Yeon; Kang, Heoung Keun

    2014-01-01

    The incidence, histologic distribution, and clinical manifestations of ovarian tumors in the pediatric population are distinct from those in adults. Although ovarian neoplasms in childhood and adolescence are rare, the diagnosis should be considered in young girls with abdominal pain and a palpable mass. Differential diagnosis in children and adolescents with ovarian tumors should be conducted on the basis of unique clinical manifestations, elevated serum tumor marker levels, and distinctive imaging findings. Although the clinical manifestations are nonspecific and may overlap, they may assist in diagnosis of some types of ovarian tumors. Children who present with a palpable mass or symptoms of precocious puberty have a high likelihood of malignancy. Many ovarian tumors are associated with abnormal hormonal activity and/or abnormal sexual development. Elevated levels of serum tumor markers, including α-fetoprotein, the beta subunit of human chorionic gonadotropin, and CA-125, raise concern for ovarian malignancies. However, negative tumor markers do not exclude the possibility of malignancy. Identification of imaging features at ultrasonography, computed tomography, and magnetic resonance imaging can help differentiate benign from malignant ovarian tumors and, in turn, plays a crucial role in determining treatment options. At imaging, malignant ovarian tumors usually appear predominantly solid or heterogeneous and are larger than benign tumors. Because surgery is the primary treatment for ovarian tumors, ovarian salvage with fertility preservation and use of a minimally invasive surgical technique are important in children and adolescents. PMID:25384300

  16. Measurement of Phospholipids May Improve Diagnostic Accuracy in Ovarian Cancer

    PubMed Central

    Davis, Lorelei; Han, Gang; Zhu, Weiwei; Molina, Ashley D.; Arango, Hector; LaPolla, James P.; Hoffman, Mitchell S.; Sellers, Thomas; Kirby, Tyler; Nicosia, Santo V.; Sutphen, Rebecca

    2012-01-01

    Background More than two-thirds of women who undergo surgery for suspected ovarian neoplasm do not have cancer. Our previous results suggest phospholipids as potential biomarkers of ovarian cancer. In this study, we measured the serum levels of multiple phospholipids among women undergoing surgery for suspected ovarian cancer to identify biomarkers that better predict whether an ovarian mass is malignant. Methodology/Principal Findings We obtained serum samples preoperatively from women with suspected ovarian cancer enrolled through a prospective, population-based rapid ascertainment system. Samples were analyzed from all women in whom a diagnosis of epithelial ovarian cancer (EOC) was confirmed and from benign disease cases randomly selected from the remaining (non-EOC) samples. We measured biologically relevant phospholipids using liquid chromatography/electrospray ionization mass spectrometry. We applied a powerful statistical and machine learning approach, Hybrid huberized support vector machine (HH-SVM) to prioritize phospholipids to enter the biomarker models, and used cross-validation to obtain conservative estimates of classification error rates. Results The HH-SVM model using the measurements of specific combinations of phospholipids supplements clinical CA125 measurement and improves diagnostic accuracy. Specifically, the measurement of phospholipids improved sensitivity (identification of cases with preoperative CA125 levels below 35) among two types of cases in which CA125 performance is historically poor - early stage cases and those of mucinous histology. Measurement of phospholipids improved the identification of early stage cases from 65% (based on CA125) to 82%, and mucinous cases from 44% to 88%. Conclusions/Significance Levels of specific serum phospholipids differ between women with ovarian cancer and those with benign conditions. If validated by independent studies in the future, these biomarkers may serve as an adjunct at the time of clinical

  17. Prediction of geomagnetic activity on time scales of one to ten years

    NASA Technical Reports Server (NTRS)

    Feynman, J.; Gu, X. Y.

    1986-01-01

    The long-term prediction of geomagnetic indices that characterize the state of the magnetosphere is discussed. While a prediction of the yearly average sunspot number is simultaneously a prediction of the yearly number of sudden-commencement storms, it is not a prediction of the number of disturbed or quiet half days. Knowledge of the sunspot cycle phase leads to a good estimate of the correlation expected between activity during one 27-day solar rotation period and the next.

  18. LSD-induced entropic brain activity predicts subsequent personality change.

    PubMed

    Lebedev, A V; Kaelen, M; Lövdén, M; Nilsson, J; Feilding, A; Nutt, D J; Carhart-Harris, R L

    2016-09-01

    Personality is known to be relatively stable throughout adulthood. Nevertheless, it has been shown that major life events with high personal significance, including experiences engendered by psychedelic drugs, can have an enduring impact on some core facets of personality. In the present, balanced-order, placebo-controlled study, we investigated biological predictors of post-lysergic acid diethylamide (LSD) changes in personality. Nineteen healthy adults underwent resting state functional MRI scans under LSD (75µg, I.V.) and placebo (saline I.V.). The Revised NEO Personality Inventory (NEO-PI-R) was completed at screening and 2 weeks after LSD/placebo. Scanning sessions consisted of three 7.5-min eyes-closed resting-state scans, one of which involved music listening. A standardized preprocessing pipeline was used to extract measures of sample entropy, which characterizes the predictability of an fMRI time-series. Mixed-effects models were used to evaluate drug-induced shifts in brain entropy and their relationship with the observed increases in the personality trait openness at the 2-week follow-up. Overall, LSD had a pronounced global effect on brain entropy, increasing it in both sensory and hierarchically higher networks across multiple time scales. These shifts predicted enduring increases in trait openness. Moreover, the predictive power of the entropy increases was greatest for the music-listening scans and when "ego-dissolution" was reported during the acute experience. These results shed new light on how LSD-induced shifts in brain dynamics and concomitant subjective experience can be predictive of lasting changes in personality. Hum Brain Mapp 37:3203-3213, 2016. © 2016 Wiley Periodicals, Inc. PMID:27151536

  19. Overexpression of proto-oncogene FBI-1 activates membrane type 1-matrix metalloproteinase in association with adverse outcome in ovarian cancers

    PubMed Central

    2010-01-01

    Background FBI-1 (factor that binds to the inducer of short transcripts of human immunodeficiency virus-1) is a member of the POK (POZ and Kruppel) family of transcription factors and play important roles in cellular differentiation and oncogenesis. Recent evidence suggests that FBI-1 is expressed at high levels in a subset of human lymphomas and some epithelial solid tumors. However, the function of FBI-1 in human ovarian cancers remains elusive. Results In this study, we investigated the role of FBI-1 in human ovarian cancers, in particularly, its function in cancer cell invasion via modulating membrane type 1-matrix metalloproteinase (MT1-MMP). Significantly higher FBI-1 protein and mRNA expression levels were demonstrated in ovarian cancers samples and cell lines compared with borderline tumors and benign cystadenomas. Increased FBI-1 mRNA expression was correlated significantly with gene amplification (P = 0.037). Moreover, higher FBI-1 expression was found in metastatic foci (P = 0.036) and malignant ascites (P = 0.021), and was significantly associated with advanced stage (P = 0.012), shorter overall survival (P = 0.032) and disease-free survival (P = 0.016). In vitro, overexpressed FBI-1 significantly enhanced cell migration and invasion both in OVCA 420 and SKOV-3 ovarian carcinoma cells, irrespective of p53 status, accompanied with elevated expression of MT1-MMP, but not MMP-2 or TIMP-2. Moreover, knockdown of MT1-MMP abolished FBI-1-mediated cell migration and invasion. Conversely, stable knockdown of FBI-1 remarkably reduced the motility of these cells with decreased expression of MT1-MMP. Promoter assay and chromatin immunoprecipitation study indicated that FBI-1 could directly interact with the promoter spanning ~600bp of the 5'-flanking sequence of MT1-MMP and enhanced its expression in a dose-dependent manner. Furthermore, stable knockdown and ectopic expression of FBI-1 decreased and increased cell proliferation respectively in OVCA 420, but not in

  20. Prediction of active control of subsonic centrifugal compressor rotating stall

    NASA Technical Reports Server (NTRS)

    Lawless, Patrick B.; Fleeter, Sanford

    1993-01-01

    A mathematical model is developed to predict the suppression of rotating stall in a centrifugal compressor with a vaned diffuser. This model is based on the employment of a control vortical waveform generated upstream of the impeller inlet to damp weak potential disturbances that are the early stages of rotating stall. The control system is analyzed by matching the perturbation pressure in the compressor inlet and exit flow fields with a model for the unsteady behavior of the compressor. The model was effective at predicting the stalling behavior of the Purdue Low Speed Centrifugal Compressor for two distinctly different stall patterns. Predictions made for the effect of a controlled inlet vorticity wave on the stability of the compressor show that for minimum control wave magnitudes, on the order of the total inlet disturbance magnitude, significant damping of the instability can be achieved. For control waves of sufficient amplitude, the control phase angle appears to be the most important factor in maintaining a stable condition in the compressor.

  1. Prediction of Geomagnetic Activity and Key Parameters in High-latitude Ionosphere

    NASA Technical Reports Server (NTRS)

    Khazanov, George V.; Lyatsky, Wladislaw; Tan, Arjun; Ridley, Aaron

    2007-01-01

    Prediction of geomagnetic activity and related events in the Earth's magnetosphere and ionosphere are important tasks of US Space Weather Program. Prediction reliability is dependent on the prediction method, and elements included in the prediction scheme. Two of the main elements of such prediction scheme are: an appropriate geomagnetic activity index, and an appropriate coupling function (the combination of solar wind parameters providing the best correlation between upstream solar wind data and geomagnetic activity). We have developed a new index of geomagnetic activity, the Polar Magnetic (PM) index and an improved version of solar wind coupling function. PM index is similar to the existing polar cap PC index but it shows much better correlation with upstream solar wind/IMF data and other events in the magnetosphere and ionosphere. We investigate the correlation of PM index with upstream solar wind/IMF data for 10 years (1995-2004) that include both low and high solar activity. We also have introduced a new prediction function for the predicting of cross-polar-cap voltage and Joule heating based on using both PM index and upstream solar wind/IMF data. As we show such prediction function significantly increase the reliability of prediction of these important parameters. The correlation coefficients between the actual and predicted values of these parameters are approx. 0.9 and higher.

  2. Coordinately up-regulated genes in ovarian cancer.

    PubMed

    Hough, C D; Cho, K R; Zonderman, A B; Schwartz, D R; Morin, P J

    2001-05-15

    A better understanding of the molecular circuitry in normal ovarian tissues and in ovarian cancer will likely provide new targets for diagnosis and therapy. Recently, much has been learned about the genes expressed in ovarian cancer through studies with cDNA arrays and serial analysis of gene expression. However, these methods do not allow highly quantitative analysis of gene expression on a large number of specimens. Here, we have used quantitative real-time RT-PCR in a panel of 39 microdissected ovarian carcinomas of various subtypes to systematically analyze the expression of 13 genes, many of which were previously identified as up-regulated in a subset of ovarian cancers by serial analyses of gene expression. The genes analyzed are glutathione peroxidase 3 (GPX3), apolipoprotein J/clusterin, insulin-like growth factor-binding protein 2, epithelial cell adhesion molecule/GA733-2, Kop protease inhibitor, matrix gla protein, tissue inhibitor of metalloproteinase 3, folate receptor 1, S100A2, signal transducer and activator of transcription 1, secretory leukocyte protease inhibitor, apolipoprotein E, and ceruloplasmin. All of the genes were found overexpressed, some at extremely high levels, in the vast majority of ovarian carcinomas irrespective of the subtype. Interestingly, GPX3 was found at much higher levels in tumors with clear cell histology and may represent a biomarker for this subtype. Some of the genes studied here may thus represent targets for early detection ovarian cancer. The gene expression patterns were not associated with age at diagnosis, stage, or K-ras mutation status in ovarian cancer. We find that several genes are coordinately regulated in ovarian cancer, likely representing the fact that many genes are activated as part of common signaling pathways or that extensive cross-talk exists between several pathways in ovarian cancer. A statistical analysis shows that genes commonly up-regulated in ovarian cancer may result from the aberrant

  3. Synergistic action of tiazofurin and genistein in human ovarian carcinoma cells.

    PubMed

    Li, W; Weber, G

    1998-01-01

    Tiazofurin, an oncolytic drug, reduces PI kinase activity and arrests chiefly in S phase. Genistein, an inhibitor of PIP kinase, tyrosine kinase, and topoisomerase-II, induces arrest in G2 and/or early M phase in most carcinoma cells. Both tiazofurin and genistein reduce second messenger IP3 concentration in ovarian carcinoma cells. Because genistein and tiazofurin attack different enzymic targets and arrest the cell cycle at different phases, we tested the hypothesis that tiazofurin might be synergistic with genistein. Human ovarian carcinoma OVCAR-5 cells were grown in flasks in monolayers. In growth inhibition assay for tiazofurin and genistein the IC50s were 26 and 18 microM, respectively, and in clonogenic assays the LC50s were 17 and 4 microM, respectively. Various combinations of the two drugs were tested. The best protocol took into consideration that tiazofurin decreased GTP concentration in cells by 50% at 12 h after administration. Tiazofurin (20 microM) and genistein (20 microM) as single agents reduced cell counts to 60% and 50%, respectively. The predicted value, as a sum of the effect of two drugs, would have been 30% of controls. However, genistein added 12 h after tiazofurin decreased cell counts to 8%, showing synergistic action of the two drugs for growth inhibition. Similar results were observed in the clonogenic assays, which also revealed synergistic cytotoxicity. The protocol yielding synergism might be of value in the clinical treatment of human ovarian carcinoma. PMID:9700722

  4. Ovarian reserve markers in unexplained infertility patients treated with clomiphene citrate during intrauterine insemination

    PubMed Central

    Ulug, Pasa; Elmali, Ferhan

    2015-01-01

    Introduction The aim of this retrospective case control study was to identify predictors of ovarian response and pregnancy outcomes in intrauterine insemination (IUI). Material and methods One hundred women undergoing IUI cycles with clomiphene citrate were enrolled. The number of antral follicles and the total ovarian volume by ultrasound, and the basal levels of follicle-stimulating hormone (FSH), estradiol, and inhibin B on cycle day 3 were measured in groups that were divided according to ovarian response. The tests were also evaluated according to ovarian response and pregnancy outcomes. All analyses were performed using the Statistical Package for the Social Sciences, version 15.0 (SPSS, Chicago, IL, USA). Results The antral follicle count (AFC) was the best single predictor for ovarian response and pregnancy outcomes. The sensitivity and specificity for prediction of ovarian response were 81% and 78% for AFC at an optimum cutoff value of ≤ 13.1. Age was negatively correlated with ovarian volume (r = –0.280, p = 0.021) and AFC (r = –0.358, p = 0.003). Increasing FSH was associated with a reduction in AFC (r = –0.273, p = 0.025). The AFC was significantly correlated with ovarian volume (r = 0.660, p < 0.0001) and FSH (r = –0.273, p = 0.03). Conclusions Our data demonstrate that the AFC provides better prognostic information on the occurrence of ovarian response during clomiphene citrate stimulation for IUI. PMID:26788087

  5. Transfer Student Success: Educationally Purposeful Activities Predictive of Undergraduate GPA

    ERIC Educational Resources Information Center

    Fauria, Renee M.; Fuller, Matthew B.

    2015-01-01

    Researchers evaluated the effects of Educationally Purposeful Activities (EPAs) on transfer and nontransfer students' cumulative GPAs. Hierarchical, linear, and multiple regression models yielded seven statistically significant educationally purposeful items that influenced undergraduate student GPAs. Statistically significant positive EPAs for…

  6. The diagnostic value of serum HE4 and CA-125 and ROMA index in ovarian cancer

    PubMed Central

    WEI, SU; LI, HUI; ZHANG, BEI

    2016-01-01

    Ovarian cancer is a common malignancy of the female reproductive system. Tumor markers serve as tools in the diagnosis of the disease. The aim of the present study was to determine the diagnostic value of sera levels of carbohydrate antigen-125 (CA-125), human epididymis protein 4 (HE4) as well as the area under the curve of the receiver operating characteristic (ROC) and the risk of ovarian malignancy algorithm (ROMA) index in ovarian cancer. The sera were measured using an electrochemiluminescence immunoassay on 158 individuals (64 patients with ovarian cancer, 64 with ovarian benign tumor and 30 healthy individuals) between September 2013 and May 2015. The results showed that levels of HE4 and CA-125 in the sera of the ovarian benign tumor group as well as their ROMA index were significantly higher (P<0.05) than those of the ovarian benign tumor and control groups, regardless of pre- or postmenopausal status. However, the level of CA-125 was significantly higher (P<0.05) in the ovarian benign tumor group compared with the healthy group, while the level of HE4 was similar in the two groups. The sensitivity of the ROMA index was higher (P<0.01) with detection of HE4 and CA-125. In the ovarian cancer group, the areas under ROC curves of ROMA, HE4 and CA-125 were 0.994, 0.990 and 0.941, respectively. The specificity and positive predictive value of HE4 in the premenopausal ovarian cancer group reached 98.36 and 95%, respectively. In conclusion, the results showed that the serum level of HE4 and the ROMA index are important indicators in the diagnosis of ovarian cancer. However, in addition to HE4 and CA-125 detection, the ROMA index is extremely valuable in improving the diagnostic efficiency of ovarian cancer. PMID:27347403

  7. [Premature ovarian failure].

    PubMed

    Assumpção, Carmen Regina Leal de

    2014-03-01

    This article is a review on different aspects of premature ovarian failure (POF) defined as the development of hypogonadism in women before 40 years of age. The review will discuss the etiopathogeny, autoimmune and iatrogenic causes, abnormalities of chromosome X, as well as clinical manifestations, diagnosis, and treatment. Most of the women with this disorder do not have menstrual history, specific of POF development, but infertility associated with the diagnosis is the most problematic aspect of the disease. PMID:24830590

  8. Prognostic values of aldehyde dehydrogenase 1 isoenzymes in ovarian cancer

    PubMed Central

    Ma, Yu-mei; Zhao, Shan

    2016-01-01

    Aldehyde dehydrogenase 1 (ALDH1) activity has been used as a functional stem cell marker to isolate cancer stem cells in different cancer types, including ovarian cancer. However, which ALDH1’s isoenzymes are contributing to ALDH1 activity in ovarian cancer remains elusive. In addition, the prognostic value of an individual ALDH1 isoenzyme in ovarian cancer is not clear. Thus, we accessed the prognostic value of ALDH1 isoenzymes in ovarian cancer patients through the “Kaplan–Meier plotter” online database, which can be used to determine the effect of the genes on ovarian cancer prognosis. We found that high mRNA expression of five ALDH1 isoenzymes, such as ALDH1A1, ALDH1A2, ALDH1A3, ALDH1B1, and ALDH1L1, was not correlated with overall survival (OS) for all 1,306 ovarian cancer patients. In addition, all five of the ALDH1 isoenzymes’ high mRNA expression was found to be uncorrelated with OS in serous cancer or endometrioid cancer patients. However, ALDH1A3’s high mRNA expression is associated with worse OS in grade II ovarian cancer patients, hazard ratio (HR) 1.53 (1.14–2.07), P=0.005. ALDH1A2’s high mRNA expression is significantly associated with worse OS in TP53 wild-type ovarian cancer patients, HR 2.86 (1.56–5.08), P=0.00036. In addition, ALDH1A3’s high mRNA expression is significantly associated with better OS in TP53 wild-type ovarian cancer patients, HR 0.56 (0.32–1.00), P=0.04. Our results indicate that although ALDH1 isoenzyme mRNA might not be a prognostic marker for overall ovarian cancer patients, some isoenzymes, such as ALDH1A2 and ALDH1A3, might be a good prognostic marker for some types of ovarian cancer patients. PMID:27110126

  9. Prediction of Geomagnetic Activity and Key Parameters in High-Latitude Ionosphere-Basic Elements

    NASA Technical Reports Server (NTRS)

    Lyatsky, W.; Khazanov, G. V.

    2007-01-01

    Prediction of geomagnetic activity and related events in the Earth's magnetosphere and ionosphere is an important task of the Space Weather program. Prediction reliability is dependent on the prediction method and elements included in the prediction scheme. Two main elements are a suitable geomagnetic activity index and coupling function -- the combination of solar wind parameters providing the best correlation between upstream solar wind data and geomagnetic activity. The appropriate choice of these two elements is imperative for any reliable prediction model. The purpose of this work was to elaborate on these two elements -- the appropriate geomagnetic activity index and the coupling function -- and investigate the opportunity to improve the reliability of the prediction of geomagnetic activity and other events in the Earth's magnetosphere. The new polar magnetic index of geomagnetic activity and the new version of the coupling function lead to a significant increase in the reliability of predicting the geomagnetic activity and some key parameters, such as cross-polar cap voltage and total Joule heating in high-latitude ionosphere, which play a very important role in the development of geomagnetic and other activity in the Earth s magnetosphere, and are widely used as key input parameters in modeling magnetospheric, ionospheric, and thermospheric processes.

  10. Individualized relapse prediction: personality measures and striatal and insular activity during reward-processing robustly predict relapse*

    PubMed Central

    Gowin, Joshua L.; Ball, Tali M.; Wittmann, Marc; Tapert, Susan F.; Paulus, Martin P.

    2015-01-01

    Background Nearly half of individuals with substance use disorders relapse in the year after treatment. A diagnostic tool to help clinicians make decisions regarding treatment does not exist for psychiatric conditions. Identifying individuals with high risk for relapse to substance use following abstinence has profound clinical consequences. This study aimed to develop neuroimaging as a robust tool to predict relapse. Methods 68 methamphetamine-dependent adults (15 female) were recruited from 28-day inpatient treatment. During treatment, participants completed a functional MRI scan that examined brain activation during reward processing. Patients were followed 1 year later to assess abstinence. We examined brain activation during reward processing between relapsing and abstaining individuals and employed three random forest prediction models (clinical and personality measures, neuroimaging measures, a combined model) to generate predictions for each participant regarding their relapse likelihood. Results 18 individuals relapsed. There were significant group by reward-size interactions for neural activation in the left insula and right striatum for rewards. Abstaining individuals showed increased activation for large, risky relative to small, safe rewards, whereas relapsing individuals failed to show differential activation between reward types. All three random forest models yielded good test characteristics such that a positive test for relapse yielded a likelihood ratio 2.63, whereas a negative test had a likelihood ratio of 0.48. Conclusions These findings suggest that neuroimaging can be developed in combination with other measures as an instrument to predict relapse, advancing tools providers can use to make decisions about individualized treatment of substance use disorders. PMID:25977206

  11. Ovulation and extra-ovarian origin of ovarian cancer.

    PubMed

    Yang-Hartwich, Yang; Gurrea-Soteras, Marta; Sumi, Natalia; Joo, Won Duk; Holmberg, Jennie C; Craveiro, Vinicius; Alvero, Ayesha B; Mor, Gil

    2014-01-01

    The mortality rate of ovarian cancer remains high due to late diagnosis and recurrence. A fundamental step toward improving detection and treatment of this lethal disease is to understand its origin. A growing number of studies have revealed that ovarian cancer can develop from multiple extra-ovarian origins, including fallopian tube, gastrointestinal tract, cervix and endometriosis. However, the mechanism leading to their ovarian localization is not understood. We utilized in vitro, ex vivo, and in vivo models to recapitulate the process of extra-ovarian malignant cells migrating to the ovaries and forming tumors. We provided experimental evidence to support that ovulation, by disrupting the ovarian surface epithelium and releasing chemokines/cytokines, promotes the migration and adhesion of malignant cells to the ovary. We identified the granulosa cell-secreted SDF-1 as a main chemoattractant that recruits malignant cells towards the ovary. Our findings revealed a potential molecular mechanism of how the extra-ovarian cells can be attracted by the ovary, migrate to and form tumors in the ovary. Our data also supports the association between increased ovulation and the risk of ovarian cancer. Understanding this association will lead us to the development of more specific markers for early detection and better prevention strategies. PMID:25135607

  12. Predicting Nitrogen Fertilizer Recommendations for Corn using an Active Sensor

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Active sensors, mounted on typical agricultural equipment, can be used to measure N (nitrogen) status in corn (Zea mays L.). This gives a producer the potential to improve N fertilizer recommendations that will reduce nitrate loss to the environment. This study examines the relationship between re...

  13. Worry tendencies predict brain activation during aversive imagery.

    PubMed

    Schienle, Anne; Schäfer, Axel; Pignanelli, Roman; Vaitl, Dieter

    2009-09-25

    Because of its abstract nature, worrying might function as an avoidance response in order to cognitively disengage from fearful imagery. The present functional magnetic resonance imaging study investigated neural correlates of aversive imagery and their association with worry tendencies, as measured by the Penn State Worry Questionnaire (PSWQ). Nineteen healthy women first viewed, and subsequently imagined pictures from two categories, 'threat' and 'happiness'. Worry tendencies were negatively correlated with brain activation in the anterior cingulate cortex, the prefrontal cortex (dorsolateral, dorsomedial, ventrolateral), the parietal cortex and the insula. These negative correlations between PSWQ scores and localized brain activation were specific for aversive imagery. Moreover, activation in the above mentioned regions was positively associated with the experienced vividness of both pleasant and unpleasant mental pictures. As the identified brain regions are involved in emotion regulation, vivid imagery and memory retrieval, a lowered activity in high PSWQ scorers might be associated with cognitive disengagement from aversive imagery as well as insufficient refresh rates of mental pictures. Our preliminary findings encourage future imagery studies on generalized anxiety disorder patients, as one of the main symptoms of this disorder is excessive worrying. PMID:19545612

  14. Spontaneous activity does not predict morphological type in cerebellar interneurons.

    PubMed

    Haar, Shlomi; Givon-Mayo, Ronit; Barmack, Neal H; Yakhnitsa, Vadim; Donchin, Opher

    2015-01-28

    The effort to determine morphological and anatomically defined neuronal characteristics from extracellularly recorded physiological signatures has been attempted with varying success in different brain areas. Recent studies have attempted such classification of cerebellar interneurons (CINs) based on statistical measures of spontaneous activity. Previously, such efforts in different brain areas have used supervised clustering methods based on standard parameterizations of spontaneous interspike interval (ISI) histograms. We worried that this might bias researchers toward positive identification results and decided to take a different approach. We recorded CINs from anesthetized cats. We used unsupervised clustering methods applied to a nonparametric representation of the ISI histograms to identify groups of CINs with similar spontaneous activity and then asked how these groups map onto different cell types. Our approach was a fuzzy C-means clustering algorithm applied to the Kullbach-Leibler distances between ISI histograms. We found that there is, in fact, a natural clustering of the spontaneous activity of CINs into six groups but that there was no relationship between this clustering and the standard morphologically defined cell types. These results proved robust when generalization was tested to completely new datasets, including datasets recorded under different anesthesia conditions and in different laboratories and different species (rats). Our results suggest the importance of an unsupervised approach in categorizing neurons according to their extracellular activity. Indeed, a reexamination of such categorization efforts throughout the brain may be necessary. One important open question is that of functional differences of our six spontaneously defined clusters during actual behavior. PMID:25632121

  15. Baseline brain activity fluctuations predict somatosensory perception in humans

    PubMed Central

    Boly, M.; Balteau, E.; Schnakers, C.; Degueldre, C.; Moonen, G.; Luxen, A.; Phillips, C.; Peigneux, P.; Maquet, P.; Laureys, S.

    2007-01-01

    In perceptual experiments, within-individual fluctuations in perception are observed across multiple presentations of the same stimuli, a phenomenon that remains only partially understood. Here, by means of thulium–yttrium/aluminum–garnet laser and event-related functional MRI, we tested whether variability in perception of identical stimuli relates to differences in prestimulus, baseline brain activity. Results indicate a positive relationship between conscious perception of low-intensity somatosensory stimuli and immediately preceding levels of baseline activity in medial thalamus and the lateral frontoparietal network, respectively, which are thought to relate to vigilance and “external monitoring.” Conversely, there was a negative correlation between subsequent reporting of conscious perception and baseline activity in a set of regions encompassing posterior cingulate/precuneus and temporoparietal cortices, possibly relating to introspection and self-oriented processes. At nociceptive levels of stimulation, pain-intensity ratings positively correlated with baseline fluctuations in anterior cingulate cortex in an area known to be involved in the affective dimension of pain. These results suggest that baseline brain-activity fluctuations may profoundly modify our conscious perception of the external world. PMID:17616583

  16. Family History Predicts Stress Fracture in Active Female Adolescents

    PubMed Central

    Loud, Keith J.; Micheli, Lyle J.; Bristol, Stephanie; Austin, S. Bryn; Gordon, Catherine M.

    2011-01-01

    OBJECTIVE Increased physical activity and menstrual irregularity have been associated with increased risk for stress fracture among adult women active in athletics. The purposes of this study were to determine whether menstrual irregularity is also a risk factor for stress fracture in active female adolescents and to estimate the quantity of exercise associated with an increased risk for this injury. PATIENTS AND METHODS A case-control study was conducted of 13- to 22-year-old females diagnosed with their first stress fracture, each matched prospectively on age and self-reported ethnicity with 2 controls. Patients with chronic illnesses or use of medications known to affect bone mineral density were excluded, including use of hormonal preparations that could alter menstrual cycles. The primary outcome, stress fracture in any extremity or the spine, was confirmed radiographically. Girls with stress fracture had bone mineral density measured at the lumbar spine by dual-energy x-ray absorptiometry. RESULTS The mean ± SD age of the 168 participants was 15.9 ± 2.1 years; 91.7% were postmenarchal, with a mean age at menarche of 13.1 ± 1.1 years. The prevalence of menstrual irregularity was similar among cases and controls. There was no significant difference in the mean hours per week of total physical activity between girls in this sample with stress fracture (8.2 hours/week) and those without (7.4 hours/week). In multivariate models, case subjects had nearly 3 times the odds of having a family member with osteoporosis or osteopenia. In secondary analyses, participants with stress fracture had a low mean spinal bone mineral density for their age. CONCLUSIONS Among highly active female adolescents, only family history was independently associated with stress fracture. The magnitude of this association suggests that further investigations of inheritable skeletal factors are warranted in this population, along with evaluation of bone mineral density in girls with stress

  17. Predicting Child Physical Activity and Screen Time: Parental Support for Physical Activity and General Parenting Styles

    PubMed Central

    Crain, A. Lauren; Senso, Meghan M.; Levy, Rona L.; Sherwood, Nancy E.

    2014-01-01

    Objective: To examine relationships between parenting styles and practices and child moderate-to-vigorous physical activity (MVPA) and screen time. Methods: Participants were children (6.9 ± 1.8 years) with a body mass index in the 70–95th percentile and their parents (421 dyads). Parent-completed questionnaires assessed parental support for child physical activity (PA), parenting styles and child screen time. Children wore accelerometers to assess MVPA. Results: Parenting style did not predict MVPA, but support for PA did (positive association). The association between support and MVPA, moreover, varied as a function of permissive parenting. For parents high in permissiveness, the association was positive (greater support was related to greater MVPA and therefore protective). For parents low in permissiveness, the association was neutral; support did not matter. Authoritarian and permissive parenting styles were both associated with greater screen time. Conclusions: Parenting practices and styles should be considered jointly, offering implications for tailored interventions. PMID:24812256

  18. IKK inhibition increases bortezomib effectiveness in ovarian cancer

    PubMed Central

    Singha, Bipradeb; Gatla, Himavanth Reddy; Phyo, Sai; Patel, Atish; Chen, Zhe-Sheng; Vancurova, Ivana

    2015-01-01

    Ovarian cancer is associated with increased expression of the pro-angiogenic chemokine interleukin-8 (IL-8, CXCL8), which induces tumor cell proliferation, angiogenesis, and metastasis. Even though bortezomib (BZ) has shown remarkable anti-tumor activity in hematological malignancies, it has been less effective in ovarian cancer; however, the mechanisms are not understood. We have recently shown that BZ unexpectedly induces the expression of IL-8 in ovarian cancer cells in vitro, by IκB kinase (IKK)-dependent mechanism. Here, we tested the hypothesis that IKK inhibition reduces the IL-8 production and increases BZ effectiveness in reducing ovarian tumor growth in vivo. Our results demonstrate that the combination of BZ and the IKK inhibitor Bay 117085 significantly reduces the growth of ovarian tumor xenografts in nude mice when compared to either drug alone. Mice treated with the BZ/Bay 117085 combination exhibit smallest tumors, and lowest levels of IL-8. Furthermore, the reduced tumor growth in the combination group is associated with decreased tumor levels of S536P-p65 NFκB and its decreased recruitment to IL-8 promoter in tumor tissues. These data provide the first in vivo evidence that combining BZ with IKK inhibitor is effective, and suggest that using IKK inhibitors may increase BZ effectiveness in ovarian cancer treatment. PMID:26267322

  19. A6 in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

    ClinicalTrials.gov

    2015-02-27

    Fallopian Tube Carcinoma; Malignant Ovarian Mixed Epithelial Tumor; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Primary Peritoneal Carcinoma; Recurrent Ovarian Carcinoma; Undifferentiated Ovarian Carcinoma

  20. Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells

    PubMed Central

    Yokota, N; Koizume, S; Miyagi, E; Hirahara, F; Nakamura, Y; Kikuchi, K; Ruf, W; Sakuma, Y; Tsuchiya, E; Miyagi, Y

    2009-01-01

    Background: Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis. Methods: In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT–PCR, western blotting and flow cytometry. Results: Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia. Conclusion: These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients. PMID:19904262

  1. Can Ovarian Cancer Be Prevented?

    MedlinePlus

    ... ovaries removed with your doctor. Prevention strategies for women with a family history of ovarian cancer or BRCA mutation If your ... what the results mean to you. For some women with a strong family history of ovarian cancer, knowing they do not have ...

  2. TH-A-9A-01: Active Optical Flow Model: Predicting Voxel-Level Dose Prediction in Spine SBRT

    SciTech Connect

    Liu, J; Wu, Q.J.; Yin, F; Kirkpatrick, J; Cabrera, A; Ge, Y

    2014-06-15

    Purpose: To predict voxel-level dose distribution and enable effective evaluation of cord dose sparing in spine SBRT. Methods: We present an active optical flow model (AOFM) to statistically describe cord dose variations and train a predictive model to represent correlations between AOFM and PTV contours. Thirty clinically accepted spine SBRT plans are evenly divided into training and testing datasets. The development of predictive model consists of 1) collecting a sequence of dose maps including PTV and OAR (spinal cord) as well as a set of associated PTV contours adjacent to OAR from the training dataset, 2) classifying data into five groups based on PTV's locations relative to OAR, two “Top”s, “Left”, “Right”, and “Bottom”, 3) randomly selecting a dose map as the reference in each group and applying rigid registration and optical flow deformation to match all other maps to the reference, 4) building AOFM by importing optical flow vectors and dose values into the principal component analysis (PCA), 5) applying another PCA to features of PTV and OAR contours to generate an active shape model (ASM), and 6) computing a linear regression model of correlations between AOFM and ASM.When predicting dose distribution of a new case in the testing dataset, the PTV is first assigned to a group based on its contour characteristics. Contour features are then transformed into ASM's principal coordinates of the selected group. Finally, voxel-level dose distribution is determined by mapping from the ASM space to the AOFM space using the predictive model. Results: The DVHs predicted by the AOFM-based model and those in clinical plans are comparable in training and testing datasets. At 2% volume the dose difference between predicted and clinical plans is 4.2±4.4% and 3.3±3.5% in the training and testing datasets, respectively. Conclusion: The AOFM is effective in predicting voxel-level dose distribution for spine SBRT. Partially supported by NIH/NCI under grant

  3. Oncolytic virotherapy for ovarian cancer

    PubMed Central

    Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant

    2012-01-01

    In the past two decades, more than 20 viruses with selective tropism for tumor cells have been developed as oncolytic viruses (OVs) for treatments of a variety of malignancies. Of these viruses, eleven have been tested in human ovarian cancer models in preclinical studies. So far, nine phase I or II clinical trials have been conducted or initiated using four different types of OVs in patients with recurrent ovarian cancers. In this article, we summarize the different OVs that are being assessed as therapeutics for ovarian cancer. We also present an overview of recent advances in identification of key genetic or immune-response pathways involved in tumorigenesis of ovarian cancer, which provides a better understanding of the tumor specificities and oncolytic properties of OVs. In addition, we discuss how next-generation OVs could be genetically modified or integrated into multimodality regimens to improve clinical outcomes based on recent advances in ovarian cancer biology. PMID:25977900

  4. Brain metastases from ovarian carcinoma.

    PubMed

    Piura, Ettie; Piura, Benjamin

    2011-01-01

    This paper will focus on knowledge related to brain metastases from ovarian carcinoma. So far, less than 600 cases were documented in the literature with an incidence among ovarian carcinoma patients ranging from 0.29% to 11.6%. The ovarian carcinoma was usually an advanced-stage epithelial serous carcinoma, and the median interval between diagnosis of ovarian carcinoma and brain metastases was 2 years. Most often, brain metastases, affected the cerebrum, were multiple and part of a disseminated disease. Treatment of brain metastasis has evolved over the years from whole brain radiotherapy (WBRT) only to multimodal therapy including surgical resection or stereotactic radiosurgery followed by WBRT and/or chemotherapy. The median survival after diagnosis of brain metastases was 6 months; nevertheless, a significantly better survival was achieved with multimodal therapy compared to WBRT only. It is suggested that brain imaging studies should be included in the followup of patients after treatment for ovarian carcinoma. PMID:22191058

  5. Robotically Assisted Endoscopic Ovarian Transposition

    PubMed Central

    Wedergren, June S.; Carlson, Mark A.

    2003-01-01

    Background: Ovarian transposition is the anatomical relocation of the ovaries from the pelvis to the abdomen. Transposition is beneficial in women who are to undergo pelvic radiation, because it allows maintenance of ovarian function and preservation of assisted reproductive capacity. Methods: The da Vinci surgical system (Intuitive Surgical™, Mountainview, CA, USA) was used to perform an endoscopic ovarian transposition. The ovaries were mobilized on their respective infundibulopelvic ligaments and sutured to the ipsilateral pericolic gutters. Results: A series of laboratory sessions using the da Vinci system was completed at our institution's training facility. Surgical experience included cadaveric pelvic dissection and abdominopelvic procedures on anesthetized porcine models. Additional didactic and labor