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Sample records for determines ovarian response

  1. Single nucleotide polymorphisms in the anti-Müllerian hormone signalling pathway do not determine high or low response to ovarian stimulation.

    PubMed

    Hanevik, Hans Ivar; Hilmarsen, Hilde Tveitan; Skjelbred, Camilla Furu; Tanbo, Tom; Kahn, Jarl A

    2010-11-01

    There is substantial variability in ovarian response to exogenous gonadotrophins in women undergoing ovarian stimulation for IVF. Genetic variation in signalling pathways of the ovary could influence ovarian stimulation outcome. Studies have shown a correlation between the serum concentration of anti-Müllerian hormone (AMH) and ovarian stimulation outcome. This paper present a retrospective case-controlled genetic association study designed to test the association between single nucleotide polymorphisms (SNP) in the AMH signalling pathway and two clinically important outcomes of ovarian stimulation: low and high response. Blood samples from 53 high responders, 38 low responders and 100 controls were analysed for eight SNP of interest. Odds ratios and 95% confidence intervals were estimated by a binary logistic regression model adjusting for age and body mass index. As far as is known, this is the first report on the influence of these SNP, present in approximately 19% of women, on ovarian stimulation outcome. No statistically significant association was found between any of the SNP studied and high or low response to ovarian stimulation. It seems unnecessary to detect these SNP when applying the serum concentration of AMH as a predictor of ovarian response to stimulation. Many infertile couples are treated by IVF. Part of this treatment is to pharmacologically stimulate the ovaries to develop many oocytes simultaneously. This process is called ovarian stimulation. Some women respond either too little (low responders) or too much (high responders) to ovarian stimulation. Both these situations are unfavourable to the woman. This study evaluates whether these chances of having one of these two outcomes of ovarian stimulationare influenced by variation in the gene for anti-Müllerian hormone (AMH) or its receptor. This is done by taking blood samples from three groups of patients: low responders, high responders and controls with a normal response. These blood samples

  2. Expression of p16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer

    PubMed Central

    Konecny, Gottfried E.; Winterhoff, Boris; Kolarova, Teodora; Qi, Jingwei; Manivong, Kanthinh; Dering, Judy; Yang, Guorong; Chalukya, Meenal; Wang, He-Jing; Anderson, Lee; Kalli, Kimberly R.; Finn, Richard S.; Ginther, Charles; Jones, Siân; Velculescu, Victor E.; Riehle, Darren; Cliby, William A.; Randolph, Sophia; Koehler, Maria; Hartmann, Lynn C.; Slamon, Dennis J.

    2015-01-01

    Purpose PD-0332991 is a selective inhibitor of the CDK4/6 kinases with the ability to block retinoblastoma (Rb) phosphorylation in the low nanomolar range. Here we investigate the role of CDK4/6 inhibition in human ovarian cancer. Experimental Design We examined the effects of PD-0332991 on proliferation, cell-cycle, apoptosis, and Rb phosphorylation using a panel of 40 established human ovarian cancer cell lines. Molecular markers for response prediction, including p16 and Rb, were studied using gene expression profiling, Western blot, and array CGH. Multiple drug effect analysis was used to study interactions with chemotherapeutic drugs. Expression of p16 and Rb was studied using immunohistochemistry in a large clinical cohort of ovarian cancer patients. Results Concentration-dependent antiproliferative effects of PD-0332991 were seen in all ovarian cancer cell lines, but varied significantly between individual lines. Rb-proficient cell lines with low p16 expression were most responsive to CDK4/6 inhibition. Copy number variations of CDKN2A, RB, CCNE1, and CCND1 were associated with response to PD-0332991. CDK4/6 inhibition induced G0/G1 cell cycle arrest, blocked Rb phosphorylation in a concentration-and time-dependent manner, and enhanced the effects of chemotherapy. Rb-proficiency with low p16 expression was seen in 97/262 (37%) of ovarian cancer patients and was independently associated with poor progression-free survival (adjusted relative risk 1.49, 95% CI 1.00 –2.24, P = 0.052). Conclusions PD-0332991 shows promising biologic activity in ovarian cancer cell lines. Assessment of Rb and p16 expression may help select patients most likely to benefit from CDK4/6 inhibition in ovarian cancer. PMID:21278246

  3. Parity History Determines a Systemic Inflammatory Response to Spread of Ovarian Cancer in Naturally Aged Mice.

    PubMed

    Urzua, Ulises; Chacon, Carlos; Lizama, Luis; Sarmiento, Sebastián; Villalobos, Pía; Kroxato, Belén; Marcelain, Katherine; Gonzalez, María-Julieta

    2017-10-01

    Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.

  4. Immune response evaluation through determination of type 1, type 2, and type 17 patterns in patients with epithelial ovarian cancer.

    PubMed

    Cândido, Eduardo Batista; Silva, Luciana Maria; Carvalho, Andréa Teixeira; Lamaita, Rívia Mara; Filho, Roberto Mundim Porto; Cota, Bianca Della Croce Vieira; da Silva-Filho, Agnaldo Lopes

    2013-07-01

    Innate and adaptive immune cells secrete different cytokines, which participate through distinct mechanisms in cell-mediated immunity and humoral immune responses. The aim of this study was to evaluate the immune response through analysis of type 1 (Th1), Th2, and Th17 cells in patients with epithelial ovarian cancer (EOC). Our study included 44 patients with EOC (study group) and 32 gynecological patients with no ovarian disease (control group). Fragments of ovarian tissue and blood samples were collected in both groups and aliquots of intracystic fluid and peritoneal fluid were recovered from the EOC patient group. Interleukin (IL)-2/IL-4/IL-6/IL-10/IL-17/tumor necrosis factor (TNF)-α/interferon (IFN)-γ levels were measured by cytometric bead array. Statistical analysis included chi-squared, Student t, Mann-Whitney, Kruskal-Wallis tests, and Cox regression model. Patients with EOC were associated with higher levels of TNF-α/IL-4/IL-6/IL-10 compared to the control group. Both IL-10 and TNF-α concentrations were higher in patients with stage III/IV EOC and also associated with higher levels of cancer antigen 125. Higher Th1-mediated immune response was observed when the cytoreduction was considered optimal. However, patients with EOC with unsatisfactory cytoreductive surgery and undifferentiated tumors were associated with higher concentrations of Th2 cytokines in the 4 sites studied. Higher IL-6/IL-10 and lower IFN-γ concentrations were also associated with a lower overall survival rate in patients with EOC. The EOC group presented a predominantly Th2 response and an immunosuppressant standard and had association between IL-6/IL-10/IFN-γ and prognosis.

  5. Drug resistance features and S-phase fraction as possible determinants for drug response in a panel of human ovarian cancer xenografts

    PubMed Central

    Kolfschoten, G M; Hulscher, T M; Pinedo, H M; Boven, E

    2000-01-01

    Multidrug resistance (MDR) and more specifically the expression of P-glycoprotein (Pgp) have been studied extensively in vitro. Unfortunately, it appears that the predictive value of MDR recognized in vitro is mostly an incorrect measure to determine the responsiveness of a particular tumour in the clinic. This misunderstood or overvalued role of MDR might explain the failure of strategies to reverse Pgp function by the use of modulators in solid tumours. To obtain more insight in in vivo drug resistance we investigated a panel of 15 human ovarian cancer xenografts consisting of the most common histological subtypes known in ovarian cancer patients. The response rate to cisplatin, cyclophosphamide and doxorubicin in the xenografts resembled the results of phase II trials with these agents in ovarian cancer patients. This resemblance justifies drug resistance studies in this experimental in vivo human tumour system. We determined the expression levels of MDR 1, MRP 1, LRP and topoisomerase IIα mRNA by the RNase protection assay and the presence of MRP1 and LRP proteins by immunohistochemistry. The S-phase fraction was investigated as a separate parameter by flow cytometry. In none of the 15 ovarian cancer xenografts was MDR 1 expression detectable. The expression levels of MRP 1 and LRP were low to moderate and resembled the presence of the MRP1 and LRP proteins. There was a weak, inverse relationship between the expression levels of LRP and sensitivity to cisplatin and cyclophosphamide (r = –0.44 and –0.45), but not to doxorubicin. The levels of topoisomerase IIα varied among the xenografts (0.73–2.66) and failed to correlate with doxorubicin resistance (r = 0.14). The S-phase fraction, however, showed a relation with the sensitivity to cisplatin (r = 0.66). Among the determinants studied in ovarian cancer in vivo, LRP mRNA and the S-phase fraction were the best predictive factors for drug response and most specifically for the activity of cisplatin.

  6. Female Reproductive Decline Is Determined by Remaining Ovarian Reserve and Age

    PubMed Central

    Wilkosz, Pawel; Greggains, Gareth D.; Tanbo, Tom G.; Fedorcsak, Peter

    2014-01-01

    The early decline and loss of female fertility in humans and other species represents an evolutionary paradox. Despite being born with a vast stock of oocytes, females encounter an exhaustion of ovarian reserve and sterility half way through their natural lives. Female reproductive ageing has been proposed to proceed as an ongoing decline in ovarian reserve, determined by remaining ovarian follicle number. However, despite extensive modelling, the respective contributions of intra-, inter-, and extra-ovarian signalling have not been fully characterised. It remains unclear whether reproductive ageing progresses simply as a pre-determined function of remaining ovarian follicles, or as an age-dependent process in humans. Here, we have analysed ovarian response to hormonal stimulation in women who have undergone surgical removal of a single ovary, in order to investigate the relative contributions of intra-, inter, and extra-ovarian signalling on reproductive ageing. Our data show that in unilaterally oophorectomised women, ovarian response to follicle stimulating hormone (FSH) declines beyond levels predicted by a total ovarian follicle pool model of reproductive ageing. Maintenance of ovarian function later in reproductive life, despite the removal of half of the total ovarian reserve, suggests a role for an extra-ovarian age-dependent regulation of reproductive decline. This highlights the need for further work to identify signalling factors that communicate age-related signals between the soma and the germline. PMID:25310678

  7. Ovarian response in consecutive cycles of ovarian stimulation in normally ovulating women.

    PubMed

    Ahmed Ebbiary, N A; Morgan, C; Martin, K; Afnan, M; Newton, J R

    1995-03-01

    Ovarian stimulation combined with intra-uterine insemination (IUI) is an effective treatment of non-tubal infertility but most women undergo several cycles of treatment to achieve a pregnancy. This prospective study was designed to assess the consistency (or variation) of ovarian responses and the effect of various ovarian stimulation protocols on this consistency in consecutive cycles of ovarian stimulation and IUI in women with non-ovulatory infertility. A total of 86 regularly menstruating ovulating patients each completed three to six cycles of ovarian stimulation and IUI (n = 347 cycles). Ovarian stimulation was achieved by sequential clomiphene citrate/human menopausal gonadotrophin (HMG), HMG-only or combined gonadotrophin-releasing hormone analogue--HMG protocols in 33, 29 and 24 patients respectively, and each patient used the same protocol consistently throughout the study. Standard methods were used to monitor ovarian response and to perform IUI. Using each patient as her own control, repeated measurements analysis of variance revealed consistency of ovarian response in consecutive ovarian stimulation cycles, as shown by the number and mean diameter of maturing pre-ovulatory follicles, peak plasma oestradiol, duration of stimulation and mean HMG requirements. This consistency existed using any of the ovarian stimulation protocols. We conclude that regularly menstruating and ovulating women are likely to have similar ovarian responses in consecutive cycles of ovarian stimulation and IUI if the same ovarian stimulation protocol is used consistently.(ABSTRACT TRUNCATED AT 250 WORDS)

  8. Reference values in ovarian response to controlled ovarian stimulation throughout the reproductive period.

    PubMed

    La Marca, Antonio; Grisendi, Valentina; Spada, Elena; Argento, Cindy; Milani, Silvano; Plebani, Maddalena; Seracchioli, Renato; Volpe, Annibale

    2014-01-01

    Abstract The age-related decline in ovarian response to gonadotropins has been well known since the beginning of ovarian stimulation in IVF cycles and has been considered secondary to the age-related decline in ovarian reserve. The objective of this study was to establish reference values and to construct nomograms of ovarian response for any specific age to gonadotropins in IVF/ICSI cycles. We analyzed our database containing information on IVF cycles. According to inclusion and exclusion criteria, a total of 703 patients were selected. Among inclusion criteria, there were regular menstrual cycle, treatment with a long GnRH agonist protocol and starting follicle-stimulating hormone (FSH) dose of at least 200 IU per day. To estimate the reference values of ovarian response, the CG-LMS method was used. A linear decline in the parameters of ovarian response with age was observed: the median number of oocytes decreases approximately by one every three years, and the median number of follicles >16 mm by one every eight years. The number of oocytes and growing follicles corresponding to the 5th, 25th, 50th, 75th and 95th centiles has been calculated. This study confirmed the well known negative relationship between ovarian response to FSH and female ageing and permitted the construction of nomograms of ovarian response.

  9. Integrated analysis reveals tubal and ovarian originated serous ovarian cancer and predicts differential therapeutic responses.

    PubMed

    Hao, Dapeng; Li, Jingjing; Jia, Shanshan; Meng, Yuan; Wang, Li; Zhang, Chao; Di, Li-Jun

    2017-09-22

    The relative importance of fallopian tube (FT) compared to ovarian surface epithelium (OSE) in the genesis of serous type of ovarian cancer (SOC) is still unsettled. Here, we followed an integrated approach to study the tissue origin of SOC, as well as its association with clinical outcome and response to therapeutic drugs. A collection of transcriptome data of 80 FTs, 89 OSEs and 2,668 SOCs was systematically analyzed to determine the characteristic of FT-like and OSE-like tumors. A molecular signature was developed for identifying tissue origin of SOC and then was used to re-evaluate the prognostic genes and therapeutic biomarkers of SOC of different tissue origins. IHC staining of tissue array and functional experiments on a panel of ovarian cancer cell lines were used to further validate the key findings. The expression patterns of tissue specific genes, prognostic genes and molecular markers all support a dualistic tissue origin of SOC, from either FT or OSE. A molecular signature was established to identify the tissue identity of SOCs. Surprisingly, the signature showed a strong association with overall survival [OSE-like versus FT-like, HR = 4.16, 95%CI, 2.67-6.48, p<10-9]. The phamacogenomic approach revealed AXL to be a therapeutic target of the aggressive OSE-derived SOC. SOC has two subtypes originated from either FT or OSE, which show different clinical and pathological features. Copyright ©2017, American Association for Cancer Research.

  10. Epigenetic determinants of ovarian clear cell carcinoma biology

    PubMed Central

    Yamaguchi, Ken; Huang, Zhiqing; Matsumura, Noriomi; Mandai, Masaki; Okamoto, Takako; Baba, Tsukasa; Konishi, Ikuo; Berchuck, Andrew; Murphy, Susan K.

    2015-01-01

    Targeted approaches have revealed frequent epigenetic alterations in ovarian cancer, but the scope and relation of these changes to histologic subtype of disease is unclear. Genome-wide methylation and expression data for 14 clear cell carcinoma (CCC), 32 non-CCC, and 4 corresponding normal cell lines were generated to determine how methylation profiles differ between cells of different histological derivations of ovarian cancer. Consensus clustering showed that CCC is epigenetically distinct. Inverse relationships between expression and methylation in CCC were identified, suggesting functional regulation by methylation, and included 22 hypomethylated (UM) genes and 276 hypermethylated (HM) genes. Categorical and pathway analyses indicated that the CCC-specific UM genes were involved in response to stress and many contain hepatocyte nuclear factor (HNF) 1 binding sites, while the CCC-specific HM genes included members of the estrogen receptor alpha (ERalpha) network and genes involved in tumor development. We independently validated the methylation status of 17 of these pathway-specific genes, and confirmed increased expression of HNF1 network genes and repression of ERalpha pathway genes in CCC cell lines and primary cancer tissues relative to non-CCC specimens. Treatment of three CCC cell lines with the demethylating agent Decitabine significantly induced expression for all five genes analyzed. Coordinate changes in pathway expression were confirmed using two primary ovarian cancer datasets (p<0.0001 for both). Our results suggest that methylation regulates specific pathways and biological functions in CCC, with hypomethylation influencing the characteristic biology of the disease while hypermethylation contributes to the carcinogenic process. PMID:24382740

  11. Inherited Determinants of Ovarian Cancer Survival

    PubMed Central

    Goode, Ellen L.; Maurer, Matthew J.; Sellers, Thomas A.; Phelan, Catherine M.; Kalli, Kimberly R.; Fridley, Brooke L.; Vierkant, Robert A.; Armasu, Sebastian M.; White, Kristin L.; Keeney, Gary L.; Cliby, William A.; Rider, David N.; Kelemen, Linda E.; Jones, Monica B.; Peethambaram, Prema P.; Lancaster, Johnathan M.; Olson, Janet E.; Schildkraut, Joellen M.; Cunningham, Julie M.; Hartmann, Lynn C.

    2010-01-01

    Purpose Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence. Experimental Design Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1 – 8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNPs). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for known prognostic factors. Results Variation within angiogenesis was most strongly associated with survival time overall (p=0.03) and among patients with serous cancer (p=0.05), particularly for EIF2B5 rs4912474 (all patients HR 0.69, 95% CI 0.54-0.89, p=0.004), VEGFC rs17697305 (serous subtype HR 2.29, 95% CI 1.34-3.92, p=0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, p=0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up. Conclusion An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain. PMID:20103664

  12. The meaning of anti-Müllerian hormone levels in patients at a high risk of poor ovarian response

    PubMed Central

    Park, Hyun Jong; Lee, Geun Ho; Gong, Du Sik; Yoon, Tae Ki

    2016-01-01

    Measurements of ovarian reserve play an important role in predicting the clinical results of assisted reproductive technology (ART). The ideal markers of ovarian reserve for clinical applications should have high specificity in order to determine genuine poor responders. Basal follicle-stimulating hormone levels, antral follicle count, and serum anti-Müllerian hormone (AMH) levels have been suggested as ovarian reserve tests that may fulfill this requirement, with serum AMH levels being the most promising parameter. Serum AMH levels have been suggested to be a predictor of clinical pregnancy in ART for older women, who are at a high risk for decreased ovarian response. We reviewed the prognostic significance of ovarian reserve tests for patients undergoing ART treatment, with a particular focus on the significance of serum AMH levels in patients at a high risk of poor ovarian response. PMID:27689035

  13. The meaning of anti-Müllerian hormone levels in patients at a high risk of poor ovarian response.

    PubMed

    Park, Hyun Jong; Lee, Geun Ho; Gong, Du Sik; Yoon, Tae Ki; Lee, Woo Sik

    2016-09-01

    Measurements of ovarian reserve play an important role in predicting the clinical results of assisted reproductive technology (ART). The ideal markers of ovarian reserve for clinical applications should have high specificity in order to determine genuine poor responders. Basal follicle-stimulating hormone levels, antral follicle count, and serum anti-Müllerian hormone (AMH) levels have been suggested as ovarian reserve tests that may fulfill this requirement, with serum AMH levels being the most promising parameter. Serum AMH levels have been suggested to be a predictor of clinical pregnancy in ART for older women, who are at a high risk for decreased ovarian response. We reviewed the prognostic significance of ovarian reserve tests for patients undergoing ART treatment, with a particular focus on the significance of serum AMH levels in patients at a high risk of poor ovarian response.

  14. [In vitro cell response to chemotherapeutic agents, to personalize ovarian cancer treatment: report of two cases].

    PubMed

    Carolina Ibáñez, C; Marcelo Garrido, S; Medina, Lidia; Kato, Sumie; Bravo, María Loreto; González, Pamela; Oliva, Barbara; Pizarro, Javier; Bustamante, Eva; Brañes, Jorge; Cuello, Mauricio; Owen, Gareth I

    2013-05-01

    Our laboratory has implemented an in vitro assay to estimate the response to chemotherapy in ovarian cancer cells pertaining to individual patients. In two selected patients, we determined the correlation between an in vitro assay of cells from suspected ovarian cancer ascites, with the clinical chemotherapy response. Cancer cells isolated from peritoneal fluid with suspected ovarian cancer were tested for cytotoxicity with corresponding chemotherapy regimens. Circulating Cal25 levels and attending physician consultation determined clinical course and response to chemotherapy. The in vitro assay result correlated with Cal25 levels, progression free survival and attending physician evaluation. The assay predicted correctly the failure of two successive chemotherapy regimes in the first patient, while predicting a favorable clinical response in the second subject.

  15. Effects of resveratrol on ovarian response to controlled ovarian hyperstimulation in ob/ob mice.

    PubMed

    Cabello, Estefanía; Garrido, Pablo; Morán, Javier; González del Rey, Carmen; Llaneza, Plácido; Llaneza-Suárez, David; Alonso, Ana; González, Celestino

    2015-02-01

    To evaluate antidiabetic and anti-inflammatory effects of resveratrol on the ovarian response to controlled ovarian hyperstimulation (COH) in obesity-related infertility. Experimental. University laboratory. Sixteen female ob/ob mice and 16 female C57BL/6J mice undergoing COH. Wild-type placebo group; wild-type resveratrol group; ob/ob mice placebo group; ob/ob mice resveratrol group. Resveratrol 3.75 mg/kg daily for 20 days and undergoing COH protocol. Body and reproductive system weight, food intake, fasting blood glucose, plasma insulin and T levels, and Homeostatic Index of Insulin Resistance; interleukin-6 and tumor necrosis factor-α levels in adipose tissue by Western blot; assessment of quality and quantity of oocytes retrieved; and quantitative analysis of ovarian follicles. Plasma insulin and T levels decreased and Homeostatic Index of Insulin Resistance improved in ob/ob mice treated with resveratrol. Interleukin-6 and tumor necrosis factor-α levels were significantly reverted back to near normalcy after resveratrol treatment in obese mice. Administration of resveratrol resulted in a significantly higher number of oocytes collected in wild-type mice. The number of primary, growing, preovulatory, and atretic follicles was found to be decreased in the group of obese mice treated with resveratrol when compared with the obese control group. Resveratrol administration could exert benefits against loss of ovarian follicles, and these actions may be mediated, at least in part, via anti-inflammatory, insulin-sensitizing, and antihyperandrogenism effects. These observations further validate the therapeutic potential of resveratrol to preserve ovarian reserve in conditions associated with obesity. Our results suggest the possible clinical use of resveratrol to enhance the ovarian response to COH in normal-weight females. Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  16. BAD phosphorylation determines ovarian cancer chemosensitivity and patient survival.

    PubMed

    Marchion, Douglas C; Cottrill, Hope M; Xiong, Yin; Chen, Ning; Bicaku, Elona; Fulp, William J; Bansal, Nisha; Chon, Hye Sook; Stickles, Xiaomang B; Kamath, Siddharth G; Hakam, Ardeshir; Li, Lihua; Su, Dan; Moreno, Carolina; Judson, Patricia L; Berchuck, Andrew; Wenham, Robert M; Apte, Sachin M; Gonzalez-Bosquet, Jesus; Bloom, Gregory C; Eschrich, Steven A; Sebti, Said; Chen, Dung-Tsa; Lancaster, Johnathan M

    2011-10-01

    Despite initial sensitivity to chemotherapy, ovarian cancers (OVCA) often develop drug resistance, which limits patient survival. Using specimens and/or genomic data from 289 patients and a panel of cancer cell lines, we explored genome-wide expression changes that underlie the evolution of OVCA chemoresistance and characterized the BCL2 antagonist of cell death (BAD) apoptosis pathway as a determinant of chemosensitivity and patient survival. Serial OVCA cell cisplatin treatments were performed in parallel with measurements of genome-wide expression changes. Pathway analysis was carried out on genes associated with increasing cisplatin resistance (EC(50)). BAD-pathway expression and BAD protein phosphorylation were evaluated in patient samples and cell lines as determinants of chemosensitivity and/or clinical outcome and as therapeutic targets. Induced in vitro OVCA cisplatin resistance was associated with BAD-pathway expression (P < 0.001). In OVCA cell lines and primary specimens, BAD protein phosphorylation was associated with platinum resistance (n = 147, P < 0.0001) and also with overall patient survival (n = 134, P = 0.0007). Targeted modulation of BAD-phosphorylation levels influenced cisplatin sensitivity. A 47-gene BAD-pathway score was associated with in vitro phosphorylated BAD levels and with survival in 142 patients with advanced-stage (III/IV) serous OVCA. Integration of BAD-phosphorylation or BAD-pathway score with OVCA surgical cytoreductive status was significantly associated with overall survival by log-rank test (P = 0.004 and P < 0.0001, respectively). The BAD apoptosis pathway influences OVCA chemosensitivity and overall survival, likely via modulation of BAD phosphorylation. The pathway has clinical relevance as a biomarker of therapeutic response, patient survival, and as a promising therapeutic target. ©2011 AACR

  17. OVARIAN RESERVE TESTS AND THEIR UTILITY IN PREDICTING RESPONSE TO CONTROLLED OVARIAN STIMULATION IN RHESUS MONKEYS

    PubMed Central

    Wu, Julie M.; Takahashi, Diana L; Ingram, Donald K.; Mattison, Julie A.; Roth, George; Ottinger, Mary Ann; Zelinski, Mary B.

    2010-01-01

    Controlled ovarian stimulation (COS) is an alternative to natural breeding in nonhuman primates; however, these protocols are costly with no guarantee of success. Toward the objective of predicting COS outcome in rhesus monkeys, the current study evaluated three clinically used ovarian reserve tests (ORTs): day 3 (d3) follicle-stimulating hormone (FSH) with d3 inhibin B (INHB), the clomiphene citrate challenge test (CCCT), and the exogenous FSH Ovarian Reserve Test (EFORT). A COS was also performed and response was classified as either successful (COS+) or unsuccessful (COS−) and retrospectively compared to ORT predictions. FSH and INHB were assessed for best hormonal index in conjunction with the aforementioned tests. INHB was consistently more accurate than FSH in all ORTs used. Overall, a modified version of the CCCT using INHB values yielded the best percentage of correct predictions. This is the first report of ORT evaluation in rhesus monkeys and may provide a useful diagnostic test prior to costly follicle stimulations, as well as predicting the onset of menopause. PMID:20336797

  18. YY1 modulates taxane response in epithelial ovarian cancer

    SciTech Connect

    Matsumura, Noriomi; Huang, Zhiqing; Baba, Tsukasa; Lee, Paula S.; Barnett, Jason C.; Mori, Seiichi; Chang, Jeffrey T.; Kuo, Wen-Lin; Gusberg, Alison H.; Whitaker, Regina S.; Gray, JoeW.; Fujii, Shingo; Berchuck, Andrew; Murphy, Susan K.

    2008-10-10

    The results of this study show that a high YY1 gene signature (characterized by coordinate elevated expression of transcription factor YY1 and putative YY1 target genes) within serous epithelial ovarian cancers is associated with enhanced response to taxane-based chemotherapy and improved survival. If confirmed in a prospective study, these results have important implications for the potential future use of individualized therapy in treating patients with ovarian cancer. Identification of the YY1 gene signature profile within a tumor prior to initiation of chemotherapy may provide valuable information about the anticipated response of these tumors to taxane-based drugs, leading to better informed decisions regarding chemotherapeutic choice. Survival of ovarian cancer patients is largely dictated by their response to chemotherapy, which depends on underlying molecular features of the malignancy. We previously identified YIN YANG 1 (YY1) as a gene whose expression is positively correlated with ovarian cancer survival. Herein we investigated the mechanistic basis of this association. Epigenetic and genetic characteristics of YY1 in serous epithelial ovarian cancer (SEOC) were analyzed along with YY1 mRNA and protein. Patterns of gene expression in primary SEOC and in the NCI60 database were investigated using computational methods. YY1 function and modulation of chemotherapeutic response in vitro was studied using siRNA knockdown. Microarray analysis showed strong positive correlation between expression of YY1 and genes with YY1 and transcription factor E2F binding motifs in SEOC and in the NCI60 cancer cell lines. Clustering of microarray data for these genes revealed that high YY1/E2F3 activity positively correlates with survival of patients treated with the microtubule stabilizing drug paclitaxel. Increased sensitivity to taxanes, but not to DNA crosslinking platinum agents, was also characteristic of NCI60 cancer cell lines with a high YY1/E2F signature. YY1

  19. Oocyte production and ovarian steroid concentrations of immature rats in response to some commercial gonadotrophin preparations.

    PubMed

    Henderson, K M; Weaver, A; Wards, R L; Ball, K; Lun, S; Mullin, C; McNatty, K P

    1990-01-01

    Four commercial gonadotrophin preparations, namely Folligon, F.S.H.-P., Folltropin and Ovagen, were examined for their effects on oocyte production and ovarian steroid concentrations in immature rats. The ratios of the FSH to LH concentrations of the preparations, determined by radioreceptor assays, were Folligon 5, F.S.H.-P. 18, Folltropin 49 and Ovagen 1090. Forty-eight hours after administering each gonadotrophin preparation to immature rats, ovulation was induced by injection of chorionic gonadotrophin. Twenty-four hours later, oocytes were recovered from the oviducts and counted. Oocytes were produced after injection of chorionic gonadotrophin following a single injection of Folligon (10-50 i.u.). However, no oocytes were produced in response to the other gonadotrophin preparations unless they were administered by continuous infusion (30-1000 micrograms day-1). When given by injection (Folligon) or infusion (others), the gonadotrophin preparations all promoted a dose-dependent increase in mean oocyte production, except at the highest doses when mean oocyte numbers either remained unchanged or declined significantly in the cases of Folligon and F.S.H.-P. The highest mean numbers of oocytes produced in response to Folltropin (48 +/- 9 oocytes, mean +/- s.e.m.) and Ovagen (47 +/- 7) were greater than those attained with Folligon (21 +/- 6) or F.S.H.-P. (31 +/- 5). Mean ovarian weights also increased in a dose-dependent fashion in response to each of the gonadotrophin preparations. Measurements of ovarian steroid concentrations 48 h after the onset of gonadotrophin treatment (i.e. immediately prior to ovulation induction with chorionic gonadotrophin) showed that the gonadotrophin preparations markedly influenced the ratios of ovarian oestradiol-17 beta and androgen (androstenedione plus testosterone) concentrations. At low doses the gonadotrophin preparations increased the ratio of oestradiol-17 beta to androgens, but at the highest doses, with the exception of

  20. Prognostic models for high and low ovarian responses in controlled ovarian stimulation using a GnRH antagonist protocol

    PubMed Central

    Broekmans, Frank J.; Verweij, Pierre J.M.; Eijkemans, Marinus J.C.; Mannaerts, Bernadette M.J.L.; Witjes, Han

    2014-01-01

    STUDY QUESTION Can predictors of low and high ovarian responses be identified in patients undergoing controlled ovarian stimulation (COS) in a GnRH antagonist protocol? SUMMARY ANSWER Common prognostic factors for high and low ovarian responses were female age, antral follicle count (AFC) and basal serum FSH and LH. WHAT IS KNOWN ALREADY Predictors of ovarian response have been identified in GnRH agonist protocols. With the introduction of GnRH antagonists to prevent premature LH rises during COS, and the gradual shift in use of long GnRH agonist to short GnRH antagonist protocols, there is a need for data on the predictability of ovarian response in GnRH antagonist cycles. STUDY DESIGN, SIZE, DURATION A retrospective analysis of data from the Engage trial and validation with the Xpect trial. Prognostic models were constructed for high (>18 oocytes retrieved) and low (<6 oocytes retrieved) ovarian response. Model building was based on the recombinant FSH (rFSH) arm (n = 747) of the Engage trial. Multivariable logistic regression models were constructed in a stepwise fashion (P < 0.15 for entry). Validation based on calibration was performed in patients with equivalent treatment (n = 199) in the Xpect trial. PARTICIPANTS/MATERIALS, SETTING, METHODS Infertile women with an indication for COS prior to IVF. The Engage and Xpect trials included patients of similar ethnic origins from North America and Europe who had regular menstrual cycles. The main causes of infertility were male factor, tubal factor and endometriosis. MAIN RESULTS AND THE ROLE OF CHANCE In the Engage trial, 18.3% of patients had a high and 12.7% had a low ovarian response. Age, AFC, serum FSH and serum LH at stimulation Day 1 were prognostic for both high and low ovarian responses. Higher AFC and LH were associated with an increased chance of high ovarian response. Older age and higher FSH correlated with an increased chance of low ovarian response. Region (North America/Europe) and BMI were

  1. Usefulness of oocyte accumulation in low ovarian response for PGS.

    PubMed

    Martínez, Francisca; Barbed, Cayetana; Parriego, Mónica; Solé, Miquel; Rodríguez, Ignacio; Coroleu, Buenaventura

    2016-07-01

    This is an observational study of the response to ovarian stimulation and preimplantational genetic screening (PGS) cycles of 188 patients with a foreseen high aneuploid rate, undergoing two or three stimulation cycles (2SC and 3SC) and oocyte vitrification to accumulate oocytes (Accumulation group = 112 patients) compared to patients undergoing one stimulation cycle (1SC Group= 76 patients) and fresh embryo transfer, between January 2011 and July 2014. Accumulation was performed when <10 MII oocytes were retrieved. Oocytes were vitrified for later warming and IVF, when the planned number of oocytes was achieved. After PGS, euploid embryos were transferred. Comparing 2SC Group with 3SC Group, AMH, AFC, number of oocytes retrieved per pick-up and total number of biopsied embryos were significantly higher in the 2SC Group. After chromosome analysis, 18.5% of biopsied embryos were euploid and 58.9% patients reached embryo transfer. There were no differences in pregnancy rates per patient between the 1SC, 2SC and 3SC Groups (36.8%, 34.9% and 31.0%, respectively) or per embryo transfer (59.6, 56.8 and 60%, respectively). In patients with <10 MII oocytes after ovarian stimulation undergoing PGS, accumulating oocytes can render a pregnancy rate per patient and per embryo transfer comparable to those of fresh PGS cycles.

  2. Small cell ovarian carcinoma: genomic stability and responsiveness to therapeutics

    PubMed Central

    2013-01-01

    Background The biology of small cell ovarian carcinoma of the hypercalcemic type (SCCOHT), which is a rare and aggressive form of ovarian cancer, is poorly understood. Tumourigenicity, in vitro growth characteristics, genetic and genomic anomalies, and sensitivity to standard and novel chemotherapeutic treatments were investigated in the unique SCCOHT cell line, BIN-67, to provide further insight in the biology of this rare type of ovarian cancer. Method The tumourigenic potential of BIN-67 cells was determined and the tumours formed in a xenograft model was compared to human SCCOHT. DNA sequencing, spectral karyotyping and high density SNP array analysis was performed. The sensitivity of the BIN-67 cells to standard chemotherapeutic agents and to vesicular stomatitis virus (VSV) and the JX-594 vaccinia virus was tested. Results BIN-67 cells were capable of forming spheroids in hanging drop cultures. When xenografted into immunodeficient mice, BIN-67 cells developed into tumours that reflected the hypercalcemia and histology of human SCCOHT, notably intense expression of WT-1 and vimentin, and lack of expression of inhibin. Somatic mutations in TP53 and the most common activating mutations in KRAS and BRAF were not found in BIN-67 cells by DNA sequencing. Spectral karyotyping revealed a largely normal diploid karyotype (in greater than 95% of cells) with a visibly shorter chromosome 20 contig. High density SNP array analysis also revealed few genomic anomalies in BIN-67 cells, which included loss of heterozygosity of an estimated 16.7 Mb interval on chromosome 20. SNP array analyses of four SCCOHT samples also indicated a low frequency of genomic anomalies in the majority of cases. Although resistant to platinum chemotherapeutic drugs, BIN-67 cell viability in vitro was reduced by >75% after infection with oncolytic viruses. Conclusions These results show that SCCOHT differs from high-grade serous carcinomas by exhibiting few chromosomal anomalies and lacking TP53

  3. Ovarian response prediction in controlled ovarian stimulation for IVF using anti-Müllerian hormone in Chinese women

    PubMed Central

    Zheng, Haiyan; Chen, Shiping; Du, Hongzi; Ling, Jiawei; Wu, Yixuan; Liu, Haiying; Liu, Jianqiao

    2017-01-01

    Abstract The predictive value of anti-Müllerian hormone (AMH) in Chinese women undergoing in vitro fertilization (IVF) treatment is data deficient. To determine the attributes of AMH in IVF, oocyte yield, cycle cancellation, and pregnancy outcomes were analyzed. All patients initiating their first IVF cycle with gonadotropin-releasing hormone agonist treatment in our center from October 2013 through December 2014 were included, except patients diagnosed with polycystic ovarian syndrome. Serum samples collected prior to IVF treatment were used to determine serum AMH levels. A total of 4017 continuous cycles were analyzed. The AMH level was positively correlated with the number of oocytes retrieved. Overall, AMH was significantly correlated with risk of cycle cancellation, poor ovarian response (POR, 3, or fewer oocytes retrieved) and high response (>15 oocytes), with an area under the curve (AUC) of 0.83, 0.89, and 0.82 respectively. An AMH cutoff of 0.6 ng/mL had a sensitivity of 54.0% and a specificity of 90.0% for the prediction of cycle cancellation, and cutoff of 0.8 ng/mL with a sensitivity of 55.0% and a specificity of 94.0% for the prediction of POR. Compared with AMH >2.0 ng/mL, patients with AMH < 0.6 ng/mL had a 53.6-fold increased risk of cancellation (P < 0.001), and AMH <0.80 ng/mL were 17.5 times more likely to experience POR (P < 0.001). However, AMH was less predictive of pregnancy and live birth, with AUCs of 0.55 and 0.53, respectively. Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate per retrieval according to the AMH level (≤0.40, 0.41–0.60, 0.61–0.80, 0.81–1.00, 1.01–1.50, 1.51–2.00, and >2.00 ng/mL) showed no significant differences. Even with AMH≤0.4 ng/mL, 50.0% of all the patients achieved pregnancy and 34.8% of patients achieved live birth after transfer. Our results suggested that AMH is a fairly robust metric for the prediction of cycle cancellation and oocyte yield for Chinese women, but it

  4. High-grade serous ovarian cancer cell lines exhibit heterogeneous responses to growth factor stimulation.

    PubMed

    Bourgeois, Danielle L; Kabarowski, Karl A; Porubsky, Veronica L; Kreeger, Pamela K

    2015-01-01

    The factors driving the onset and progression of ovarian cancer are not well understood. Recent reports have identified cell lines that are representative of the genomic pattern of high-grade serous ovarian cancer (HGSOC), in which greater than 90 % of tumors have a mutation in TP53. However, many of these representative cell lines have not been widely used so it is unclear if these cell lines capture the variability that is characteristic of the disease. We investigated six TP53-mutant HGSOC cell lines (Caov3, Caov4, OV90, OVCA432, OVCAR3, and OVCAR4) for migration, MMP2 expression, proliferation, and VEGF secretion, behaviors that play critical roles in tumor progression. In addition to comparing baseline variation between the cell lines, we determined how these behaviors changed in response to four growth factors implicated in ovarian cancer progression: HB-EGF, NRG1β, IGF1, and HGF. Baseline levels of each behavior varied across the cell lines and this variation was comparable to that seen in tumors. All four growth factors impacted cell proliferation or VEGF secretion, and HB-EGF, NRG1β, and HGF impacted wound closure or MMP2 expression in at least two cell lines. Growth factor-induced responses demonstrated substantial heterogeneity, with cell lines sensitive to all four growth factors, a subset of the growth factors, or none of the growth factors, depending on the response of interest. Principal component analysis demonstrated that the data clustered together based on cell line rather than growth factor identity, suggesting that response is dependent on intrinsic qualities of the tumor cell rather than the growth factor. Significant variation was seen among the cell lines, consistent with the heterogeneity of HGSOC.

  5. Complex Determinants of Epithelial: Mesenchymal Phenotypic Plasticity in Ovarian Cancer

    PubMed Central

    Klymenko, Yuliya; Kim, Oleg; Stack, M. Sharon

    2017-01-01

    Unlike most epithelial malignancies which metastasize hematogenously, metastasis of epithelial ovarian cancer (EOC) occurs primarily via transcoelomic dissemination, characterized by exfoliation of cells from the primary tumor, avoidance of detachment-induced cell death (anoikis), movement throughout the peritoneal cavity as individual cells and multi-cellular aggregates (MCAs), adhesion to and disruption of the mesothelial lining of the peritoneum, and submesothelial matrix anchoring and proliferation to generate widely disseminated metastases. This exceptional microenvironment is highly permissive for phenotypic plasticity, enabling mesenchymal-to-epithelial (MET) and epithelial-to-mesenchymal (EMT) transitions. In this review, we summarize current knowledge on EOC heterogeneity in an EMT context, outline major regulators of EMT in ovarian cancer, address controversies in EMT and EOC chemoresistance, and highlight computational modeling approaches toward understanding EMT/MET in EOC. PMID:28792442

  6. Clinical response in patients with ovarian cancer treated with metronomic chemotherapy

    PubMed Central

    Perroud, Herman Andrés; Scharovsky, O Graciela; Rozados, Viviana Rosa; Alasino, Carlos María

    2017-01-01

    Ovarian cancer (OC) is the leading cause of death from gynaecological cancer. It is extremely hard to diagnose in the early stages and around 70% of patients present with advanced disease. Metronomic chemotherapy (MCT) is described as the chronic administration of, generally low, equally spaced, doses of chemotherapeutic drugs with therapeutic efficacy and low toxicity. This is an effective and low-cost way to treat several types of tumours, including ovarian cancer. Here, we present six cases of advanced ovarian cancer treated with MCT with low doses of cyclophosphamide, which showed clinical response and stable disease. PMID:28275392

  7. Effect of body mass index and follicular synchrony in the ovarian response to ovulation induction with menotropins.

    PubMed

    Kably-Ambe, A; Barrón-Vallejo, J; Limón-Luque, L M

    1999-01-01

    To determine the correlation between body mass index, follicular synchrony, and pregnancy rate in a controlled ovarian hyperstimulation program with menotropins. Seventy-nine hyperstimulation cycles were evaluated. Transvaginal ultrasonographic control was performed and 10,000 IU of human chorionic gonadotropin were administered when the dominant follicle reached a diameter > 16 mm. In order to evaluate the follicular response, the ovarian synchrony factor was used (# follicles > or =16 mm/# follicles > 10 mm). For the statistical analysis, linear correlation and chi-square tests were used. When patients had a normal body mass index there was a positive correlation ( r = .52) between body mass index (kg/m(1.5)) and the ovarian synchrony factor. Weight deficiency and obesity had a deleterious effect on the ovarian response ( r = -.47 and r = -.77, respectively). There was a significant difference in the number of pregnancies in patients with ideal weight in relationship to the subgroup with weight deficit. An adequate body constitution increases the possibilities of achieving success in ovulation induction programs; on the other hand, weight disturbances have a deleterious effect on ovulation.

  8. Determination of BRAF V600E (VE1) protein expression and BRAF gene mutation status in codon 600 in borderline and low-grade ovarian cancers.

    PubMed

    Sadlecki, Pawel; Walentowicz, Pawel; Bodnar, Magdalena; Marszalek, Andrzej; Grabiec, Marek; Walentowicz-Sadlecka, Malgorzata

    2017-05-01

    Epithelial ovarian tumors are a group of morphologically and genetically heterogeneous neoplasms. Based on differences in clinical phenotype and genetic background, ovarian neoplasms are classified as low-grade and high-grade tumor. Borderline ovarian tumors represent approximately 10%-20% of all epithelial ovarian masses. Various histological subtypes of ovarian malignancies differ in terms of their risk factor profiles, precursor lesions, clinical course, patterns of spread, molecular genetics, response to conventional chemotherapy, and prognosis. The most frequent genetic aberrations found in low-grade serous ovarian carcinomas and serous borderline tumors, as well as in mucinous cancers, are mutations in BRAF and KRAS genes. The most commonly observed BRAF mutation is substitution of glutamic acid for valine in codon 600 (V600E) in exon 15. The primary aim of this study was to determine whether fully integrated, real-time polymerase chain reaction-based Idylla™ system may be useful in determination of BRAF gene mutation status in codon 600 in patients with borderline ovarian tumors and low-grade ovarian carcinomas. The study included tissue specimens from 42 patients with histopathologically verified ovarian masses, who were operated on at the Department of Obstetrics and Gynecology, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz (Poland). Based on histopathological examination of surgical specimens, 35 lesions were classified as low-grade ovarian carcinomas, and 7 as borderline ovarian tumors. Specimens with expression of BRAF V600E (VE1) protein were tested for mutations in codon 600 of the BRAF gene, using an automated molecular diagnostics platform Idylla™. Cytoplasmic immunoexpression of BRAF V600E (VE1) protein was found in three specimens: serous superficial papilloma, serous papillary cystadenoma of borderline malignancy, and partially proliferative serous cystadenoma. All specimens with the expression of BRAF V600E (VE1) protein were

  9. Spheroid growth in ovarian cancer alters transcriptome responses for stress pathways and epigenetic responses.

    PubMed

    Paullin, Trillitye; Powell, Chase; Menzie, Christopher; Hill, Robert; Cheng, Feng; Martyniuk, Christopher J; Westerheide, Sandy D

    2017-01-01

    Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. These poor statistics are related to a lack of early symptoms and inadequate screening techniques. This results in the cancer going undetected until later stages when the tumor has metastasized through a process that requires the epithelial to mesenchymal transition (EMT). In lieu of traditional monolayer cell culture, EMT and cancer progression in general is best characterized through the use of 3D spheroid models. In this study, we examine gene expression changes through microarray analysis in spheroid versus monolayer ovarian cancer cells treated with TGFβ to induce EMT. Transcripts that included Coiled-Coil Domain Containing 80 (CCDC80), Solute Carrier Family 6 (Neutral Amino Acid Transporter), Member 15 (SLC6A15), Semaphorin 3E (SEMA3E) and PIF1 5'-To-3' DNA Helicase (PIF1) were downregulated more than 10-fold in the 3D cells while Inhibitor Of DNA Binding 2, HLH Protein (ID2), Regulator Of Cell Cycle (RGCC), Protease, Serine 35 (PRSS35), and Aldo-Keto Reductase Family 1, Member C1 (AKR1C1) were increased more than 50-fold. Interestingly, EMT factors, stress responses and epigenetic processes were significantly affected by 3D growth. The heat shock response and the oxidative stress response were also identified as transcriptome responses that showed significant changes upon 3D growth. Subnetwork enrichment analysis revealed that DNA integrity (e.g. DNA damage, genetic instability, nucleotide excision repair, and the DNA damage checkpoint pathway) were altered in the 3D spheroid model. In addition, two epigenetic processes, DNA methylation and histone acetylation, were increased with 3D growth. These findings support the hypothesis that three dimensional ovarian cell culturing is physiologically different from its monolayer counterpart.

  10. Spheroid growth in ovarian cancer alters transcriptome responses for stress pathways and epigenetic responses

    PubMed Central

    Paullin, Trillitye; Powell, Chase; Menzie, Christopher; Hill, Robert; Cheng, Feng; Martyniuk, Christopher J.

    2017-01-01

    Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. These poor statistics are related to a lack of early symptoms and inadequate screening techniques. This results in the cancer going undetected until later stages when the tumor has metastasized through a process that requires the epithelial to mesenchymal transition (EMT). In lieu of traditional monolayer cell culture, EMT and cancer progression in general is best characterized through the use of 3D spheroid models. In this study, we examine gene expression changes through microarray analysis in spheroid versus monolayer ovarian cancer cells treated with TGFβ to induce EMT. Transcripts that included Coiled-Coil Domain Containing 80 (CCDC80), Solute Carrier Family 6 (Neutral Amino Acid Transporter), Member 15 (SLC6A15), Semaphorin 3E (SEMA3E) and PIF1 5'-To-3' DNA Helicase (PIF1) were downregulated more than 10-fold in the 3D cells while Inhibitor Of DNA Binding 2, HLH Protein (ID2), Regulator Of Cell Cycle (RGCC), Protease, Serine 35 (PRSS35), and Aldo-Keto Reductase Family 1, Member C1 (AKR1C1) were increased more than 50-fold. Interestingly, EMT factors, stress responses and epigenetic processes were significantly affected by 3D growth. The heat shock response and the oxidative stress response were also identified as transcriptome responses that showed significant changes upon 3D growth. Subnetwork enrichment analysis revealed that DNA integrity (e.g. DNA damage, genetic instability, nucleotide excision repair, and the DNA damage checkpoint pathway) were altered in the 3D spheroid model. In addition, two epigenetic processes, DNA methylation and histone acetylation, were increased with 3D growth. These findings support the hypothesis that three dimensional ovarian cell culturing is physiologically different from its monolayer counterpart. PMID:28793334

  11. Proliferation of rhesus ovarian surface epithelial cells in culture: Lack of mitogenic response to steroid or gonadotropic hormones

    SciTech Connect

    Wright, Jay W.; Toth-Fejel, Suellen; Stouffer, Richard L.; Rodland, Karin D.

    2002-06-30

    Ovarian cancer is the most lethal gynecological cancer and approximately 90% of ovarian cancers derive from the ovarian surface epithelium (OSE), yet the biology of the OSE is poorly understood. Factors associated with increased risk of non-hereditary ovarian cancer include the formation of inclusion cysts, effects of reproductive hormones cytokeratin, vimentin, N-cadherin, E-cadherin, estrogen receptor-a, and progesterone receptor. We show that these cells activate MAP Kinase and proliferate in response to extracellular calcium, as do human and rat OSE. In contrast, the gonadotropic hormones FSH (4-400 IU/L), LH (8.5-850 IU/l), and hCG (10-1000 IU/l) fail to stimulate proliferation. We find that concentrations of progesterone and estrogen normally present in follicles just prior to ovulation ( ~1000 ng/ml) significantly decrease the number of mitotically active RhOSE cells as determined by PCNA labelling, total cell count, and 3H-thymidine uptake, while lower steroid concentrations have no effect.

  12. Ovarian response markers lead to appropriate and effective use of corifollitropin alpha in assisted reproduction.

    PubMed

    La Marca, Antonio; D'Ippolito, Giovanni

    2014-02-01

    Corifollitropin alpha is a highly effective gonadotrophin, which maintains multifollicular growth for a week. The advantages of its administration include ease of use of the drug, making the treatment more patient friendly, resulting in a lower level of distress for the patient. At the same time, the pregnancy rate resulting from its use in IVF/intracytoplasmic sperm injection cycles is similar to that found when daily recombinant FSH is administered. The ovarian response to corifollitropin alpha is dependent on clinically established predictors such as baseline FSH, antral follicle count (AFC) and age. There is a general trend towards a higher ovarian response with an increasing AFC and the number of oocytes per attempt decreased with increasing baseline FSH and age. Even if the risk of ovarian hyperstimulation syndrome following corifollitropin alpha is very similar to the rate reported in literature for young women undergoing IVF, the risk of overstimulation may be reduced by avoiding maximal ovarian stimulation in women anticipated to be hyperresponders. High basal anti-Müllerian hormone and/or AFC can identify women with enhanced functional ovarian reserve at risk of overstimulation, and the risk is even higher if maximally stimulated with corifollitropin alpha or high dose of daily recombinant FSH. Corifollitropin alpha is a highly effective gonadotrophin which maintains multifollicular growth for a week. The ovarian response to corifollitropin was demonstrated to be dependent on clinically established predictors such as baseline FSH, antral follicle count (AFC) and age. There was a general trend toward a higher ovarian response with an increasing AFC and the mean number of oocytes per attempt decreased with increasing baseline FSH and age. Even if the risk of ovarian hyperstimulation syndrome (OHSS) following corifollitropin alpha is very similar to the rate of OHSS reported in literature for young women undergoing IVF, the risk of overstimulation may be

  13. Seminal plasma regulates ovarian progesterone production, leukocyte recruitment and follicular cell responses in the pig.

    PubMed

    O'Leary, S; Jasper, M J; Robertson, S A; Armstrong, D T

    2006-07-01

    Seminal plasma (SP) acts to influence the uterine endometrium after mating, activating synthesis of embryotrophic cytokines and inflammatory changes that condition the tract for embryo implantation and establishing pregnancy. The objective of this study was to investigate in pigs whether the ovary might also be responsive to SP exposure. Prepubertal gilts were synchronised with exogenous gonadotrophins and received transcervical treatment with pooled boar SP or PBS; then the ovarian tissue was recovered at 34 h (preovulation) and on days 5 and 9 after treatment. The ovarian response was assessed by measuring ovulation rate, number and size of corpora lutea, ovarian leukocyte populations, progesterone production in vivo, as well as responses of retrieved granulosa cells cultured in vitro. In SP-treated gilts, leukocyte recruitment into the ovarian tissues was increased fourfold at 34 h, with macrophages comprising the most abundant cell lineage. There was no effect of SP on the number of oocytes ovulated; however, the weight of corpora lutea was increased in SP-treated gilts. SP also induced an increase in plasma progesterone content seen from day 5 to at least day 9 after treatment. In addition, granulosa cells and thecal tissue retrieved from preovulatory follicles of SP-treated gilts were more responsive in vitro to growth factor- and gonadotrophin-stimulated cell proliferation and progesterone synthesis. These results suggest that uterine exposure to SP influences immune cell trafficking in the ovary and enhances steroidogenesis in early pregnancy. The effects of SP on ovarian function potentially contribute to reproductive success in the pig.

  14. Follicle-stimulating hormone receptor (FSHR) alternative skipping of exon 2 or 3 affects ovarian response to FSH.

    PubMed

    Karakaya, Cengiz; Guzeloglu-Kayisli, Ozlem; Hobbs, Rebecca J; Gerasimova, Tsilya; Uyar, Asli; Erdem, Mehmet; Oktem, Mesut; Erdem, Ahmet; Gumuslu, Seyhan; Ercan, Deniz; Sakkas, Denny; Comizzoli, Pierre; Seli, Emre; Lalioti, Maria D

    2014-07-01

    Genes critical for fertility are highly conserved in mammals. Interspecies DNA sequence variation, resulting in amino acid substitutions and post-transcriptional modifications, including alternative splicing, are a result of evolution and speciation. The mammalian follicle-stimulating hormone receptor (FSHR) gene encodes distinct species-specific forms by alternative splicing. Skipping of exon 2 of the human FSHR was reported in women of North American origin and correlated with low response to ovarian stimulation with exogenous follicle-stimulating hormone (FSH). To determine whether this variant correlated with low response in women of different genetic backgrounds, we performed a blinded retrospective observational study in a Turkish cohort. Ovarian response was determined as low, intermediate or high according to retrieved oocyte numbers after classifying patients in four age groups (<35, 35-37, 38-40, >40). Cumulus cells collected from 96 women undergoing IVF/ICSI following controlled ovarian hyperstimulation revealed four alternatively spliced FSHR products in seven patients (8%): exon 2 deletion in four patients; exon 3 and exons 2 + 3 deletion in one patient each, and a retention of an intron 1 fragment in one patient. In all others (92%) splicing was intact. Alternative skipping of exons 2, 3 or 2 + 3 were exclusive to low responders and was independent of the use of agonist or antagonist. Interestingly, skipping of exon 3 occurs naturally in the ovaries of domestic cats--a good comparative model for human fertility. We tested the signaling potential of human and cat variants after transfection in HEK293 cells and FSH stimulation. None of the splicing variants initiated cAMP signaling despite high FSH doses, unlike full-length proteins. These data substantiate the occurrence of FSHR exon skipping in a subgroup of low responders and suggest that species-specific regulation of FSHR splicing plays diverse roles in mammalian ovarian function.

  15. Genetic and clinical predictors of ovarian response in assisted reproductive technology

    NASA Astrophysics Data System (ADS)

    Wiweko, B.; Damayanti, I.; Suryandari, D.; Natadisastra, M.; Pratama, G.; Sumapraja, K.; Meutia, K.; Iffanolia, P.; Harzief, A. K.; Hestiantoro, A.

    2017-08-01

    Several factors are known to influence ovarian response to rFSH stimulation such as age, antral follicle count (AFC), and basal FSH level, Mutation of allele Ser680Asn in FSHR gene was responsible to ovarian resistance toward exogenous FSH. The aim of this study is to develop a prediction model of ovarian response to COS in IVF. This study was a prospective cohort study. One hundred and thirteen women undergoing their first cycle of IVF in Yasmin IVF Clinic Jakarta were recruited to this study. Clinical datas included were age, BMI, and AFC. Basal FSH and E2 as well as serum AMH was measured from peripheral blood taken at second day of cycle. Bsr-1 enzyme is used to identify the polymorphism in exon 10 position 680 with RFLP technique. Three genotype polymorphism, Asn/Asn (255 bp ribbon), Asn/Ser (97 bp and 158 bp), and Ser/Ser (97 bp, 158 bp, and 255 bp). AFC has the highest predictor for ovarian response with AUC 0.922 (CI 95% 0.833-1.000). AMH also showed high predicting value (AUC 0.843 CI 95% 0.663-1.000). The multivariate analysis revealed combination of AFC, AMH, age, and basal FSH is a good model for ovarian response prediction (AUC=0.97). No significant relation between Asn/Asn, Asn/Ser, or Ser/Ser genotype FSHR polymorphism with ovarian response (p = 0.866) and total dose of rRSH (p = 0.08). This study showed that model combination of AFC, AMH, patient’s age and basal FSH are very good to predict number of mature oocytes.

  16. Is there a critical endometrioma size associated with reduced ovarian responsiveness in assisted reproduction techniques?

    PubMed

    Coccia, Maria Elisabetta; Rizzello, Francesca; Barone, Stefano; Pinelli, Sara; Rapalini, Erika; Parri, Cristiana; Caracciolo, Domenico; Papageorgiou, Savvas; Cima, Gianpaolo; Gandini, Loredana

    2014-08-01

    This study investigated the relationships between ovarian endometrioma size, ovarian responsiveness and the number of retrieved oocytes following ovarian stimulation. A prospective study was conducted in a public clinical assisted reproduction centre. A total of 64 infertile women with monolateral endometriomas undergoing IVF or intracytoplasmic sperm injection were included in the study. The total number of follicles, number of follicles ≥ 16 mm and number of oocytes retrieved of ovaries containing endometrioma and normal ovaries were compared. Multivariate linear regression was used to assess whether number of follicles and collected oocytes varied by endometrioma size, age, basal FSH concentration. Significantly lower numbers of follicles ≥ 16 mm (P = 0.024) and oocytes retrieved (P = 0.001) in the ovaries containing endometrioma were observed. In patients with endometriomas ≥ 30 mm, endometrioma size was the most influential contributor to the total number of follicles and oocytes retrieved. Ovarian endometriomas result in reduced response to ovarian stimulation, compared with the response of the contralateral normal ovary in the same individual. In case of endometriomas <30 mm, basal FSH concentration remains the most important prognostic factor for oocyte retrieval. Copyright © 2014 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  17. [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.

  18. Small-Molecule RA-9 Inhibits Proteasome-Associated DUBs and Ovarian Cancer in Vitro and in Vivo Via Exacerbating Unfolded Protein Responses

    PubMed Central

    Coughlin, Kathleen; Anchoori, Ravi; Iizuka, Yoshie; Meints, Joyce; MacNeill, Lauren; Vogel, Rachel Isaksson; Orlowski, Robert Z.; Lee, Michael K.; Roden, Richard BS; Bazzaro, Martina

    2014-01-01

    Purpose Ovarian cancer is the deadliest of the gynecological malignancies. Carcinogenic progression is accompanied by up-regulation of ubiquitin-dependent protein degradation machinery as a mechanism to compensate with elevated endogenous proteotoxic stress. Recent studies support the notion that deubiquitinating enzymes (DUBs) are essential factors in proteolytic degradation and that their aberrant activity is linked to cancer progression and chemoresistance. Thus, DUBs are an attractive therapeutic target for ovarian cancer. Experimental Design The potency and selectivity of RA-9 inhibitor for proteasome-associated DUBs was determined in ovarian cancer cell lines and primary cells. The anticancer activity of RA-9 and its mechanism of action was evaluated in multiple cancer cell lines in vitro and in vivo in immunodeficient mice bearing an intra-peritoneal ES-2 xenograft model of human ovarian cancer. Results Here we report the characterization of RA-9 as a small-molecule inhibitor of proteasome-associated DUBs. Treatment with RA-9 selectively induces onset of apoptosis, in ovarian cancer cell lines and primary cultures derived from donors. Loss of cell viability following RA-9 exposure is associated with an Unfolded Protein Response (UPR) as mechanism to compensate for unsustainable levels of proteotoxic stress. In vivo treatment with RA-9 retards tumor growth, increases overall survival and was well tolerated by the host. Conclusions Our preclinical studies support further evaluation of RA-9 as an ovarian cancer therapeutic. PMID:24727327

  19. The combined use of antimullerian hormone and age to predict the ovarian response to controlled ovarian hyperstimulation in poor responders: A novel approach.

    PubMed

    Jeve, Yadava Bapurao

    2013-10-01

    Reduced ovarian response to stimulation represents one of the most intractable problems in infertility treatment. As failed cycle can cause considerable amount of emotional and economical loss, there are various attempts made to predict ovarian response. To evaluate different factors influencing outcome of assisted reproduction in women with predicted reduced response (antimullerian hormone between 1 and 5 pmol/L) and to develop a model using of AMH and age to predict the number of oocytes in poor responders. Retrospective study in a teaching hospital. We analyzed 85 cycles (57 women) with predicted reduced response with serum AMH value between 1 and 5 pmol/L. Standard ovarian stimulation protocol was used. Primary outcome measures were clinical pregnancy rates and oocytes retrieved. Data were analyzed using Microsoft excel and MetlabR software. Clinical pregnancy rate/ET was 20.33%, in this group. AMH and age was analyzed using linear regression model which produced an equation to give predicted oocyte count if AMH and age are known. (Oocytes = age × (-ß) + Serum AMH × α) (Constant ß=0.0102 and α = 1.0407). Combined use of serum AMH and age to predict ovarian response within reduced responder group should be further evaluated. For first time, we suggested combining both factors to predict ovarian response using a simple equation which allow developing tailored strategy.

  20. Association between individual ovarian dimensions with ovarian reserve indices

    PubMed Central

    Naeini, Elham Hashemian; Neyestanak, Mohammad Zare; Berjis, Katayon; Shokoohi, Mostafa

    2013-01-01

    Introduction: In some young female candidates of assisted reproductive technology (ART), ovarian response to simulative treatments is less than what is expected. More precise assessment of oocyte quality and quantity through studying ovarian dimensions can be useful for determining the dose of ovarian stimulant drugs and for preventing ART cycles cancellation. The aim of the present study is to determine the association between ovarian dimensions and ovarian reserve (OR) indices and whether ovarian dimensions can predict ovarian reserve. Methods: In this cross-sectional study, 85 infertile women were studied. In early follicular phase, ovarian diameters (including length and width of the ovaries) were measured using transvaginal ultrasonography. Mean ovarian diameters (MOD) were calculated according to average length and width of the ovaries. A serum sample was taken from all patients to measure the level of Follicular Stimulating Hormone (FSH) and oestradiol as OR indices. Results: The results of univariate analysis showed that FSH and oestradiol had a negative significant association with width, length and MOD (P < 0.01). The results of multivariate regression analysis showed that FSH and oestradiol had a negative significant association with width (βFSH = -0.59, P = 0.001 and βOestradiol = -0.019, P = 0.029) and MOD (βFSH = -0.52, P = 0.003 and βOestradiol = -0.021, P = 0.017) and had a borderline negative significant correlation with ovarian length (βFSH = -0.49, P=0.077 and βOestradiol = 0.022, P = 0.08) Conclusions: The results of this study revealed that despite a moderate correlation, ovarian diameters could be an applicable index for predicting OR. Using this method along with other methods may be useful in treatment with ovarian stimulants. PMID:26966426

  1. Hormone response in ovarian cancer: time to reconsider as a clinical target?

    PubMed Central

    Modugno, Francesmary; Laskey, Robin; Smith, Ashlee L; Andersen, Courtney L; Haluska, Paul; Oesterreich, Steffi

    2013-01-01

    Ovarian cancer is the sixth most common cancer worldwide among women in developed countries and the most lethal of all gynecologic malignancies. There is a critical need for the introduction of targeted therapies to improve outcome. Epidemiological evidence suggests a critical role for steroid hormones in ovarian tumorigenesis. There is also increasing evidence from in vitro studies that estrogen, progestin, and androgen regulate proliferation and invasion of epithelial ovarian cancer cells. Limited clinical trials have shown modest response rates; however, they have consistently identified a small subset of patients that respond very well to endocrine therapy with few side effects. We propose that it is timely to perform additional well-designed trials that should include biomarkers of response. PMID:23045324

  2. Clinical and genetic determinants of ovarian metastases from colorectal cancer.

    PubMed

    Ganesh, Karuna; Shah, Ronak H; Vakiani, Efsevia; Nash, Garrett M; Skottowe, Hugh P; Yaeger, Rona; Cercek, Andrea; Lincoln, Anne; Tran, Christina; Segal, Neil H; Reidy, Diane L; Varghese, Anna; Epstein, Andrew S; Sonoda, Yukio; Chi, Dennis; Guillem, Jose; Temple, Larissa; Paty, Philip; Hechtman, Jaclyn; Shia, Jinru; Weiser, Martin; Aguilar, Julio Garcia; Kemeny, Nancy; Berger, Michael F; Saltz, Leonard; Stadler, Zsofia K

    2017-04-01

    Ovarian metastases from colorectal cancer (OM-CRC) often are unresponsive to chemotherapy and are associated with poor survival. To the authors' knowledge, the clinicopathologic and genomic predictors of OM-CRC are poorly characterized and optimal clinical management remains unclear. Women with a histopathological diagnosis of OM-CRC who were treated at Memorial Sloan Kettering Cancer Center from 1999 to 2015 were identified. Next-generation somatic mutation profiling (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT]) was performed on 38 OM-CRC cases, including 21 matched tumor pairs/trios. Regression models were used to analyze variables associated with progression-free survival and overall survival (OS). Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), SMAD family member 4 (SMAD4), and neurotrophic receptor tyrosine kinase 1 (NTRK1) mutations were more frequent in cases of OM-CRC than in instances of CRC occurring without OM. SMAD4 and lysine methyltransferase 2D (KMT2D) mutations were associated with reduced OS. Matched multisite tumor sequencing did not identify OM-specific genomic alterations. Of the 195 patients who underwent oophorectomy for OM-CRC (median age, 49 years with a progression-free survival of 9.4 months and an OS of 23 months from oophorectomy), 76% had extraovarian metastasis (EOM). In multivariable analysis, residual disease after surgery (R2 resection) was associated with worse survival. Patients with EOM were less likely to achieve R0/R1 surgical resection status (complete macroscopic resection without clinical/radiological evidence of disease) (48% vs 94%). However, if R0/R1 resection status was achieved, both patients with (35.9 months vs 12 months) and without (43.2 months vs 14.5 months) EOM were found to have better OS. Among 114 patients with R0/R1 resection status, 23 (20%) had no disease recurrence, including 10 patients (9%) with > 3 years of follow-up. Loss

  3. Morphologic responses of the mouse ovarian surface epithelium to ovulation and steroid hormonal milieu.

    PubMed

    Gotfredson, Garry S; Murdoch, William J

    2007-02-01

    Ovarian cancer of surface epithelial origin is an ovulation- and endocrine-related disease. It appears that a cell transformed by genotoxins generated at follicular rupture is propagated during postovulatory wound repair. A consequent steroid hormonal imbalance favoring the mitogenic estrogens is a prospective predisposing factor in ovarian neoplasia. Protection against epithelial ovarian cancer is conferred by progesterone. The objective of this study was to characterize the acute effects of ovulation and steroid hormonal exposure on morphologic responses of surface epithelial cells of mouse ovaries. Follicular development and ovulation were induced in immature animals with equine and human (=Day 0) choriogonadotropins, respectively. On Day 2 (approximately 36 hrs after ovulation), surface epithelial classifications presented in histologic sections were altered from simple (single-layered) squamous and cuboidal toward stratification; this trend was reversed (i.e., reverted to the control status) on Days 4-8. Shifts in the ovarian epithelium from simple to stratified were accentuated following postovulatory (Days 1-8) treatment with estradiol. Surface epithelia of ovaries obtained after 1 week of progesterone administration were exclusively of a simple phenotype. We conclude that the proliferative/procarcinogenic reaction of the ovarian surface epithelium to ovulation is exacerbated by estrogen and counteracted by progesterone.

  4. In vitro ovarian tumor growth and treatment response dynamics visualized with time-lapse OCT imaging

    PubMed Central

    Evans, Conor L.; Rizvi, Imran; Hasan, Tayyaba; de Boer, Johannes F.

    2010-01-01

    In vitro three-dimensional models for metastatic ovarian cancer have been useful for recapitulating the human disease. These spheroidal tumor cultures, however, can grow in excess of 1 mm in diameter, which are difficult to visualize without suitable imaging technology. Optical coherence tomography (OCT) is an ideal live imaging method for non-perturbatively visualizing these complex systems. OCT enabled detailed observations of the model at both nodular and cellular levels, revealing growth dynamics not previously observed. The development of a time-lapse OCT system, capable of automated, multidimensional acquisition, further provided insights into the growth and chemotherapeutic response of ovarian cancer. PMID:19466138

  5. Altered ovarian responsiveness to gonadotropins in neonatally irradiated immature rats

    SciTech Connect

    Freud, A.; Sod-Moriah, U.A.

    1988-01-01

    Female rats which were exposed to a single low dose of gamma irradiation (6R or 15R) at the age of 8 days produce smaller litters when mature than untreated controls. In order to study the possibility that such an impaired reproductive performance could result from a reduced ovulation rate, neonatally irradiated females were treated with PMSG (12 iu/rat) at the age of 26 days. Another group of rats, similarly treated, was further injected with hCG (5 iu/rat) 48 hours later. Animals were killed 48, 55, 60 and 72 hours after PMSG treatment or 72 and 120 after hCG injection. The results indicated that PMSG treatment increased the ovarian weight of non-irradiated controls as well as of irradiated rats and in all animals induced a proestrus like profile of LH. Only a combined treatment of PMSG and hCG resulted in ovulation and corpora lutea formation with significantly increased numbers of corpora lutea in the ovaries of the irradiated rats. The latter was associated with higher progesterone plasma levels not correlated to the number of corpora lutea. The gradual decrease in the number of ovarian binding sites for hCG with increased radiation dose and the increased association constant in the 15R group could not explain the increased sensitivity of the ovary to exogenous gonadotropins which results from neonatal exposure to low doses of gamma irradiation.

  6. Basal serum testosterone levels correlate with ovarian reserve and ovarian response in cycling women undergoing in vitro fertilization.

    PubMed

    Xiao, Shan; Li, Yubin; Long, Lingli; Luo, Canqiao; Mai, Qingyun

    2016-01-01

    This study aimed to investigate the association between basal serum testosterone levels and in vitro fertilization (IVF) parameters in cycling women. A retrospective cohort study was performed at a clinical IVF center, and 495 women with regular menstruation were enrolled. Serum testosterone levels were measured before the start of IVF treatment cycle. We found that basal serum testosterone levels were negatively associated with female age and FSH/LH ratios. In contrast, we found a positive correlation between serum testosterone levels and the number of oocytes and available embryos. However, there was no significant association between testosterone levels and pregnancy outcome. Our results suggest that basal serum testosterone levels were significantly related to certain classic indicators of ovarian reserve, such as age and FSH/LH ratios. Increased testosterone levels improved ovarian response in cycling women, but they fail to predict pregnancy and miscarriage rate.

  7. Effects of high progesterone on outcomes of in vitro fertilization-embryo transfer in patients with different ovarian responses.

    PubMed

    Li, Peng-fen; Zhu, Hong; Tan, Li; Zhao, Dong-mei; Ma, Li-ying; Xiang, Yun-gai; Zhang, Dan; Dou, Qian; Lu, Na

    2015-06-01

    The data of 3,841 cycles undergoing in vitro fertilization-embryo transfer (IVF-ET) in our reproductive Center between January 2003 and December 2013 were retrospectively analyzed. According to the number of oocytes retrieved, this study was divided into the high ovarian response group (oocyte retrieval≥20, 842 cycles), the moderate ovarian response group (5ovarian response group (oocyte retrieval≤5, 991 cycles). The treatment outcomes were compared between the patients with an increased progesterone (P) level and the patients where the P level did not increase. With increase in ovarian response, the cut-off values of serum P on the day of human chorionic gonadotrophin (hCG) rose, and respectively were 2.5 ng/ml in the high ovarian response group, 2.25 ng/ml in the moderate ovarian response group, and 1.5 ng/ml in the low ovarian response group. In each group, the clinical pregnancy rate and embryo implantation rate were lower in the patients with an increased P level compared to those where the P level did not increase (all p<0.05). However, there were no significant difference in the fertilization rate, cleavage rate, and high-quality embryo rate (all p>0.05). The increased level of P on the day of hCG may affect the treatment outcomes of IVF-ET. The cut-off values of serum P seem to be associated with ovarian response. Increased ovarian response causes the cut-off values of serum P to rise.

  8. Determine the Role of Canonical Wnt Signaling in Ovarian Tumorigenesis

    DTIC Science & Technology

    2012-10-01

    Goldstein M, Sellers WR, Yaron Y , et al. Multiple genes in human 20q13 chromosomal region are involved in an advanced prostate cancer xenograft...Months 1-12) Specifically, we will determine whether inhibition of canonical Wnt signaling induces the expression of markers of senescence in human...cells treated with FJ9 demonstrated features of senescence such as a large flat cell morphology (Figure 1B). However, examination of markers of canonical

  9. Clinical value of serum anti-mullerian hormone and inhibin B in prediction of ovarian response in patients with polycystic ovary syndrome.

    PubMed

    Zhang, Fan; Liu, Xiao-Ling; Rong, Nan; Huang, Xiao-Wen

    2017-02-01

    The present study aimed to investigate the clinical value of serum anti-mullerian hormone (AMH) and inhibin B (INHB) in predicting the ovarian response of patients with polycystic ovary syndrome (PCOS). A total of 120 PCOS patients were enrolled and divided into three groups in terms of the ovarian response: a low-response group (n=36), a normal-response group (n=44), and a high-response group (n=40). The serum AMH and INHB levels were measured by enzyme-linked immunosorbent assay (ELISA). The follicle stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels were determined by chemiluminescence microparticle immunoassay. The correlation of the serum AMH and INHB levels with other indicators was analyzed. A receiver operating characteristic (ROC) curve was established to analyze the prediction of ovarian response by AMH and INHB. The results showed that there were significant differences in age, body mass index (BMI), FSH, total gonadotropin-releasing hormone (GnRH), LH, E2, and antral follicle counts (AFCs) between the groups (P<0.05). The serum AMH and INHB levels were increased significantly with the ovarian response of PCOS patients increasing (P<0.05). The serum AMH and INHB levels were negatively correlated with the age, BMI, FSH level, Gn, and E2 levels (P<0.05). They were positively correlated with the LH levels and AFCs (P<0.05). ROC curve analysis of serum AMH and INHB in prediction of a low ovarian response showed that the area under the ROC curve (AUC) value of the serum AMH level was 0.817, with a cut-off value of 1.29 ng/mL. The sensitivity and specificity were 71.2% and 79.6%, respectively. The AUC value of serum INHB was 0.674, with a cut-off value of 38.65 ng/mL, and the sensitivity and specificity were 50.7% and 74.5%, respectively. ROC curve analysis showed when the serum AMH and INHB levels were used to predict a high ovarian response, the AUC value of the serum AMH level was 0.742, with a cut-off value of 2.84 ng/mL, and

  10. Involvement of FOXL2 and RSPO1 in Ovarian Determination, Development, and Maintenance in Mammals.

    PubMed

    Pannetier, Maëlle; Chassot, Anne-Amandine; Chaboissier, Marie-Christine; Pailhoux, Eric

    2016-01-01

    In mammals, sex determination is a process through which the gonad is committed to differentiate into a testis or an ovary. This process relies on a delicate balance between genetic pathways that promote one fate and inhibit the other. Once the gonad is committed to the female pathway, ovarian differentiation begins and, depending on the species, is completed during gestation or shortly after birth. During this step, granulosa cell precursors, steroidogenic cells, and primordial germ cells start to express female-specific markers in a sex-dimorphic manner. The germ cells then arrest at prophase I of meiosis and, together with somatic cells, assemble into functional structures. This organization gives the ovary its definitive morphology and functionality during folliculogenesis. Until now, 2 main genetic cascades have been shown to be involved in female sex differentiation. The first is driven by FOXL2, a transcription factor that also plays a crucial role in folliculogenesis and ovarian fate maintenance in adults. The other operates through the WNT/CTNNB1 canonical pathway and is regulated primarily by R-spondin1. Here, we discuss the roles of FOXL2 and RSPO1/WNT/ CTNNB1 during ovarian development and homeostasis in different models, such as humans, goats, and rodents. © 2016 S. Karger AG, Basel.

  11. Platinum-DNA adducts in leukocyte DNA correlate with disease responses in ovarian cancer patients receiving platinum-based chemotherapy

    SciTech Connect

    Reed, E.; Ozols, R.F.; Tarone, R.; Yuspa, S.H.; Poirier, M.C.

    1987-07-01

    Fifty-five ovarian cancer patients receiving platinum drug-based chemotherapy have been studied prospectively to determine the extent of formation of the bidentate intrastrand adducts of diammineplatinum covalently attached to the N/sup 7/ positions of adenosine and/or guanosine in leukocyte DNA. Data for clinical response, obtained from medical records, were then correlated with the adduct values. Patients were treated with platinum-based single-agent or combination chemotherapy containing cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum on approved experimental protocols. Adduct measurements were performed by ELISA, and disease response to therapy was assessed by standard oncologic criteria. This study comprises a total of 101 blood samples obtained after intravenous cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum infusion from 55 individuals, and in each case the highest (or peak) adduct level for each patient was chosen for statistical analysis. Analysis of these data by Jonckheere's test shows that higher levels of adduct formation correlates with disease response with a two-sided P value of 0.030. Of eight patients on single-agent therapy whose buffy-coast samples did not have measurable adduct levels, none responded to therapy. Thus in ovarian cancer patients, the formation of the intrastrand diammineplatinum adducts in leukocyte DNA is associated with favorable disease response to cis-diamminedichloroplatinum (II) or diamminecyclobutane-dicarboxylatoplatinum chemotherapy.

  12. ALDH enzymatic activity and CD133 positivity and response to chemotherapy in ovarian cancer patients.

    PubMed

    Ricci, Francesca; Bernasconi, Sergio; Porcu, Luca; Erba, Eugenio; Panini, Nicolò; Fruscio, Robert; Sina, Federica; Torri, Valter; Broggini, Massimo; Damia, Giovanna

    2013-01-01

    The prognostic/predictive role of both CD133 and Aldehyde dehydrogenase (ALDH) expression in human ovarian cancer remains elusive. This is an observational study that investigated the expression of CD133 and of ALDH enzymatic activity in fresh ovarian cancer samples and their association with different clinic-pathological patient' characteristics and explored their possible predictive/prognostic role. We analyzed the expression of CD133 and ALDH enzymatic activity in 108 human ovarian cancer samples. We found that among the total patients analyzed, 13% of them was completely negative for ALDH activity and 26% was negative for CD133 staining. Both markers were variably expressed within the samples and when both studied in the same tumor sample, no statistically significant correlation between ALDH enzymatic activity and CD133 expression was found. No statistical significant correlation was found also between the percentage values of positive ALDH and CD133 cells and the number of serial passages patient's cultures underwent, suggesting that these markers do not confer by themselves a self-renewal growth advantage to the cultures. Lower levels of CD133 were associated with higher tumor grade. No correlation with response to therapy, progression free survival and overall survival was found. Our data suggest that neither ALDH enzymatic activity nor CD133 expression provide additional predictive/prognostic information in ovarian cancer patients.

  13. High progesterone levels in women with high ovarian response do not affect clinical outcomes: a retrospective cohort study

    PubMed Central

    2014-01-01

    Background The potentially detrimental role of progesterone during the follicular phase has been a matter of controversy for several years; however, few studies have analyzed the effects of combined raised estradiol and progesterone levels on pregnancy outcomes. The aim of the present study was to determine the influence of high progesterone levels on clinical outcomes in the context of high ovarian response. Methods We performed a retrospective cohort study that included 2850 women classified as high responders. The women were subdivided into six groups depending on their progesterone concentration on the day of human chorionic gonadotropin (hCG) administration: <0.5 ng/ml (1.81 ng/ml (>p90). Ovarian response was classified as high when > =20 oocytes were retrieved or when estradiol was > =3000 pg/ml. Clinical outcomes of each subgroup were analyzed. We also examined data from frozen-thawed embryo transfers. Results were analyzed with Student’s t- test to compare continuous variables and chi-squared test to compare proportions. A p-value of < =0.05 was considered statistically significant. Results The progesterone concentration increased with ovarian response, and elevated progesterone did not show a significant clinical impact on implantation rate and pregnancy rates. These data provide evidence that progesterone levels higher than 1.8 ng/ml do not have detrimental effect on oocyte quality or endometrial receptivity. Conclusions These data allow us to conclude that high progesterone levels correlate significantly with high estradiol levels and that in high responder women; progesterone levels do not show a significant clinical impact on results. PMID:25064138

  14. Genetic testing for hereditary breast and ovarian cancer: responsibility and choice.

    PubMed

    d'Agincourt-Canning, Lori

    2006-01-01

    Genetic testing for hereditary breast-ovarian cancer has become an important part of clinical genetics practice. Although considerable work has focused on the psychological impact of this technology, there has been little research into the moral implications of genetic information on hereditary cancer families. In this article, the author examines moral issues related to individuals' decisions to seek or decline testing. In-depth interviews with 53 participants make up the core of the research. Analysis of participants' accounts illustrates how the decision to be tested (or not) interconnects with moral agency and aspects of self (embodied, familial-relational, and civic self). The findings form the foundation for inquiry into conceptualization of moral responsibility, autonomy, and choice. They also provide insight that might assist clinicians to understand more fully the needs and responses of those who seek genetic testing for hereditary breast-ovarian cancer.

  15. Relationship Between 17-Hydroxyprogesterone Responses to Human Chorionic Gonadotropin and Markers of Ovarian Follicle Morphology in Women With Polycystic Ovary Syndrome

    PubMed Central

    Maas, Kevin H.; Chuan, Sandy S.; Cook-Andersen, Heidi; Su, H. Irene; Duleba, A.

    2015-01-01

    Context: Women with polycystic ovary syndrome (PCOS) have increased 17-hydroxyprogesterone (17-OHP) responses to gonadotropin stimulation although individual variability is substantial, as reflected by exaggerated as well as normal responses. The relationship between 17-OHP responses to gonadotropin stimulation and markers of ovarian function has not been assessed. Objective: To determine whether 17-OHP responses are associated with antral follicle count (AFC), anti-Mullerian hormone (AMH), or inhibin B (Inh B) levels in PCOS and normal women. Design: Prospective study. Setting: Research center at an academic medical center. Participants: Women with PCOS (n = 18) and normal controls (n = 18). Interventions: Blood samples were obtained before and 24 hours after administration of 25 μg recombinant-human chorionic gonadotropin. Ovarian imaging was conducted with three-dimensional pelvic ultrasound. Main Outcome Measures: Basal and stimulated levels of 17-OHP, androgens, estrogen, AMH, Inh B, and AFC. Results: In women with PCOS, 17-OHP responses were heterogeneous and inversely correlated with AMH and Inh B levels, but not AFC. In a subgroup of PCOS women with exaggerated 17-OHP responses, AMH levels were equivalent to that of normal women. In PCOS women with normal 17-OHP responses, AMH levels were markedly elevated. Conclusion: Based on heterogeneous 17-OHP responses to human chorionic gonadotropin in women with PCOS, AMH levels are inversely linked to ovarian androgen production while positively correlated with AFC. These findings suggest that in PCOS, AMH production may reflect redistribution of the follicle population or regulation by intraovarian mechanisms. PMID:25313914

  16. The immunomodulatory effects of pegylated liposomal doxorubicin are amplified in BRCA1--deficient ovarian tumors and can be exploited to improve treatment response in a mouse model.

    PubMed

    Mantia-Smaldone, Gina; Ronner, Lukas; Blair, Anne; Gamerman, Victoria; Morse, Christopher; Orsulic, Sandra; Rubin, Stephen; Gimotty, Phyllis; Adams, Sarah

    2014-06-01

    Women with BRCA-associated ovarian cancer demonstrate excellent responses to Pegylated Liposomal Doxorubicin (PLD). PLD has also been shown to enhance T cell recognition of tumor cells. Here we characterize immunophenotypic changes associated with BRCA1 dysfunction in ovarian cancer cells, and evaluate the T cell contribution to the therapeutic efficacy of PLD in a BRCA1- ovarian cancer model to determine whether enhanced anti-tumor immunity contributes to the improved response to PLD in BRCA1- ovarian cancers. The immunophenotype of BRCA1- and wild-type (WT) ovarian cancer cells and their response to PLD were compared in vitro using flow cytometry. T cell recruitment to BRCA1- tumors was evaluated with flow cytometry and immunohistochemistry. The contribution of T cell populations to the therapeutic effect of PLD in a BRCA1- model was evaluated using immunodepleting antibodies with PLD in vivo. The cytotoxic response to PLD was similar in BRCA1- and WT cells in vitro. BRCA1- inactivation resulted in higher expression of Fas and MHC-I at baseline and after PLD exposure. PLD prolonged the survival of BRCA1- tumor bearing mice and increased intratumoral T cell recruitment. CD4+ depletion combined with PLD significantly prolonged overall survival (p=0.0204) in BRCA1- tumor-bearing mice. Differences in the immunophenotype of BRCA1- and WT cells are amplified by PLD exposure. The enhanced immunomodulatory effects of PLD in BRCA1- tumors may be exploited therapeutically by eliminating suppressive CD4+ T cells. Our results support further study of combination therapy using PLD and immune agents, particularly in women with BRCA gene mutations. Copyright © 2014 Elsevier Inc. All rights reserved.

  17. Ovarian response prediction in controlled ovarian stimulation for IVF using anti-Müllerian hormone in Chinese women: A retrospective cohort study.

    PubMed

    Zheng, Haiyan; Chen, Shiping; Du, Hongzi; Ling, Jiawei; Wu, Yixuan; Liu, Haiying; Liu, Jianqiao

    2017-03-01

    The predictive value of anti-Müllerian hormone (AMH) in Chinese women undergoing in vitro fertilization (IVF) treatment is data deficient. To determine the attributes of AMH in IVF, oocyte yield, cycle cancellation, and pregnancy outcomes were analyzed. All patients initiating their first IVF cycle with gonadotropin-releasing hormone agonist treatment in our center from October 2013 through December 2014 were included, except patients diagnosed with polycystic ovarian syndrome. Serum samples collected prior to IVF treatment were used to determine serum AMH levels. A total of 4017 continuous cycles were analyzed. The AMH level was positively correlated with the number of oocytes retrieved. Overall, AMH was significantly correlated with risk of cycle cancellation, poor ovarian response (POR, 3, or fewer oocytes retrieved) and high response (>15 oocytes), with an area under the curve (AUC) of 0.83, 0.89, and 0.82 respectively. An AMH cutoff of 0.6 ng/mL had a sensitivity of 54.0% and a specificity of 90.0% for the prediction of cycle cancellation, and cutoff of 0.8 ng/mL with a sensitivity of 55.0% and a specificity of 94.0% for the prediction of POR. Compared with AMH >2.0 ng/mL, patients with AMH < 0.6 ng/mL had a 53.6-fold increased risk of cancellation (P < 0.001), and AMH <0.80 ng/mL were 17.5 times more likely to experience POR (P < 0.001). However, AMH was less predictive of pregnancy and live birth, with AUCs of 0.55 and 0.53, respectively. Clinical pregnancy rate, ongoing pregnancy rate, and live birth rate per retrieval according to the AMH level (≤0.40, 0.41-0.60, 0.61-0.80, 0.81-1.00, 1.01-1.50, 1.51-2.00, and >2.00 ng/mL) showed no significant differences. Even with AMH≤0.4 ng/mL, 50.0% of all the patients achieved pregnancy and 34.8% of patients achieved live birth after transfer. Our results suggested that AMH is a fairly robust metric for the prediction of cycle cancellation and oocyte yield for Chinese women, but it is a relatively

  18. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria.

    PubMed

    Ferraretti, A P; La Marca, A; Fauser, B C J M; Tarlatzis, B; Nargund, G; Gianaroli, L

    2011-07-01

    The definition presented here represents the first realistic attempt by the scientific community to standardize the definition of poor ovarian response (POR) in a simple and reproducible manner. POR to ovarian stimulation usually indicates a reduction in follicular response, resulting in a reduced number of retrieved oocytes. It has been recognized that, in order to define the poor response in IVF, at least two of the following three features must be present: (i) advanced maternal age or any other risk factor for POR; (ii) a previous POR; and (iii) an abnormal ovarian reserve test (ORT). Two episodes of POR after maximal stimulation are sufficient to define a patient as poor responder in the absence of advanced maternal age or abnormal ORT. By definition, the term POR refers to the ovarian response, and therefore, one stimulated cycle is considered essential for the diagnosis of POR. However, patients of advanced age with an abnormal ORT may be classified as poor responders since both advanced age and an abnormal ORT may indicate reduced ovarian reserve and act as a surrogate of ovarian stimulation cycle outcome. In this case, the patients should be more properly defined as 'expected poor responder'. If this definition of POR is uniformly adapted as the 'minimal' criteria needed to select patients for future clinical trials, more homogeneous populations will be tested for any new protocols. Finally, by reducing bias caused by spurious POR definitions, it will be possible to compare results and to draw reliable conclusions.

  19. A Higher Ovarian Response after Stimulation for IVF Is Related to a Higher Number of Euploid Embryos.

    PubMed

    Labarta, Elena; Bosch, Ernesto; Mercader, Amparo; Alamá, Pilar; Mateu, Emilia; Pellicer, Antonio

    2017-01-01

    This study has analysed the relationship between ovarian response and the number of euploid embryos. This is a post hoc analysis of a subset of data generated during a prospective cohort study previously published. Forty-six oocyte donors were subjected to ovarian stimulation with 150 IU of rFSH and 75 IU of hp-hMG in a GnRH agonist long protocol. Preimplantation genetic screening was performed in all viable embryos. We observed a positive relationship between ovarian response and the number of euploid embryos. When ovarian response was above the median (≥17 oocytes), the mean number of euploid embryos per donor was 5.0 ± 2.4, while when <17 oocytes were obtained the mean number of euploid embryos was 2.7 ± 1.4 (p = 0.000). Aneuploidy rate did not increase with ovarian response or gonadotropin doses. Also, the number of euploid embryos was inversely related to the amount of gonadotropins needed per oocyte obtained (ovarian sensitivity index). These results suggest that the number of euploid embryos available for embryo transfer increases as the number of oocytes obtained does. Considering the total number of euploid embryos seems more relevant than the aneuploidy rate.

  20. Sulforaphane reduces molecular response to hypoxia in ovarian tumor cells independently of their resistance to chemotherapy.

    PubMed

    Pastorek, Michal; Simko, Veronika; Takacova, Martina; Barathova, Monika; Bartosova, Maria; Hunakova, Luba; Sedlakova, Olga; Hudecova, Sona; Krizanova, Olga; Dequiedt, Franck; Pastorekova, Silvia; Sedlak, Jan

    2015-07-01

    One of the recently emerging anticancer strategies is the use of natural dietary compounds, such as sulforaphane, a cancer-chemopreventive isothiocyanate found in broccoli. Based on the growing evidence, sulforaphane acts through molecular mechanisms that interfere with multiple oncogenic pathways in diverse tumor cell types. Herein, we investigated the anticancer effects of bioavailable concentrations of sulforaphane in ovarian carcinoma cell line A2780 and its two derivatives, adriamycin-resistant A2780/ADR and cisplatin-resistant A2780/CP cell lines. Since tumor microenvironment is characterized by reduced oxygenation that induces aggressive tumor phenotype (such as increased invasiveness and resistance to chemotherapy), we evaluated the effects of sulforaphane in ovarian cancer cells exposed to hypoxia (2% O2). Using the cell-based reporter assay, we identified several oncogenic pathways modulated by sulforaphane in hypoxia by activating anticancer responses (p53, ARE, IRF-1, Pax-6 and XRE) and suppressing responses supporting tumor progression (AP-1 and HIF-1). We further showed that sulforaphane decreases the level of HIF-1α protein without affecting its transcription and stability. It can also diminish transcription and protein level of the HIF-1 target, CA IX, which protects tumor cells from hypoxia-induced pH imbalance and facilitates their migration/invasion. Accordingly, sulforaphane treatment leads to diminished pH regulation and reduced migration of ovarian carcinoma cells. These effects occur in all three ovarian cell lines suggesting that sulforaphane can overcome the chemoresistance of cancer cells. This offers a path potentially exploitable in sensitizing resistant cancer cells to therapy, and opens a window for the combined treatments of sulforaphane either with conventional chemotherapy, natural compounds, or with other small molecules.

  1. Dehydroepiandrosterone improves the ovarian reserve of women with diminished ovarian reserve and is a potential regulator of the immune response in the ovaries.

    PubMed

    Zhang, Jiali; Qiu, Xuemin; Gui, Yuyan; Xu, Yingping; Li, Dajin; Wang, Ling

    2015-12-01

    Diminished ovarian reserve (DOR) has a high morbidity rate worldwide and has become a primary cause of infertility. DOR is a daunting obstacle in in vitro fertilization (IVF) and leads to poor ovarian response, high cancellation rates, poor IVF outcomes, and low pregnancy rates. Abnormal autoimmune function may also contribute to DOR. Dehydroepiandrosterone (DHEA) is a C19 androgenic steroid. DHEA is secreted mainly by the adrenal gland, and its secretion declines with age. DHEA has a pro-inflammatory immune function that opposes cortisol. The cortisol to DHEA ratio increases with age, which may lead to decreased immune function. DHEA supplementation helps improve this situation. A number of clinical case control studies and several prospective randomized clinical trials have observed a positive effect of DHEA supplementation in women with DOR. However, the underlying mechanism by which DHEA improves ovarian reserve remains unclear. DHEA functions as an immune regulator in many different tissues in mammals and may also play an important role in regulating the immune response in the ovaries. The conversion of DHEA to downstream sex steroids may allow it to regulate the immune response there. DHEA can also enhance the Th1 immune response and regulate the balance of the Th1/Th2 response. DHEA treatment can increase selective T lymphocyte infiltration in mice, resulting in a decline in the CD4+ T lymphocyte population and an upregulation of the CD8+ T lymphocyte population in ovarian tissue, thus regulating the balance of CD4+/CD8+ T cells. This review mainly focuses on how DHEA supplementation affects regulation of the immune response in the ovaries.

  2. Metabolic state defines the response of rabbit ovarian cells to leptin.

    PubMed

    Harrath, Abdel Halim; Østrup, Olga; Rafay, Jan; Koničková Florkovičová, Iveta; Laurincik, Jozef; Sirotkin, Alexander V

    2017-03-01

    Leptin is a hormone that mediates the effect of the metabolic state on several biological functions, including reproduction. Leptin affects reproductive functions via alterations in the release of hormonal regulators. However, the extent to which caloric restriction (CR) can affect the complex processes of reproduction by other mechanisms, such as altering ovarian functions via direct binding/response to leptin, is unknown. Therefore, the aim of the present study was to show basic ovarian cell functions and CR on the response of ovarian cells to leptin. Female rabbits were subjected to 50% CR restriction for 10days before ovulation. On the day of ovulation, both control and CR animals were sacrificed. Isolated granulosa cells were cultured for 2days with and without leptin (100ng/ml), and the accumulation of various markers was evaluated using immunocytochemistry; i.e., cell proliferation (PCNA and cyclin B1), apoptosis (bax), MAP/ERK1,2 kinase (MAPK), protein kinase A (PKA), and IGF-I. In addition, the release of IGF-I and estradiol (E2) by cells cultured with and without leptin (1, 10, 100, 1000, or 10,000ng/ml) was assessed by radioimmunoassay (RIA). In the granulosa cells of control animals, leptin promoted cyclin B1, MAPK, and PKA accumulation, but not that of PCNA, and reduced bax and IGF-I accumulation. These cells responded to leptin by increased IGF-I, but not E2 release. In cells of CR animals, leptin increased cyclin B1 accumulation, but decreased PCNA, MAPK, and IGF-I expression. Bax and PKA were not affected. Leptin resulted in a decrease in IGF-I release. CR modulated the influence of leptin on E2 release dose dependently, i.e., E2 increased at 10 and decreased at 10,000ng/ml. Therefore, CR modified the influence of leptin on PCNA, E2, bax, PKA, MAPK, and IGF-I release, but it did not change the effect of leptin on cyclin B1 and IGF-I accumulation within the cells. Our data showed that leptin directly affected proliferation, apoptosis, and hormone

  3. Seasonal effects on ovarian responsiveness to exogenous gonadotrophins and successful artificial insemination in the snow leopard (Uncia uncia).

    PubMed

    Roth, T L; Armstrong, D L; Barrie, M T; Wildt, D E

    1997-01-01

    Ovaries of the seasonally-breeding snow leopard (Uncia uncia) were examined to determine whether they were responsive to exogenous gonadotrophins throughout the year. The potential of laparoscopic artificial insemination (AI) also was assessed for producing offspring. During the non-breeding, pre-breeding, breeding and post-breeding seasons, females (n = 20) were treated with a standardized, dual-hormone regimen given intramuscularly (600 I.U. of equine chorionic gonadotrophin followed 80-84 h later with 300 I.U. of human chorionic gonadotrophin (hCG)). Laparoscopy was performed 45-50 h after administration of hCG, and all ovarian structures were described. Females with fresh corpora lutea (CL) were inseminated, and anovulatory females were subjected to follicular aspiration to examine oocyte quality. Snow leopards responded to exogenous gonadotrophins throughout the year. Mean number of total ovarian structures (distinct follicles mature in appearance plus CL) did not differ (P > or = 0.05) with season, but the proportion of CL: total ovarian structures was greater (P < 0.01) for the breeding season compared with all other seasons. The proportion of females ovulating was greater (P < 0.05) during the breeding and post-breeding seasons than during the pre-breeding and non-breeding seasons respectively. No Grade-1 quality oocytes were recovered from follicles of anovulatory females. Serum concentrations of oestradiol-17 beta appeared elevated in all females, and neither oestradiol-17 beta concentrations nor progesterone concentrations differed (P > or = 0.05) among seasons. Of 15 females artificially inseminated, the only one that was inseminated in the non-breeding season became pregnant and delivered a single cub. This is the first successful pregnancy resulting from AI in this endangered species.

  4. Differential physiological responses of the German cockroach to social interactions during the ovarian cycle.

    PubMed

    Uzsák, Adrienn; Schal, Coby

    2012-09-01

    In many animal species, social interactions can influence the morphology, physiology and behavior of individuals, including their rate of development and reproduction. Reproduction in cockroaches is regulated by juvenile hormone III (JH), and social interactions have been shown to accelerate female reproduction in the German cockroach, Blattella germanica (L.), by stimulating JH production. However, it is not clear in this or any other insect species whether social facilitation of the reproductive rate occurs throughout the ovarian cycle or only at certain stages. We compared the effects of social interactions during the pre-oviposition period (when JH production is high) and during gestation (when little JH is produced), as well as during the first ovarian cycle (when females are virgin) and the second ovarian cycle (after females had mated). Social interaction with one conspecific female was sufficient to accelerate JH production and oocyte maturation, but this effect was reversed by crowding. Social interactions also accelerated the onset of sexual receptivity in virgin females. However, social interactions failed to shorten gestation, suggesting that social cues stimulate JH production only when the corpora allata (CA) are active and not when CA activity is suppressed by the central nervous system. Females were most responsive to transient social isolation and transient social interactions when 2-3 days old, suggesting that they are particularly sensitive to social interactions when their CA become active. Overall, these results show that all JH-dependent events in the reproductive cycle of B. germanica females are under the strong influence of social interactions.

  5. Polymorphisms in gonadotropin and gonadotropin receptor genes as markers of ovarian reserve and response in in vitro fertilization.

    PubMed

    La Marca, Antonio; Sighinolfi, Giovanna; Argento, Cindy; Grisendi, Valentina; Casarini, Livio; Volpe, Annibale; Simoni, Manuela

    2013-03-15

    Since gonadotropins are the fundamental hormones that control ovarian activity, genetic polymorphisms may alter gonadal responsiveness to glycoproteins; hence they are important regulators of hormone activity at the target level. The establishment of the pool of primordial follicles takes place during fetal life and is mainly under genetic control. Consequently, single nucleotide polymorphisms (SNPs) in gonadotropins and their receptors do not seem to be associated with any significant modification in the endowment of nongrowing follicles in the ovary. Indeed, the age at menopause, a biological characteristic strongly related to ovarian reserve, as well as markers of functional ovarian reserve such as anti-Müllerian hormone and antral follicle count, are not different in women with different genetic variants. Conversely, some polymorphisms in FSH receptor (FSHR) seem to be associated with modifications in ovarian activity. In particular, studies suggest that the Ser680 genotype for FSHR is a factor of relative resistance to FSH stimulation resulting in slightly higher FSH serum levels, thus leading to a prolonged duration of the menstrual cycle. Moreover, some FSHR gene polymorphisms show a positive association with ovarian response to exogenous gonadotropin administration, hence exhibiting some potential for a pharmacogenetic estimation of the FSH dosage in controlled ovarian stimulation. The study of SNPs of the FSHR gene is an interesting field of research that could provide us with new information about the way each woman responds to exogenous gonadotropin administration during ovulation induction.

  6. Why we may abandon basal follicle-stimulating hormone testing: a sea change in determining ovarian reserve using antimüllerian hormone.

    PubMed

    Toner, James P; Seifer, David B

    2013-06-01

    Antimüllerian hormone is the most informative serum marker of ovarian reserve currently available and should be considered an important part of any contemporary reproductive medicine practice. It is both more convenient and informative than basal FSH and can be assessed at any point in the cycle. It is the most useful serum method of determining ovarian reserve, which guides pretreatment counseling, choice of infertility treatment, and avoidance of ovarian hyperstimulation. The future role of basal FSH testing is in doubt.

  7. Intrinsic determinants and predictors of superovulatory yields in sheep: Circulating concentrations of reproductive hormones, ovarian status, and antral follicular blood flow.

    PubMed

    Bartlewski, Pawel M; Seaton, Patricia; Franco Oliveira, Maria Emilia; Kridli, Rami T; Murawski, Maciej; Schwarz, Tomasz

    2016-07-01

    Hormonal ovarian superstimulation has contributed to small ruminant reproduction around the world, impacting genetic improvement and zoosanitary programs, contributing to the conservation of endangered species, and supporting other related biotechnologies. Advanced knowledge surrounding the superovulatory treatments in sheep has resulted in enhanced control of influencing factors and improved the protocols currently used. However, in spite of minimization of some adverse factors, superovulatory responses in ewes still remain variable, preventing the more widespread use of superovulation in commercial embryo transfer programs and reproductive research in this species. Recent evidence demonstrates that changes in antral follicular populations and blood supply, and circulating concentrations of certain reproductive hormones determined at the specific time points just before or during the superovulatory treatment are associated with superovulation success in ewes. This review attempts to compile the data from available literature to identify ovarian and hormonal determinants of the superovulatory outcome in ewes, which can be used to substantially improve the existing protocols and to reduce the extra cost and unnecessary stress imposed on poorly responding animals. An overview of most commonly used and some recently developed, FSH-based ovarian stimulation protocols is given at the outset to highlight variation in the frequency and timing of gonadotropin injections, estrus synchronization methods, and follicular wave synchronization and/or ovulation induction techniques during the superovulatory treatments in ewes.

  8. Bypassing multidrug resistant ovarian cancer using ultrasound responsive doxorubicin/curcumin co-deliver alginate nanodroplets.

    PubMed

    Baghbani, Fatemeh; Moztarzadeh, Fathollah

    2017-05-01

    Ultrasound-responsive perfluorocarbon nanoemulsions are a class of new multifunctional smart nanocarriers which combine diagnostic properties with therapeutic properties and release their drug payload in a controlled manner in response to ultrasound. Therefore, combination therapy using chemotherapeutic and chemosensitizing agents co-entrapped in these nanocarriers seems beneficial for cancer treatment. In the present study, multifunctional smart alginate/perfluorohexane nanodroplets were developed for co-delivery of doxorubicin and curcumin (a strong chemosensitizer). The nanodroplets with the average particle size of 55.1nm were synthesized via nanoemulsion process. The entrapment efficiency of doxorubicin was 92.3%. To improve curcumin entrapment into the alginate shell, Span 60 was added to the formulation as a co-surfactant and finally curcumin entrapment of about 40% was achieved. Ultrasound-mediated drug release kinetic was evaluated at two different frequencies of 28kHz (low frequency) and 1MHz (high frequency). Low frequency ultrasound resulted in higher triggered drug release from nanodroplets. The nanodroplets showed strong ultrasound contrast via droplet to bubble transition as confirmed via B-mode ultrasound imaging. Enhanced cytotoxicity in adriamycin-resistant A2780 ovarian cancer cells was observed for Dox-Cur-NDs compared to Dox-NDs because of the synergistic effects of doxorubicin and curcumin. However, ultrasound irradiation significantly increased the cytotoxicity of Dox-Cur-NDs. Finally, in vivo ovarian cancer treatment using Dox/Cur-NDs combined with ultrasound irradiation resulted in efficient tumor regression. According to the present study, nanotherapy of multidrug resistant human ovarian cancer using ultrasound responsive doxorubicin/curcumin co-loaded alginate-shelled nanodroplets combined with ultrasound irradiation could be a promising modality for the future of cancer treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  9. Evaluation of chemotherapy response in ovarian cancer treatment using quantitative CT image biomarkers: a preliminary study

    NASA Astrophysics Data System (ADS)

    Qiu, Yuchen; Tan, Maxine; McMeekin, Scott; Thai, Theresa; Moore, Kathleen; Ding, Kai; Liu, Hong; Zheng, Bin

    2015-03-01

    The purpose of this study is to identify and apply quantitative image biomarkers for early prediction of the tumor response to the chemotherapy among the ovarian cancer patients participated in the clinical trials of testing new drugs. In the experiment, we retrospectively selected 30 cases from the patients who participated in Phase I clinical trials of new drug or drug agents for ovarian cancer treatment. Each case is composed of two sets of CT images acquired pre- and post-treatment (4-6 weeks after starting treatment). A computer-aided detection (CAD) scheme was developed to extract and analyze the quantitative image features of the metastatic tumors previously tracked by the radiologists using the standard Response Evaluation Criteria in Solid Tumors (RECIST) guideline. The CAD scheme first segmented 3-D tumor volumes from the background using a hybrid tumor segmentation scheme. Then, for each segmented tumor, CAD computed three quantitative image features including the change of tumor volume, tumor CT number (density) and density variance. The feature changes were calculated between the matched tumors tracked on the CT images acquired pre- and post-treatments. Finally, CAD predicted patient's 6-month progression-free survival (PFS) using a decision-tree based classifier. The performance of the CAD scheme was compared with the RECIST category. The result shows that the CAD scheme achieved a prediction accuracy of 76.7% (23/30 cases) with a Kappa coefficient of 0.493, which is significantly higher than the performance of RECIST prediction with a prediction accuracy and Kappa coefficient of 60% (17/30) and 0.062, respectively. This study demonstrated the feasibility of analyzing quantitative image features to improve the early predicting accuracy of the tumor response to the new testing drugs or therapeutic methods for the ovarian cancer patients.

  10. Application of X-Ray Fluorescence Analysis to Determine the Elemental Composition of Tissues from Different Ovarian Neoplasms

    NASA Astrophysics Data System (ADS)

    Motevich, I. G.; Strekal, N. D.; Papko, N. M.; Glebovich, M. I.; Shulha, A. V.; Maskevich, S. A.

    2015-03-01

    We present the results of x-ray fluorescence analysis of tissues from healthy ovaries and from ovaries with different pathologies: benign and borderline tumors, mucinous and endometrioid cancers, serous carcinomas. We determine the average copper, zinc, calcium, selenium, cadmium, lead, and mercury levels. We observed that in the benign ovarian tumors, we see a significant decrease in the cadmium, mercury, and lead levels compared with healthy tissues. In the borderline neoplasms, the copper level is reduced relative to zinc (Cu/Zn), cadmium, mercury, and lead, and also the zinc concentration is increased. In the ovarian carcinomas, we observed changes in the ratio of the chemical elements in the tumor tissues, depending on the histologic type. The results obtained can be used for differentiation, diagnosis, and adjustment of treatment for different ovarian neoplasms.

  11. Effects of breed on kinetics of ovine FSH and ovarian response in superovulated sheep.

    PubMed

    Ammoun, I; Encinas, T; Veiga-Lopez, A; Ros, J M; Contreras, I; Gonzalez-Añover, P; Cocero, M J; McNeilly, A S; Gonzalez-Bulnes, A

    2006-09-01

    Embryo production is a useful tool for ex situ conservation of endangered species and breeds, despite a high variability in the ovarian response to superovulatory treatments. The current study evaluated the incidence and mechanisms of genetic factors in such variability, by determining the pharmacokinetics and pharmacodynamics of a standard treatment with ovine FSH (oFSH) in two endangered Spanish sheep breeds (Rubia del Molar, R, and Negra de Colmenar, N) in comparison to Manchega ewes (M, control group). In the first experiment, pharmacokinetics of an i.m. single dose of 1.32 mg of oFSH was evaluated in seven animals of each breed. Plasma FSH concentrations reached their maximum at 4h post-administration in all the ewes, but several of the kinetic parameters (plasma FSH concentration at 4h post-administration, maximum plasma FSH concentration, C(max), and both the area under the plasma concentration-time curve extrapolated to the infinite, AUC(inf), and to the last moment of sampling, AUC(last)) were higher in the N group. In the second trial, 10 animals of each breed were superovulated using eight decreasing doses of oFSH (3 x 1.32 mg, 2 x 1.10 mg, and 3 x 0.88 mg). The R group, when compared to N and M, showed both a higher number of corpora lutea (13.7+/-0.6 versus 10.0+/-0.4 in N and 9.8+/-0.6 in M, P<0.05 for both) and embryos (7.9+/-0.8 versus 4.3+/-0.4 in N, P<0.05, and 6.7+/-0.5 in M, n.s.). Evaluation of pharmacokinetic and dynamic parameters showed that, although there was a trend for a higher hormone availability in R sheep, mean FSH plasma concentrations were similar between breeds (0.54+/-0.08 ng/ml for R, 0.45+/-0.05 ng/ml for N and 0.35+/-0.05 ng/ml for M). However, differences were found in the number of preovulatory follicles growing in response to the FSH treatment between R (24.4+/-2.2), M (18.9+/-1.5, n.s.) and N sheep (14.1+/-1.4; P<0.01). Thus, differences in embryo yields between breeds would be related to differences in the pattern of

  12. Aerobic physical training increases contractile response and reduces cardiac fibrosis in rats subjected to early ovarian hormone deprivation.

    PubMed

    Felix, Ana Carolina S; Dutra, Sabrina G V; Tezini, Geisa C S V; Simões, Marcus Vinicius; de Souza, Hugo Celso Dutra

    2015-05-15

    We investigated the effects of early ovarian hormone deprivation on the heart and the role of physical training in this condition using different approaches: cardiac autonomic tone, contractility, morphology and function, and cardiac fibrosis. Female Wistar rats (n = 48) were assigned into two groups: ovariectomized (Ovx; 10-wk-old) and control rats (Sham; 10-wk-old). Each group was further divided into two subgroups, sedentary and trained (aerobic training by swimming for 10 wk). The sedentary groups showed similar cardiac autonomic tone values; however, only the Sham group had an increase in vagal participation for the determination of the basal heart rate after physical training. The contractile responses to cardiac β-agonists of the sedentary groups were similar, including an increased response to a β1-agonist (dobutamine) observed after physical training. The Ovx sedentary group presented changes in cardiac morphology, which resulted in decreases in the ejection fraction, fractional shortening, and cardiac index compared with the Sham sedentary group. Physical training did little to alter these findings. Moreover, histology analysis showed a significant increase in cardiac fibrosis in the sedentary Ovx group, which was not observed in the trained Ovx group. We conclude that early ovarian hormone deprivation in rats impairs autonomic control, cardiac morphology, and cardiac function and increases cardiac fibrosis; however, it does not affect the contractility induced by dobutamine and salbutamol. Furthermore, this model of physical training prevented an increase in fibrosis and promoted an increase in the cardiac contractile response but had little effect on cardiac autonomic control or morphological and functional parameters.

  13. Concentrations of steroid hormones, estrous, ovarian and reproductive responses in sheep estrous synchronized with different prostaglandin-based protocols.

    PubMed

    Fierro, S; Viñoles, C; Olivera-Muzante, J

    2016-04-01

    To determine estrous, ovarian and reproductive responses after different prostaglandin (PG)-based protocols, ewes were assigned to groups PG10, PG12, PG14 or PG16 (twoPG injections administered 10, 12, 14 or 16 days apart; respectively). Experiment I (n=132) was conducted to evaluate the estrous response, ovulation rate (OR), conception and fertility. Experiment II (n=24) was conducted to evaluate ovarian follicle growth, steroid concentrations and the interval from the second PG injection to estrus (PG-estrus) and ovulation (PG-ovulation). Estrous response was less with the PG16 (P<0.05) treatment, and the extent of estrous synchrony was greater with the PG10 and PG12 treatments. Ovarian follicle growth and the intervals for the variables PG-estrus, PG-ovulation and OR were similar among groups (P>0.05). From 8 to 4 days before estrus, progesterone (P4) concentrations were greater for the PG14 and PG16 than for the PG10 and PG12 (P<0.05) groups. There were more days where concentrations of P4 were above 3.18 nmol/L with the PG14 and PG16 than PG10 and PG12 (P<0.05) treatments. Use of the PG14 and PG16 treatments resulted in greater estradiol (E2) at estrus and 12h later than use of the PG10 and PG12 treatments. A positive correlation was observed between the duration of the luteal phase and maximum E2 concentrations, and between duration of the luteal phase and days with E2 concentrations above 10 pmol/L. Conception and fertility were greater with use of the PG14 compared with PG10 and PG12 (P<0.05) treatments. The administration of two PG injections 10, 12, 14 or 16 days apart resulted in different durations of the luteal phase that were positively associated with E2 concentrations and the reproductive outcome. The shorter luteal phases were associated with greater synchrony in time of estrus. The intervals for the variables PG-estrus, PG-ovulation and OR were similar among groups. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Toll-Like Receptors Expression in Follicular Cells of Patients with Poor Ovarian Response

    PubMed Central

    Taghavi, Seyed Abdolvahab; Ashrafi, Mahnaz; Mehdizadeh, Mehdi; Karimian, Leili; Joghataie, Mohammad Taghi; Aflatoonian, Reza

    2014-01-01

    Background Poor ovarian response (POR) to gonadotropin stimulation has led to a significant decline in success rate of fertility treatment. The immune system may play an important role in pathophysiology of POR by dysfunctions of cytokines and the growth factor network, and the presence of ovarian auto-antibodies. The aim of this study is to investigate the expression of toll-like receptors (TLR) 1, 2, 4, 5, 6 and cyclooxygenase (COX) 2 genes in follicular cells and concentration of interleukin (IL)-6, IL-8 and macrophage migration inhibitory factor (MIF), as major parts of innate immunity, in follicular fluid (FF) obtained from POR women in comparison with normal women. Materials and Methods In this case-control study, 20 infertile POR patients and 20 normal women took part in this study and underwent controlled ovarian stimulation. The FF was obtained from the largest follicle (>18 mm). The FF was centrifuged and cellular pellet was then used for evaluation of expression of TLRs and COX2 genes by real-time PCR. FF was used for quantitative analysis for IL-6, IL-8 and MIF by enzyme-linked immunosorbent assay (ELISA). Results TLR1, 2, 4, 5, 6 and COX2 gene expression were significantly higher in POR (p<0.05). Concentration of IL-6, IL-8 and MIF proteins was significantly increased in POR compared with normal women (p<0.05). Conclusion These findings support the hypothesis that the immune system may be involved in pathophysiology of POR through TLRs. PMID:25083184

  15. Which cut-off value of serum anti-Müllerian hormone level can predict poor ovarian reserve, poor ovarian response to stimulation and in vitro fertilization success? A prospective data analysis.

    PubMed

    Ficicioglu, Cem; Cenksoy, Pinar Ozcan; Yildirim, Gazi; Kaspar, Cigdem

    2014-05-01

    The aim of our study is to demonstrate which cut-off value of serum anti-Müllerian hormone (AMH) level can predict poor ovarian reserve, poor ovarian response to stimulation and IVF outcomes. About 311 of 520 women enrolled IVF treatment cycle that meets inclusion criteria were recruited for this prospective data analysis. Data were collected for: age, duration of infertility, basal FSH and AMH level, total dosage of gonadotropins, maximum estradiol levels, duration of stimulations, total number of oocytes retrieved and clinical PR. Mean AMH was 1.76 ± 1.4 ng/ml and mean age was 33.25 ± 5.5 years. Clinical PR was 39.8% (n = 124). AMH was inversely correlated to total dosage of gonadotropins and age, AMH positively had a significant correlation with maximum estradiol levels, duration of stimulations and total number of oocytes retrieved. The patients in both categories of AMH levels, ≤0.5 and ≤1 ng/ml responded poorly to ovarian stimulation, had significantly higher total dosage of gonadotropins used and FSH levels on cycle day 3, lower maximum E2 levels and clinical PR. AMH could be an acceptable screening test in prediction of ovarian reserve, response to ovarian stimulation and PRs. AMH cut-off value ≤1 ng/ml may predict poor ovarian reserve, poor ovarian response to stimulation and IVF outcomes.

  16. Knockdown of ICB-1 gene enhanced estrogen responsiveness of ovarian and breast cancer cells.

    PubMed

    Konwisorz, Anna; Springwald, Anette; Haselberger, Martina; Goerse, Regina; Ortmann, Olaf; Treeck, Oliver

    2010-03-01

    ICB-1 chromosome 1 open reading frame 38 (C1orf38) is a human gene initially described by our group to be involved in differentiation processes of cancer cells. Recently, we have reported ICB-1 as a novel estrogen target gene and identified an estrogen response element in its promoter. In this study, we examined the role of ICB-1 in regulation of proliferation of breast and ovarian cancer cells. We knocked down its expression in estrogen-dependent MCF-7 breast cancer cells and hormone-unresponsive SK-OV-3 ovarian cancer cells by stable transfection with a specific shRNA plasmid followed by G-418 selection. Knockdown of ICB-1 enabled a considerable estrogen response of SK-OV-3 cells in terms of proliferation. This transformation of SK-OV-3 cells into an estrogen-responsive phenotype was accompanied by upregulation of estrogen receptor alpha (ERalpha) expression and a significant decrease of ERbeta expression on the mRNA level. Expression of ERalpha-dependent genes progesterone receptor, pS2, fibulin 1c, and c-fos was elevated in SK-OV-3 cells stably expressing ICB-1 shRNA. In MCF-7 cells, ICB-1 knockdown exerted similar effects on gene expression, supporting a general role of ICB-1 in estrogen responsiveness. Our data suggest that differentiation-associated gene ICB-1 might exert antagonistic actions on cellular estrogen response, which can result in inhibition of estradiol-triggered proliferation. The molecular mechanisms mediating this inhibitory effect of ICB-1 on estrogen signaling are suggested to be limitation of ERalpha transcript levels but sustaining high levels of ERbeta, reducing both activation of ERalpha target genes and cellular proliferation. The identification of ICB-1 as a new player in endocrine-related cancer encourages further studies on the significance of this gene in cancer development and therapy.

  17. Effect of high ovarian response on the expression of endocrine gland-derived vascular endothelial growth factor (EG-VEGF) in peri-implantation endometrium in IVF women

    PubMed Central

    Xu, Li-Zhen; Gao, Min-Zhi; Yao, Li-Hua; Liang, A-Juan; Zhao, Xiao-Ming; Sun, Zhao-Gui

    2015-01-01

    Objective: To investigate the effect of ovarian stimulation on the expression of EG-VEGF mRNA and protein in peri-implantation endometrium in women undergoing IVF and its relation with endometrial receptivity (ER). Design: Prospective laboratory study. Setting: University hospital. Patients: Eighteen women in stimulated cycles (SC) as study subjects and 18 women in natural cycles (NC) as controls. Women in SC group were classified with two subgroups, high ovarian response (SC1, n=9) with peak serum E2>5,000 pg/mL and moderate ovarian response (SC2, n=9) with peak serum E2 1,000-5,000 pg/mL. Intervention(s): Endometrial biopsies were collected 6 days after ovulation in NC or after oocyte retrieval in SC. Main outcome measure(s): Endometrium histological dating was observed with HE staining. EG-VEGF mRNA expression levels determined by real-time polymerase chain reaction analysis, and protein levels by immunohistochemistry. Results: All endometrial samples were in the secretory phase. The endometrial development in SC1 was 1 to 2 days advanced to NC, and with dyssynchrony between glandular and stromal tissue. Immunohistochemistry analysis showed that EG-VEGF protein was predominantly expressed in the glandular epithelial cells and endothelial cells of vessels, and also presented in the stroma. The image analysis confirmed that both the gland and stroma of endometrium in SC1 had a significantly lower EG-VEGF protein expression than that in SC2 and NC endometrium. Moreover, EG-VEGF mRNA levels were significantly lower in SC1 than in NC. Both EG-VEGF protein and mRNA levels had no significant difference between SC2 and NC. Conclusion: Decreased expression of EG-VEGF in the peri-implantation is associated with high ovarian response, which may account for the impaired ER and lower implantation rate in IVF cycles. PMID:26464631

  18. Molecular identification of GD3 as a suppressor of the innate immune response in ovarian cancer

    PubMed Central

    Webb, Tonya J.; Li, Xiangming; Giuntoli, Robert L.; Lopez, Pablo H.H.; Heuser, Christoph; Schnaar, Ronald L.; Tsuji, Moriya; Kurts, Christian; Oelke, Mathias; Schneck, Jonathan P.

    2012-01-01

    Tumors often display mechanisms to avoid or suppress immune recognition. One such mechanism is the shedding of gangliosides into the local tumor microenvironment, and a high concentration of circulating gangliosides is associated with poor prognosis. In this study, we identify ganglioside GD3, which was isolated from the polar lipid fraction of ovarian cancer-associated ascites, as an inhibitory factor that prevents innate immune activation of natural killer T (NKT) cells. Purified GD3 displayed a high affinity for both human and mouse CD1d, a molecule involved in the presentation of lipid antigens to T cells. Purified GD3, as well as substances within the ascites, bound to the CD1d antigenic binding site and did not require additional processing for its inhibitory effect on NKT cells. Importantly, in vivo administration of GD3 inhibited α-GalCer- induced NKT cell activation in a dose dependent manner. These data therefore indicate that ovarian cancer tumors may use GD3 to inhibit the anti-tumor NKT cell response as an early mechanism of tumor immune evasion. PMID:22649190

  19. Immunohistochemical expression of VEGF predicts response to platinum based chemotherapy in patients with epithelial ovarian cancer.

    PubMed

    Siddiqui, G K; Maclean, A B; Elmasry, K; Wong te Fong, A; Morris, R W; Rashid, M; Begent, R H J; Boxer, G M

    2011-05-01

    For patients with epithelial ovarian cancer (EOC) cytoreduction, with a combination of taxane and platinum, is the standard of care. Despite this, approximately 50% of patients with advanced disease will relapse and moreover 15-20% of cases of EOC are resistant to platinum based chemotherapy. Vascular Endothelial Growth Factor (VEGF), an angiogenic factor, is associated with poor prognosis. This study was undertaken to examine whether there is an association between VEGF-A expression in the tumour of EOC patients and their response to platinum based chemotherapy. The study cohort consisted of 66 patients with advanced stage EOC (FIGO III-IV). Ovarian cancer tissue was analysed for VEGF-A expression immunohistochemically. Protein expression was measured and correlated, with platinum sensitivity and overall patient survival. Median age of patients was 53 years, 45 patients had platinum sensitive disease (68%), the remaining patients being platinum resistant (32%). Of the platinum resistant group, 18 (86%) patients had high VEGF score compared to only 1 (2%) with high VEGF score in the platinum sensitive group. Median survival was 11 months in the patient group with high VEGF score versus 32 months in that cohort with low VEGF score. VEGF expression was significantly inversely correlated with overall survival (P < 0.0001). We demonstrated that tumours of patients with platinum resistant EOC exhibit higher levels of VEGF expression compared to the platinum sensitive group. VEGF in EOC, may be of clinical and therapeutic relevance and suggests a role for first line anti-angiogenic therapy.

  20. An in vivo mouse reporter gene (human secreted alkaline phosphatase) model to monitor ovarian tumor growth and response to therapeutics.

    PubMed

    Nilsson, Eric E; Westfall, Suzanne D; McDonald, Claudia; Lison, Tiffany; Sadler-Riggleman, Ingrid; Skinner, Michael K

    2002-02-01

    Developing new anticancer therapeutic regimens requires the measurement of tumor cell growth in response to treatment. This is often accomplished by injecting immunocompromised mice with cells from cancer tissue or cell lines. After treating the animals, tumor weight or volume is measured. Such methods are complicated by inaccuracies in measuring tumor mass and often animals must be killed to measure tumor burden. An in vivo tumor model system is presented in which the tumor cell line was stably transfected with a constitutively expressed marker gene: secreted human placental alkaline phosphatase protein (SEAP). The SEAP gene codes for a heat-stable protein that is produced at levels proportional to the amount of tumor cells in the animal. The SEAP protein is detectable in small blood samples so that animals can be repeatedly sampled over the trial period to monitor the course of tumor progression. OCC1 ovarian carcinoma cells were stably transfected with pCMV-SEAP. The OCC1-SEAP cells were maintained in vitro to monitor the relationship between cell number and SEAP production. Experiments were performed in vivo to determine whether SEAP levels in blood corresponded to tumor burden. OCC1-SEAP cells were injected s.c. or intraperitoneally into nude mice and tumor volume was measured as well as plasma SEAP levels as the tumors developed. S.c. tumor volume correlated well with plasma SEAP levels ( R(2)=0.95). OCC1-SEAP cells were also injected intraperitoneally into nude mice and grown as abdominal tumors. After 3 weeks the animals were killed and the tumors were dissected and weighed. SEAP levels in plasma samples from the time of death correlated with intraperitoneal tumor weight ( R(2)=0.87). Experiments were performed to determine whether measuring SEAP levels could be used to monitor ovarian carcinoma cell response to platinum-containing chemotherapeutic drugs. OCC1-SEAP cells cultured in vitro were treated with the platinum-containing drug carboplatin

  1. Ovarian cancer

    MedlinePlus

    ... cancer, CT scan Ovarian cancer dangers Ovarian growth worries Uterus Ovarian cancer Ovarian cancer metastasis References Coleman ... Duplication for commercial use must be authorized in writing by ADAM Health Solutions. About MedlinePlus Site Map ...

  2. Improving efficacy of metastatic tumor segmentation to facilitate early prediction of ovarian cancer patients' response to chemotherapy

    NASA Astrophysics Data System (ADS)

    Danala, Gopichandh; Wang, Yunzhi; Thai, Theresa; Gunderson, Camille C.; Moxley, Katherine M.; Moore, Kathleen; Mannel, Robert S.; Cheng, Samuel; Liu, Hong; Zheng, Bin; Qiu, Yuchen

    2017-02-01

    Accurate tumor segmentation is a critical step in the development of the computer-aided detection (CAD) based quantitative image analysis scheme for early stage prognostic evaluation of ovarian cancer patients. The purpose of this investigation is to assess the efficacy of several different methods to segment the metastatic tumors occurred in different organs of ovarian cancer patients. In this study, we developed a segmentation scheme consisting of eight different algorithms, which can be divided into three groups: 1) Region growth based methods; 2) Canny operator based methods; and 3) Partial differential equation (PDE) based methods. A number of 138 tumors acquired from 30 ovarian cancer patients were used to test the performance of these eight segmentation algorithms. The results demonstrate each of the tested tumors can be successfully segmented by at least one of the eight algorithms without the manual boundary correction. Furthermore, modified region growth, classical Canny detector, and fast marching, and threshold level set algorithms are suggested in the future development of the ovarian cancer related CAD schemes. This study may provide meaningful reference for developing novel quantitative image feature analysis scheme to more accurately predict the response of ovarian cancer patients to the chemotherapy at early stage.

  3. Quality of life and treatment response among women with platinum-resistant versus platinum-sensitive ovarian cancer treated for progression: a prospective analysis.

    PubMed

    Beesley, Vanessa L; Green, Adele C; Wyld, David K; O'Rourke, Peter; Wockner, Leesa F; deFazio, Anna; Butow, Phyllis N; Price, Melanie A; Horwood, Keith R; Clavarino, Alexandra M; Australian Ovarian Cancer Study Group; Australian Ovarian Cancer Study-Quality Of Life Study Investigators; Webb, Penelope M

    2014-01-01

    Most women with ovarian cancer relapse and undergo further chemotherapy however evidence regarding the benefits of this for women with platinum-resistant disease is limited. Our objective was to determine whether there was a quality of life improvement or treatment response among women treated for platinum-resistant recurrent ovarian cancer. We combined data from 2 studies where women treated with chemotherapy for recurrent ovarian cancer (n=172) completed a quality of life questionnaire every 3 months. Cancers were classified as platinum-resistant if they progressed within 6 months of completing first-line chemotherapy. Mixed effects models were used to analyze change in quality of life during the first 6 months after second-line chemotherapy. One-quarter of women (n=44) were classified as having platinum-resistant disease. Overall, their quality of life did not significantly increase or decrease, following commencement of second-line chemotherapy (least square mean scores=107, 105, 103 at chemotherapy start, 3 and 6 months later, respectively), although 26% of these women reported a meaningful increase and 31% reported a meaningful decline. One-third of the platinum-resistant group responded (11% complete and 21% partial response) to second-line chemotherapy, and this figure increased to 54% among the subset (36%) re-treated with platinum-based agents with or without other agents. Preliminary analyses suggest that quality of life may be higher at chemotherapy initiation in women whose disease responded (median score 121 vs 110). Overall, quality of life appears to be maintained in women with platinum-resistant ovarian cancer who receive further chemotherapy and some women respond to re-treatment. © 2013.

  4. Serous ovarian carcinoma patients with high alpha-folate receptor had reducing survival and cytotoxic chemo-response.

    PubMed

    Chen, Yu-Li; Chang, Ming-Cheng; Huang, Chia-Yen; Chiang, Ying-Cheng; Lin, Han-Wei; Chen, Chi-An; Hsieh, Chang-Yao; Cheng, Wen-Fang

    2012-06-01

    The alpha-folate receptor (α-FR) is highly-expressed in various non-mucinous tumors of epithelial origin, including ovarian carcinoma. The aim of this study was to investigate the relationship between alpha-folate receptor (α-FR) and the clinico-pathologic features and outcomes of serous ovarian carcinoma patients and the possible mechanism of α-FR to chemo-resistance. Therefore, semi-quantitative reverse-transcription polymerase chain reactions for α-FR expression were performed in the 91 specimens of serous ovarian carcinomas. The expression of α-FR in each ovarian cancer tissue specimen was defined as the ratio of density of α-FR to density of glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In vitro apoptotic experiments were tested in the original OVCAR-3 tumor cells and various OVCAR-3 α-FR-transfectants. Patients with an increased α-FR expression level had poorer responses to chemotherapy (per α-FR expression level increase: odds ratio (OR): 8.97 (95% confidence interval (CI): 1.40-57.36), p = 0.021). An increased α-FR expression level was an independently poor prognostic factor for disease free interval (DFI) (per α-FR expression level increase: hazard ratio (HR): 2.45 (95% CI: 1.16-5.18), p = 0.02) and had a negative impact on overall survival (OS) of these serous ovarian cancer patients (per α-FR expression level increase: HR: 3.6 (95% CI: 0.93-13.29), p = 0.03) by multivariate analyses. α-FR inhibited cytotoxic drug-induced apoptosis in our in vitro apoptotic assays. α-FR could induce chemo-resistance via regulating the expression of apoptosis-related molecules, Bcl-2 and Bax. Therefore, α-FR can be a potential biomarker for the prediction of chemotherapeutic responses and clinical prognosis. It also could be the target of ovarian cancer treatment.

  5. Effect of Nrf2 on rat ovarian tissues against atrazine-induced anti-oxidative response

    PubMed Central

    Zhao, Fan; Li, Kun; Zhao, Lijing; Liu, Jian; Suo, Qi; Zhao, Jing; Wang, Hebin; Zhao, Shuhua

    2014-01-01

    The environmental persistence and bioaccumulation of herbicide atrazine may pose a significant threat to human health. In this experiment, Wistar rats were treated by 5, 25 and 125 mg·kg-1 atrazine respectively for 28 days, and the oxidative stress responses as well as the activations of Nrf2 signaling pathway in ovarian tissues induced by atrazine were observed. The results showed that after be treated by atrazine, the proportion of atretic follicles in the rat ovary were increased, the contents of NO and MDA in the tissue homogenates were increased, the over-expressed Nrf2 transferred into the nuclei and played an antioxidant role by up-regulated the expression of II phase detoxifying enzymes such as HO1 and NQO1 and the expression of antioxidant enzymes such as CAT, SOD and GSH-PX. PMID:25031697

  6. Adenovirus type 12 E1B 55-kilodalton oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin.

    PubMed

    Wang, Junnai; Gao, Qinglei; Li, Qiang

    2015-08-01

    The tumor suppressor p53-mediated apoptotic response plays an important role in cisplatin resistant in ovarian cancer. The adenovirus (Ad) type 12 E1B 55-kDa protein binds to p53 and inactivates its transcriptional transactivation function. In this study, we test the hypothesis that Ad12 E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin. First, we observed the upregulation protein level of p53 target genes in cisplatin-resistant or cisplatin-sensitive ovarian cancer by Western blotting. Second, after transfection of Ad12 E1b 55-kDa expression plasmid, the expressions of p53 target genes in A2780 cells were further enhanced. Co-IP experiment demonstrated Ad12 E1b 55 kDa associated with p53. MTT assay confirmed that the cell proliferation was enhanced after transfection, as well as the enhanced cell inhibitory rate in the presence of cisplatin. Using flow cytometry, transfection of Ad12 E1B 55-kDa protein induced apoptosis and promoted S-phase transition in proliferation. Finally, results showed that all these changes promoted by Ad12 E1b 55 kDa were attenuated by the exposure of specific inhibitor of p53 signaling, pifithrin-α. Taken together, we concluded that Ad E1B 55-kDa oncoprotein promotes p53-mediated apoptotic response of ovarian cancer to cisplatin.

  7. NF-κB-HOTAIR axis links DNA damage response, chemoresistance and cellular senescence in ovarian cancer

    PubMed Central

    Özeş, Ali R.; Miller, David F.; Özeş, Osman N.; Fang, Fang; Liu, Yunlong; Matei, Daniela; Huang, Tim; Nephew, Kenneth P.

    2016-01-01

    The transcription factor nuclear factor kappa B (NF-κB) and the long non-coding RNA (lncRNA) HOTAIR (HOX transcript antisense RNA) play diverse functional roles in cancer. In this study, we show that upregulation of HOTAIR induced platinum resistance in ovarian cancer, and increased HOTAIR levels were observed in recurrent platinum-resistant ovarian tumors vs. primary ovarian tumors. To investigate the role of HOTAIR during DNA damage induced by platinum, we monitored double-strand breaks and show that HOTAIR expression results in sustained activation of DNA damage response after platinum treatment. We demonstrate that ectopic expression of HOTAIR induces NF-κB activation during DNA damage response and MMP-9 and IL-6 expression, both key NF-κB target genes. We show that HOTAIR regulates activation of NF-κB by decreasing Iκ-Bα (NF-κB inhibitor) and establish that by inducing prolonged NF-κB activation and expression of NF-κB target genes during DNA damage, HOTAIR plays a critical role in cellular senescence and platinum sensitivity. Our findings suggest that a NF-κB-HOTAIR axis drives a positive-feedback loop cascade during DNA damage response and contributes to cellular senescence and chemotherapy resistance in ovarian and other cancers. PMID:27041570

  8. Plasma prorenin response to human chorionic gonadotropin in ovarian-hyperstimulated women: correlation with the number of ovarian follicles and steroid hormone concentrations.

    PubMed Central

    Itskovitz, J; Sealey, J E; Glorioso, N; Rosenwaks, Z

    1987-01-01

    Plasma prorenin and active renin were measured before and after human chorionic gonadotropin (hCG) administration in two groups of patients undergoing ovarian stimulation for 4-6 days with follicle-stimulating hormone alone or in combination with luteinizing hormone, for in vitro fertilization. Baseline total plasma renin (prorenin plus active renin; n = 12) averaged 25 +/- 8 ng/ml per hr (mean +/- SD). Total renin did not change during ovarian stimulation but it increased to 46 +/- 16 ng/ml per hr (P less than 0.05) 1 or 2 days later, just before hCG administration. Thirty-six hours after hCG administration, just before laparoscopy and egg retrieval, total renin was 123 +/- 97 ng/ml per hr; a peak of 182 +/- 143 ng/ml per hr occurred 2-6 days later--i.e., during the luteal phase of the menstrual cycle. In eight of the patients who did not conceive, total renin returned to baseline 14 days after hCG administration. In four who conceived, a nadir was reached (57 +/- 13 ng/ml per hr) 8-12 days after hCG administration and then total renin increased again as the plasma beta hCG measurement began to rise. By day 16 it averaged 225 +/- 157 ng/ml per hr. In a second group of five patients active renin and prorenin were measured separately. Active renin comprised less than 20% of the total renin at all times. It was unchanged until day 4 after hCG administration and then increased significantly only when plasma progesterone was high. Thus, the initial response to hCG was entirely due to an increase in prorenin. A highly significant correlation was observed between the number of follicles and the total renin increases on the day of aspiration (r = 0.93, P less than 0.001) and at the peak (r = 0.89, P less than 0.001). After hCG administration, a temporal relationship was observed between the rise in total renin and plasma estradiol and progesterone levels. These results demonstrate that plasma prorenin increases markedly after administration of hCG and that the rise is

  9. Pre-treatment prediction of chemoresistance in second-line chemotherapy of ovarian carcinoma: value of serological tumor marker determination (tetranectin, YKL-40, CASA, CA 125).

    PubMed

    Gronlund, B; Høgdall, E V S; Christensen, I J; Johansen, J S; Nørgaard-Pedersen, B; Engelholm, S A; Høgdall, C

    2006-01-01

    To examine if the determination of the levels of serological tumor markers at time of relapse had any predictive value for chemoresistance in the second-line treatment of ovarian cancer patients. From a registry of consecutive single-institution patients with epithelial ovarian carcinoma pretreated with paclitaxel plus platinum, we selected 82 patients with (a) solid tumor recurrence, and (b) second-line chemotherapy consisting of topotecan (platinum-resistant disease) or paclitaxel plus carboplatin (platinum-sensitive disease). Stored serum samples were analyzed for the biochemical tumor markers tetranectin, YKL-40, CASA (cancer-associated serum antigen), and CA 125. The serum tumor marker levels at time of relapse were correlated with response status at landmark time after 4 cycles of second-line chemotherapy. Univariate and multivariate logistic regression analyses (chemoresistant vs non-chemoresistant disease) were performed. At landmark time, 26% of patients had progression according to the GCIG (Gynecologic Cancer Intergroup) progression criteria. In univariate logistic regression analysis, the tumor markers tetranectin (OR 0.4; 95% CI: 0.2-0.8; p=0.008), YKL-40 (OR 1.8; 95% CI: 1.0-3.3; p=0.045), and CASA (OR 1.8; 95% CI: 1.2-2.7; p=0.007) had predictive value for second-line chemoresistance, whereas serum CA 125 had no predictive value. In a multivariate logistic regression analysis, serum tetranectin and CASA both had independent predictive value for chemoresistance. The combined determination of tetranectin and CASA had a specificity of 90% with 33% sensitivity for the prediction of chemoresistance (area under the receiver operating characteristic curve = 0.78; 95% CI: 0.66-0.91; p=0.001). Low serum levels of tetranectin, or high serum levels of CASA or YKL-40, are associated with increased risk of second-line chemoresistance in patients with ovarian cancer.

  10. Biochemical composition of malignant ascites determines high aggressiveness of undifferentiated ovarian tumors.

    PubMed

    Mikuła-Pietrasik, Justyna; Uruski, Paweł; Szubert, Sebastian; Moszyński, Rafał; Szpurek, Dariusz; Sajdak, Stefan; Tykarski, Andrzej; Książek, Krzysztof

    2016-08-01

    Although undifferentiated tumors are the most lethal among all ovarian cancer histotypes, the exact reasons for this situation are unclear. This report was aimed at investigating whether the high aggressiveness of undifferentiated ovarian cancer may be associated with a biochemical composition of malignant ascites accumulating in the peritoneal cavity. We analyzed ascites from patients with undifferentiated, high-grade serous, endometrioid and clear-cell ovarian cancers, and from non-cancerous patients with respect to a group of soluble agents involved in cancer cell progression. Moreover, the effect of these fluids on proliferation and migration of ovarian cancer cells (A2780, OVCAR-3 and SKOV-3) was evaluated. The study showed that the level of all tested proteins in malignant ascites was higher than in the benign fluids. Concentration of 9/11 agents (CCL2, CXCL1, CXCL5, CXCL8, CXCL12, HGF, PAI-1, TGF-β1 and VEGF) was the greatest in the fluids from undifferentiated cancer, while the level of remaining 2 (IL-6 and uPA) was the highest in ascites from serous carcinoma. Proliferation of cancer cells was the most effective when they were subjected to ascites from patients with undifferentiated and serous cancer, whereas the migration was the highest in the case of undifferentiated tumors. Our findings indicate that the aggressiveness of undifferentiated ovarian tumors may be associated with the composition of malignant ascites, in particular the concentration of specific proinflammatory, cancer-promoting agents.

  11. Short-form Ron is a novel determinant of ovarian cancer initiation and progression

    PubMed Central

    Moxley, Katherine M.; Wang, Luyao; Welm, Alana L.; Bieniasz, Magdalena

    2016-01-01

    Short-form Ron (sfRon) is an understudied, alternative isoform of the full-length Ron receptor tyrosine kinase. In contrast to Ron, which has been shown to be an important player in many cancers, little is known about the role of sfRon in cancer pathogenesis. Here we report the striking discovery that sfRon expression is required for development of carcinogen-induced malignant ovarian tumors in mice. We also show that sfRon is expressed in several subtypes of human ovarian cancer including high-grade serous carcinomas, which is in contrast to no detectable expression in healthy ovaries. In addition, we report that introduction of sfRon into OVCAR3 cells resulted in epithelial-to-mesenchymal transition, activation of the PI3K and PDK1 pathway, and inhibition of the MAPK pathway. We demonstrated that sfRon confers an aggressive cancer phenotype in vitro characterized by increased proliferation and migration, and decreased adhesion of ovarian cancer cells. Moreover, the in vivo studies show that OVCAR3 tumors expressing sfRon exhibit significantly more robust growth and spreading to the abdominal cavity when compared with the parental sfRon negative OVCAR3 cells. These data suggest that sfRon plays a significant role in ovarian cancer initiation and progression, and may represent a promising therapeutic target for ovarian cancer treatment. PMID:27551332

  12. Significance of HE4 estimation in comparison with CA125 in diagnosis of ovarian cancer and assessment of treatment response

    PubMed Central

    2013-01-01

    Background Human epididymis protein 4 (HE4) is a novel and specific biomarker for ovarian cancer. The aim of this study is to evaluate a new tumor marker, HE4, in comparison with CA125 in diagnosis of epithelial ovarian cancer (EOC) and benign gynecological diseases. Methods CA125 and HE4 serum levels were determined in 30 patients with epithelial ovarian cancer (21 serous, 6 endometrioid and 3 mucinous tumors), 20 patients with benign gynecological diseases (8 patients with ovarian cyst, 5 patients with endometriosis, 4 patients with fibroid and 3 patients with pelvic inflammatory disease) and 20 healthy women. CA125 and HE4 cut-offs were 35 U/ml and 150 pmol/l, respectively. Results Serum HE4 and CA125 concentrations were significantly higher in the ovarian cancer patients compared with those seen in patients with benign disease or in the healthy controls (p = 0.001 and p < 0.001 respectively). In the receiver operating characteristic analysis (ROC), the area under the curve (AUC) values for HE4 was 0.96 (95% confidence interval, 0.9-1.0) and CA125 was 0.82 (95% confidence interval, 0.7-0.94). Compared to CA125, HE4 had higher sensitivity (90% vs. 83.3%), specificity (95% vs. 85%), PPV (93.1% vs. 80.7%) and NPV (92.7% vs. 87.2%), the combination of HE4 + CA125 the sensitivity and PPV reached 96.7% and 97% respectively. Conclusion Measuring serum HE4 concentrations along with CA125 concentrations may provide higher accuracy for detecting epithelial ovarian cancer. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1060413168685759 PMID:23343214

  13. Does poor ovarian response to gonadotrophins predict early menopause? A retrospective cohort study with minimum of 10-year follow-up.

    PubMed

    Szmidt, Natasha A K; Bhattacharya, Siladitya; Maheshwari, Abha

    2016-09-01

    One in 10 women reach menopause before they are 45 years of age, and 1 in 100 before 40. In most cases, poor ovarian response to gonadotrophins is a result of poor ovarian reserve. An early menopause is associated with long-term health risks. Identifying women at risk may allow appropriate measures to be instigated early. Women aged <40 years treated in the Aberdeen Fertility Centre between 1998 and 2002 were identified. Those with poor response to an age appropriate dose of gonadotrophins (obtaining ≤3 eggs or had cycle cancelled) after exclusion of hypothalamic insufficiency, or whose cycle was cancelled due to poor response were age matched with good responders (6-15 eggs). In this retrospective cohort study, women who have had IVF at least 10 years ago (157 poor responders and 314 good responders) were sent a postal questionnaire to determine age at menopause. A total of 219 women (64 poor responders, 155 good responders) returned their questionnaires. Poor responders were more likely to have premature menopause (3% vs. 0%; p = .024). A higher proportion of poor responders experienced early menopause (11% vs. 3%; p = .044). Despite being the first study with a 10-year follow-up, this study is limited to one centre and has a small number of women reaching premature menopause. Poor response to gonadotrophins in the context of IVF treatment is a marker of reduced ovarian reserve and is associated with early menopause. Results of this study underline the need for larger studies with long-term follow-up.

  14. Ovarian Hyper-Response to Administration of an GnRH-Agonist Without Gonadotropins

    PubMed Central

    Park, Hyun Tae; Bae, Hyo Sook; Kim, Tak

    2011-01-01

    Several case reports have indicated that a small subgroup of patients may develop ovarian hyperstimulation following the administration of gonadotropin-releasing hormone agonists (GnRHa) without gonadotropins. However, since only few such cases have been published, it is unclear what course to follow in subsequent cycles after ovarian hyperstimulation in the first cycle using only GnRHa. A 33-yr-old woman was referred to in vitro fertilization for oocyte donation. A depot preparation (3.75 mg) of tryptorelin without gonadotropins induced ovarian multifollicular enlargement with high estradiol level, and was followed by human chorionic gonadotropin administration and oocyte retrieval. In a subsequent cycle of the same patient, a low dose of tryptorelin (0.05 mg) did not induce ovarian hyperstimulation, and resulted in clinical pregnancy. This report shows potential management of ovarian hyperstimulation following the administration of GnRHa without gonadotropins. PMID:22022197

  15. Red and processed meat consumption and risk of ovarian cancer: a dose-response meta-analysis of prospective studies

    PubMed Central

    Wallin, A; Orsini, N; Wolk, A

    2011-01-01

    Background: During the last decade, the epidemiological evidence on consumption of meat and risk of ovarian cancer has accumulated. Methods: We assessed the relationship between red and processed meat consumption and risk of ovarian cancer with a dose-response meta-analysis. Relevant prospective cohort studies were identified by searching the PubMed and EMBASE databases through 21 January 2011, and by reviewing the reference lists of retrieved articles. Study-specific relative risk (RR) estimates were combined using a random-effects model. Results: Eight cohort studies were included in the meta-analysis. The summary RR for an intake increment of 100 g per week was 1.02 (95% confidence interval (CI), 0.99–1.04) for red meat and 1.05 (95% CI, 0.98–1.14) for processed meat. For an intake increment of four servings per week, the summary RR of ovarian cancer was 1.07 (95% CI, 0.97–1.19) for red meat (100 g per serving) and 1.07 (95% CI, 0.97–1.17) for processed meat (30 g per serving). Conclusion: Results from this dose-response meta-analysis suggest that red and processed meat consumption is not associated with risk of ovarian cancer. Although a lower consumption of red and processed meat may offer protection against other types of cancer, other interventions are needed to reduce the risk of ovarian cancer. PMID:21343939

  16. Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

    SciTech Connect

    Ganesan, Shanthi Keating, Aileen F.

    2015-02-01

    Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. - Highlights: • PM forms ovarian DNA adducts. • DNA damage marker γH2AX increased by PM exposure. • PM induces ovarian DNA double strand break repair.

  17. Ovarian response to repeated administration of alternating exogenous gonadotropin regimens in the ocelot (Leopardus pardalis) and tigrinus (Leopardus tigrinus).

    PubMed

    da Paz, Regina Celia Rodrigues; Dias, Eduardo Antunes; Adania, Cristina Harumi; Barnabe, Valquíria Hippólito; Barnabe, Renato Campanarut

    2006-10-01

    Exogenous gonadotropins are used to stimulate ovarian follicular growth and ovulation in mammalian species, including wild cats. However, successes in application of assisted reproduction techniques in nondomestic felids have been sparse. Our objectives were to assess the effectiveness of alternating gonadotropin regimens on ovarian responses. Five adult female ocelots and four adult female tigrinus were treated four to six times, using alternating eCG/hCG and pFSH/pLH at 4-month intervals. Laparoscopies were done to assess follicular development and to collect oocytes from matures follicles. The average number of follicles and corpus luteum (CL) per stimulation was higher in ocelots (7.0 +/- 0.8; mean +/- S.E.M.) than in tigrinus (2.5 +/- 0.4; P < 0.05), but the percentage of mature oocytes did not differ between the two species (mean range, 54-55%). Within species, both gonadotropin regimens were equally effective in inducing follicular growth and oocyte maturation. The total number of ovarian structures and oocyte maturation percentages did not decrease in either species with sequential stimulations. In summary, female ocelots and tigrinus continued to respond to repeated alternating ovarian stimulation protocols. In conclusion, the use of alternating gonadotropin regimens may permit more intensive reproductive management in these endangered cats.

  18. The effect of GnRH analogues for pituitary suppression on ovarian response in repeated ovarian stimulation cycles

    PubMed Central

    Cavagna, Mario; Paes de Almeida Ferreira Braga, Daniela; Biaggioni Lopes, Fabio; de Cássia Savio Figueira, Rita; Iaconelli, Assumpto; Borges, Edson

    2011-01-01

    Introduction Ovarian stimulation is employed in assisted reproduction techniques in order to obtain as many oocytes as possible. The early rise in oestradiol levels may lead to the premature end of the respective cycle. In order to avoid such an effect, pituitary suppression has been employed. The aim of this study was to evaluate whether maintenance or replacement of the type of GnRH analogue (i.e., agonist or antagonist) employed for pituitary suppression in the consecutive intracytoplasmic sperm injection (ICSI) cycle would negatively influence oocyte quality and ICSI outcome. Material and methods A retrospective observational study was conducted including 181 women with primary infertility. Patients were divided into four different groups according to the GnRH analogue used for pituitary suppression in the first and consecutive cycle. Results When a GnRH agonist was employed for pituitary suppression in the first cycle, the consecutive cycle showed comparable outcomes when performed with either a GnRH agonist or a GnRH antagonist. When the first cycle was performed with a GnRH antagonist, the use of the GnRH agonist in the successive cycle led to an increased number of oocytes retrieved (7.5% vs. 10.3%, p = 0.032) and the production of a higher number of embryos (4.5% vs. 6.3%, p = 0.036). Conclusions When the first cycle is carried out with a GnRH antagonist, the use of a GnRH agonist in the successive cycle would lead to increased numbers of oocytes collected and embryos produced. PMID:22295031

  19. Intravital fiber-optic fluorescence imaging for monitoring ovarian carcinoma progression and treatment response

    NASA Astrophysics Data System (ADS)

    Spring, Bryan Q.; Celli, Jonathan P.; Evans, Conor L.; Zhong, Wei; Rizvi, Imran; Mai, Zhiming; Mertz, Jerome; Yun, Seok H.; Hasan, Tayyaba

    2009-06-01

    Our laboratory has constructed a custom fluorescence microendoscope for detecting and monitoring tumor nodules in a mouse model of metastatic ovarian carcinoma (OVCA). The microendoscope is being applied for tumor recognition and for quantifying tumor burden reduction following photodynamic therapy (PDT). Benzoporphyrin derivative monoacid ring A (BPD-MA), a photosensitizing agent for PDT, is administered to the mice and imaged with the microendoscope prior to PDT. BPD-MA fluorescence is a convenient means for locating tumor sites and quantifying tumor burden (despite the fact that BPD-MA is a non-targeted contrast agent). The miniature, flexible microendoscope probe is delivered via a 14-gauge catheter for imaging metastases along the outer surfaces of the internal organs and the inner walls of the peritoneal cavity. The minimal invasiveness of this approach facilitates frequent imaging of the mice in order to monitor cancer progression and treatment response. We present promising data for intravital imaging of treatment response following PDT and new developments in the microendoscope instrumentation for improved image quality.

  20. A proteomic kinetic analysis of IGROV1 ovarian carcinoma cell line response to cisplatin treatment.

    PubMed

    Le Moguen, Karen; Lincet, Hubert; Marcelo, Paulo; Lemoisson, Edwige; Heutte, Natacha; Duval, Marilyne; Poulain, Laurent; Vinh, Joëlle; Gauduchon, Pascal; Baudin, Bruno

    2007-11-01

    Ovarian cancer is one of the leading causes of mortality by gynecological cancer. Despite good response to surgery and initial chemotherapy, essentially based on cisplatin (cis-diamino-dichloro-platinum(II) (CDDP)) compounds, frequent recurrences with chemoresistance acquisition are responsible for poor prognosis. Several mechanisms have been described as implicated in CDDP resistance, however they are not sufficient to exhaustively account for this resistance emergence. We applied a proteomic approach based on 2-DE coupled with MS (MALDI-TOF/TOF) to identify proteins associated with chemoresistance induced by CDDP. A kinetic analysis of IGROV1 cell behavior following treatment with CDDP and subsequent statistical analysis revealed time and/or concentration-dependent modifications in protein expression. We evidenced events such as decreased amino-acid and nucleotide synthesis potentially associated with cell cycle blockade, and variations that may be related to resistance acquisition, such as possible enhanced glycolysis and increased proliferating potential. Moreover, overexpressions of aldehyde dehydrogenase 1 and both cytokeratins 8 and 18 were consistent with our previous findings, demonstrating that expression of these proteins was increased in cisplatin-resistant IGROV1-R10 as compared to IGROV1 parental cells. Identification of such proteins could allow improved understanding of the mechanisms leading to cell death or survival and, thus, to the acquisition of chemoresistance.

  1. Anti-ovarian tumor response of donor peripheral blood mononuclear cells is due to infiltrating cytotoxic NK cells.

    PubMed

    Pandey, Veethika; Oyer, Jeremiah L; Igarashi, Robert Y; Gitto, Sarah B; Copik, Alicja J; Altomare, Deborah A

    2016-02-09

    Treatment of ovarian cancer, a leading cause of gynecological malignancy, has good initial efficacy with surgery and platinum/taxane-based chemotherapy, but poor long-term survival in patients. Inferior long-term prognosis is attributed to intraperitoneal spreading, relapse and ineffective alternate therapies. Adoptive cell therapy is promising for tumor remission, although logistical concerns impede widespread implementation. In this study, healthy PBMCs were used to examine the immune response in a mouse model with human ovarian cancer, where natural killer (NK) cells were found to be the effector cells that elicited an anti-tumor response. Presence of tumor was found to stimulate NK cell expansion in mice treated intraperitoneally with PBMC+Interleukin-2 (IL-2), as compared to no expansion in non-tumor-bearing mice given the same treatment. PBMC+IL-2 treated mice exhibiting NK cell expansion had complete tumor remission. To validate NK cell mediated anti-tumor response, the intratumoral presence of NK cells and their cytotoxicity was confirmed by immunohistochemistry and granzyme activity of NK cells recovered from the tumor. Collectively, this study highlights the significance of NK cell-cytotoxic response to tumor, which may be attributed to interacting immune cell types in the PBMC population, as opposed to clinically used isolated NK cells showing lack of anti-tumor efficacy in ovarian cancer patients.

  2. Impaired ovarian response to exogenous gonadotropins in female rat offspring born to mothers perinatally exposed to Bisphenol A.

    PubMed

    Santamaría, C G; Rodriguez, H A; Abud, J E; Rivera, O E; Muñoz-de-Toro, M; Luque, E H

    2017-06-23

    The ovary is sensitive to disruption by the environmental estrogen Bisphenol A (BPA). Our aim was to investigate whether perinatal exposure to BPA (50μg/kgday), orally administered, affects ovarian response to exogenous gonadotrophins (PMSG or PMSG+hCG) in prepubertal female offspring. An altered response to gonadotrophins was observed in BPA-exposed rats. Increased proportion of antral follicles, altered levels of ovarian steroidogenic enzymes, gonadotropin receptors, AR and ERβ were observed in PMSG group. Besides that, in response to PMSG+hCG, a persistent high Fshr mRNA expression and a decreased number of follicles with high expression of PR before ovulation were observed. After ovulation, there was an increase in antral atretic follicles, reduced Lhcgr mRNA expression and high serum levels of E2. Therefore, an early exposure to a low dose of BPA during perinatal period induces ovarian changes leading to an altered response to exogenous gonadotropin treatment later in life. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Anti-ovarian tumor response of donor peripheral blood mononuclear cells is due to infiltrating cytotoxic NK cells

    PubMed Central

    Pandey, Veethika; Oyer, Jeremiah L.; Igarashi, Robert Y.; Gitto, Sarah B.; Copik, Alicja J.; Altomare, Deborah A.

    2016-01-01

    Treatment of ovarian cancer, a leading cause of gynecological malignancy, has good initial efficacy with surgery and platinum/taxane-based chemotherapy, but poor long-term survival in patients. Inferior long-term prognosis is attributed to intraperitoneal spreading, relapse and ineffective alternate therapies. Adoptive cell therapy is promising for tumor remission, although logistical concerns impede widespread implementation. In this study, healthy PBMCs were used to examine the immune response in a mouse model with human ovarian cancer, where natural killer (NK) cells were found to be the effector cells that elicited an anti-tumor response. Presence of tumor was found to stimulate NK cell expansion in mice treated intraperitoneally with PBMC+Interleukin-2 (IL-2), as compared to no expansion in non-tumor-bearing mice given the same treatment. PBMC+IL-2 treated mice exhibiting NK cell expansion had complete tumor remission. To validate NK cell mediated anti-tumor response, the intratumoral presence of NK cells and their cytotoxicity was confirmed by immunohistochemistry and granzyme activity of NK cells recovered from the tumor. Collectively, this study highlights the significance of NK cell-cytotoxic response to tumor, which may be attributed to interacting immune cell types in the PBMC population, as opposed to clinically used isolated NK cells showing lack of anti-tumor efficacy in ovarian cancer patients. PMID:26802025

  4. The role of HDAC2 in chromatin remodelling and response to chemotherapy in ovarian cancer

    PubMed Central

    Huang, Rui; Langdon, Simon P; Tse, Matthew; Mullen, Peter; Um, In Hwa; Faratian, Dana; Harrison, David J

    2016-01-01

    Chromatin undergoes structural changes in response to extracellular and environmental signals. We observed changes in nuclear morphology in cancer tissue biopsied after chemotherapy and hypothesised that these DNA damage-induced changes are mediated by histone deacetylases (HDACs). Nuclear morphological changes in cell lines (PE01 and PE04 models) and a xenograft model (OV1002) were measured in response to platinum chemotherapy by image analysis of nuclear texture. HDAC2 expression increased in PEO1 cells treated with cisplatin at 24h, which was accompanied by increased expression of heterochromatin protein 1 (HP1). HDAC2 and HP1 expression were also increased after carboplatin treatment in the OV1002 carboplatin-sensitive xenograft model but not in the insensitive HOX424 model. Expression of DNA damage response pathways (pBRCA1, γH2AX, pATM, pATR) showed time-dependent changes after cisplatin treatment. HDAC2 knockdown by siRNA reduced HP1 expression, induced DNA double strand breaks (DSB) measured by γH2AX, and interfered with the activation of DNA damage response induced by cisplatin. Furthermore, HDAC2 depletion affected γH2AX foci formation, cell cycle distribution, and apoptosis triggered by cisplatin, and was additive to the inhibitory effect of cisplatin in cell lines. By inhibiting expression of HDAC2, reversible alterations in chromatin patterns during cisplatin treatment were observed. These results demonstrate quantifiable alterations in nuclear morphology after chemotherapy, and implicate HDAC2 in higher order chromatin changes and cellular DNA damage responses in ovarian cancer cells in vitro and in vivo. PMID:26683361

  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. 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

  7. Aberrant DNA damage response pathways may predict the outcome of platinum chemotherapy in ovarian cancer.

    PubMed

    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

  8. Ovarian response and embryo yield of Angora and Kilis goats given the day 0 protocol for superovulation in the non-breeding season.

    PubMed

    Taşdemir, Umut; Ağaoğlu, Ali Reha; Kaymaz, Mustafa; Karakaş, Kübra

    2011-06-01

    The aim of this study was to compare ovarian response and embryo yield of Day 0 protocol in Angora goats (AG) and indigenous Kilis goats (KG) in the non-breeding season. A total of 16 Angora goats (AG group) and 11 Kilis goats (KG group) were used in this study. In the synchronization process, after controlled internal drug release withdrawal, when estrus signs were observed, natural mating was performed. Ovarian response was determined by synchronized laparotomy 6 days after natural mating, and number of corpora lutea (CL) was recorded. Embryos were collected and morphologically evaluated by stereomicroscope. Synchronization rates did not differ between AG (88%, 14/16) and KG group (91%, 10/11). In AG and KG groups, the proportion of CL on the right (44% and 53%, respectively) and left (56% and 47%, respectively) ovaries were similar. The CL number per animal did not differ significantly between the two breeds and was determined as 4.4 ± 0.90 in AG group and 6.4 ± 1.44 in KG group. Transferable embryo yields were significantly higher in AG group (31/42, 74%) compared to KG group (16/46, 35%) in the non-breeding season (P < 0.01). In conclusion, it is suggested that the day 0 protocol can be used for goat superovulation in the non-breeding season; however, transferable embryo yields are affected by the breed.

  9. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas.

    PubMed

    Pennington, Kathryn P; Walsh, Tom; Harrell, Maria I; Lee, Ming K; Pennil, Christopher C; Rendi, Mara H; Thornton, Anne; Norquist, Barbara M; Casadei, Silvia; Nord, Alexander S; Agnew, Kathy J; Pritchard, Colin C; Scroggins, Sheena; Garcia, Rochelle L; King, Mary-Claire; Swisher, Elizabeth M

    2014-02-01

    Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain. Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway. Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation. Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials. ©2013 AACR.

  10. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase.

    PubMed

    Grabowski, Jacek P; Harter, Philipp; Heitz, Florian; Pujade-Lauraine, Eric; Reuss, Alexander; Kristensen, Gunnar; Ray-Coquard, Isabelle; Heitz, Julia; Traut, Alexander; Pfisterer, Jacobus; du Bois, Andreas

    2016-03-01

    Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIBIV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor >1cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p<0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p<0.001). Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Abnormalities of the RB1 pathway in ovarian serous papillary carcinoma as determined by overexpression of the p16(INK4A) protein.

    PubMed

    Armes, Jane E; Lourie, Rohan; de Silva, Melanie; Stamaratis, Georgia; Boyd, Alison; Kumar, Beena; Price, Gareth; Hyde, Simon; Allen, David; Grant, Peter; Venter, Deon J

    2005-10-01

    Dysfunction of proteins involved in the G1 to S transition of the cell cycle, such as p16(INK4A) and RB1, is common in many cancer types. A screen of p16 protein expression was performed in benign, borderline, and invasive ovarian tumors, together with endometrial cancers, aligned on a tissue microarray. We observed frequent p16 overexpression in serous papillary carcinomas of ovarian and endometrial origin. An extended cohort of ovarian serous papillary carcinomas was examined to further evaluate the frequency of p16 overexpression. Strong, uniform staining in the majority of cancer cells occurred commonly in invasive serous papillary ovarian cancers, particularly in grade 3 carcinomas. RB1 protein expression abnormalities were rare. Our data indicate that abnormalities in the retinoblastoma pathway, as determined by p16 overexpression, are common in serous papillary carcinomas and are probably an early event.

  12. Inovium Ovarian Rejuvenation Trials

    ClinicalTrials.gov

    2017-10-03

    Perimenopausal Disorder; Menopause; Menopause, Premature; Menopause Related Conditions; Menopause Premature Symptomatic; Menopause Premature Asymptomatic; Premature Ovarian Failure; Premature Ovarian Failure, Familial; Premature Ovarian Failure 2A; Premature Ovarian Failure 3; Premature Ovarian Failure 4; Premature Ovarian Failure 1; Premature Ovarian Failure 5; Premature Ovarian Failure 6; Premature Ovarian Failure 7; Premature Ovarian Failure 9; Premature Ovarian Failure 8; Infertility; Infertility, Female; Infertility Unexplained

  13. Younger poor ovarian response women achieved better pregnancy results in the first three IVF cycles.

    PubMed

    Yang, Yajuan; Sun, Xiuhua; Cui, Linlin; Sheng, Yan; Tang, Rong; Wei, Daimin; Qin, Yingying; Li, Weiping; Chen, Zi-Jiang

    2016-05-01

    This retrospective cohort study observed the live birth rates as well as cumulative live birth rates in women with poor ovarian response (POR) undergoing IVF-embryo transfer treatment, stratified for age and cycle number. Four hundred and one patients with POR diagnosed according to the Bologna criteria were enrolled and 700 IVF-ET cycles were analysed. The overall live-birth rate per cycle was 18.3%. From cycle 1 up to cycle 3, the live-birth rates decreased significantly from 22.2% to 11.1%. The live-birth rate fell to 2.4% in cycles 4 and over. When age advanced, the live birth rates decreased obviously (P < 0.01): 30.0% for women < 35 years old, 17.0% for those 35-40 years old, and 9.0% for women older than 40 years. Similarly, the cumulative live birth rates dropped from 48.0% (< 35 years) to 16.9% (≥ 40 years) accordingly. Younger patients (< 35 years old) with POR achieved better pregnancy results compared with patients of advanced age. Extremely low live-birth rates could be anticipated after three unsuccessful cycles; therefore it may not be appropriate to suggest more IVF cycles in POR women.

  14. Cellular and biomolecular responses of human ovarian cancer cells to cytostatic dinuclear platinum(II) complexes.

    PubMed

    Lin, Miaoxin; Wang, Xiaoyong; Zhu, Jianhui; Fan, Damin; Zhang, Yangmiao; Zhang, Junfeng; Guo, Zijian

    2011-03-01

    Polynuclear platinum(II) complexes represent a class of potential anticancer agents that have shown promising pharmacological properties in preclinical studies. The nature of cellular responses induced by these complexes, however, is poorly understood. In this research, the cellular responses of human ovarian cancer COC1 cells to dinuclear platinum(II) complexes {[cis-Pt(NH₃)₂Cl]₂L¹}(NO₃)₂ (1) and {[cis-Pt(NH₃)₂Cl]₂L²}(NO₃)₂ (2) (L¹ = α,α'-diamino-p-xylene, L² = 4,4'-methylenedianiline) has been studied using cisplatin as a reference. The effect of platinum complexes on the proliferation, death mode, mitochondrial membrane potential, and cell cycle progression has been examined by MTT assay and flow cytometry. The activation of cell cycle checkpoint kinases (CHK1/2), extracellular signal-regulated kinases (ERK1/2), and p38 mitogen-activated protein kinase (p38 MAPK) of the cells by the complexes has also been analyzed using phospho-specific flow cytometry. Complex 1 is more cytotoxic than complex 2 and cisplatin at most concentrations; complex 2 and cisplatin are comparably cytotoxic. These complexes kill the cells through an apoptotic or apoptosis-like pathway characterized by exposure of phosphatidylserine and dissipation of mitochondrial membrane potential. Complex 1 shows the strongest inductive effect on the morphological changes of the cells, followed by cisplatin and complex 2. Complexes 1 and 2 arrest the cell cycle in G2 or M phase, while cisplatin arrests the cell cycle in S phase. The influence of these complexes on CHK1/2, ERK1/2, and p38 MAPK varies with the dose of the drugs or reaction time. Activation of phospho-ERK1/2 and phospho-p38 MAPK by these complexes is closely related to the cytostatic activity. The results demonstrate that dinuclear platinum(II) complexes can induce some cellular responses different from those caused by cisplatin.

  15. Mink aging is associated with a reduction in ovarian hormone release and the response to FSH and ghrelin.

    PubMed

    Sirotkin, Alexander V; Mertin, Dušan; Süvegová, Karina; Lauričik, Jozef; Morovič, Martin; Harrath, Abdel Halim; Kotwica, Jan

    2016-09-15

    The endocrine mechanisms of mink ovarian hormones release and reproductive aging are poorly investigated. The aims of our study were to: (1) identify hormones produced by mink ovaries (the steroids progesterone [P] and estradiol [E], the peptide hormone oxytocin [OT], and the prostaglandin F [PGF] and prostaglandin E [PGE]); (2) examine the effect of FSH and ghrelin on the release of the hormones listed previously; and (3) understand whether these hormones can be involved in the control of mink reproductive aging, i.e., whether aging can be associated with changes (a) in the basal release of P, E, OT, PGF, or PGE and (b) their response to FSH and ghrelin. Fragments of ovaries of young (yearlings) and old (3-5 years of age) minks were cultured with and without FSH and ghrelin (0, 1, 10, or 100 ng/mL), and the release of hormones was analyzed by EIA/RIA. We found that isolated ovaries were able to release P, E, OT, PGF, and PGE, and the levels of P produced in the ovaries of old animals were lower than those produced in the ovaries of young animals, whereas the levels of other hormones did not differ. FSH was able to stimulate P and E and suppress OT and PGF and did not affect PGE release. Aging was associated with the inhibition of the effect of FSH on ovarian P and E, the appearance of the inhibitory action of FSH on OT, and the disappearance of this action on ovarian PGF. PGE was not affected by FSH, irrespective of animal age. Ghrelin was able to promote E (but not P) and suppress OT, PGF, and PGE output. Aging was associated with the appearance of an inhibitory influence of ghrelin on ovarian OT and PGE and with the disappearance of this influence on PGF output. Aging did not affect the action of ghrelin on ovarian P and E. Our observations (1) confirm the production of P and E and show that OT, PGF, and PGE are released from mink ovaries, (2) confirm the involvement of FSH and demonstrate the involvement of ghrelin in the control of mink ovarian hormone

  16. 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.

  17. Ovarian responses and pregnancy rate with previously used intravaginal progesterone releasing devices for fixed-time artificial insemination in sheep.

    PubMed

    Vilariño, M; Rubianes, E; Menchaca, A

    2013-01-01

    The objective was to determine serum progesterone concentrations, ovarian responses, and pregnancy rate in sheep inseminated following a short-term protocol (6 days of treatment) with a previously used controlled internal drug release-G (CIDR-G) device. In experiment 1, 30 ewes were put on a short-term protocol using a CIDR-G of first use (new devices, N = 10), second use (previously used for 6 days, N = 10), or third use (previously used twice for 6 days, N = 10). All ewes were given prostaglandin F(2α) (10 mg dinoprost) and eCG (300 IU) im at device withdrawal. Mean serum progesterone concentrations were greater for ewes treated with new versus reused devices (P < 0.05), but there were no significant effects on ovarian follicular development, namely: proportion of ewes that reached ovulation/treated ewes (8/10, 9/10, and 10/10); day of emergence of the ovulatory follicle (2.9 ± 1.8, 1.8 ± 2.4, and 2.5 ± 1.1 days after CIDR-G insertion); and lifespan of the ovulatory follicle (5.4 ± 1.8, 6.5 ± 2.2, and 5.6 ± 1.0 days) for devices of first, second, and third use, respectively. The proportion of ewes that ovulated from a new follicle emerging after CIDR-G insertion was 100% (10/10) with new devices, and 77.8% (7/9) and 80% (8/10) with devices used two and three times, respectively (P = not significant). In experiment 2, ewes (N = 319) received the short-term protocol as in experiment 1, using CIDR-G of first or third use (N = 158 and N = 161, respectively) for 6 days, with prostaglandin F(2α) and eCG given im at device withdrawal. Intrauterine (laparoscopy) fixed-time AI with fresh semen (100 × 10(6) sperm) was done 52 to 57 hours after device withdrawal. Pregnancy rates were 80.4% (127/158) and 71.4% (115/161) for devices of first and third use, respectively (P = 0.06). We concluded that the CIDR-G with short-term protocol was effective for estrous synchronization and ovulation, with lower serum progesterone concentrations for reused devices. Three times

  18. Plasma endothelial protein C receptor influences innate immune response in ovarian cancer by decreasing the population of natural killer and TH17 helper cells

    PubMed Central

    AZZAZENE, DALEL; THAWADI, HAMDA AL; FARSI, HALEMA AL; BESBES, SAMAHER; GEYL, CAROLINE; MIRSHAHI, SHAHSOLTAN; PARDO, JULIA; FAUSSAT, ANNE MARIE; JEANNETTE, SORIA; THERWATH, AMU; PUJADE-LAURAINE, ERIC; MIRSHAHI, MASSOUD

    In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman’s rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100±28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by

  19. Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells

    PubMed Central

    Ganesan, Shanthi; Keating, Aileen F.

    2015-01-01

    Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6 μM) for 24 or 48 h. Cell viability was reduced (P < 0.05) after 48 h of exposure to 3 or 6 μM PM. The NOR-G-OH DNA adduct was detected after 24 h of 6 μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48 h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. PMID:25497287

  20. FSH and LH responses to LH--RH stimulation during intravenous estrogen administration in women with polycystic ovary syndrome before and after ovarian wedge resection.

    PubMed

    Shterev, A D; Dokumov, S I; Matrosov, P I

    1983-01-01

    FSH and LH responses to LH--RH stimulation were investigated at 0,3rd and 6th hrs in a six hours exogenous intravenous administration of 300 mg conjugated estrogens before ovarian cuneiformic resection and on the 10th day thereafter in seven patients with polycystic ovarian syndrome. Before operation exogenous pituitary LH--RH stimulation following estrogen administration increased the serum FSH concentrations and response, and decreased LH concentrations and response, while after operation a slight increase of FSH response with a concomitant excessive LH response was observed. A dual action of estrogens in modifying the pituitary gonadotrophins, as well as hypothalamic LH--RH release was supposed.

  1. Application of microwave-assisted micro-solid-phase extraction for determination of parabens in human ovarian cancer tissues.

    PubMed

    Sajid, Muhammad; Basheer, Chanbasha; Narasimhan, Kothandaraman; Choolani, Mahesh; Lee, Hian Kee

    2015-09-01

    Parabens (alkyl esters of p-hydroxybenzoic acid) are widely used as preservatives in food, cosmetics and pharmaceutical products. However, weak estrogenicity of some parabens has been reported in several studies, which provided the impetus for this work. Here, a simple and efficient analytical method for quantifying parabens in cancer tissues has been developed. This technique involves the simultaneous use of microwave-assisted solvent extraction (MASE) and micro-solid phase extraction (μ-SPE), in tandem with high performance liquid chromatography (HPLC/UV) analysis for the determination of parabens. The pollutants studied included four parabens (methyl, ethyl, propyl and butyl parabens). Optimization of the experimental parameters for MASE and μ-SPE was performed. Good relative standard deviation (%RSD) ranged from 0.09 to 2.81% and high enrichment factors (27-314) were obtained. Coefficients of determination (r(2)) up to 0.9962 were obtained across a concentration range of 5.0-200ngg(-1). The method detection limits for parabens ranged from 0.005 to 0.0244ngg(-1). The procedure was initially tested on prawn samples to demonstrate its feasibility on a complex biological matrix. Preliminary studies on human ovarian cancer (OC) tissues showed presence of parabens. Higher levels of parabens were detected in malignant ovarian tumor tissues compared to benign tumor tissue samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Laparoscopic ovarian treatment in infertile patients with polycystic ovarian syndrome (PCOS): endocrine changes and clinical outcome.

    PubMed

    Liguori, G; Tolino, A; Moccia, G; Scognamiglio, G; Nappi, C

    1996-08-01

    During the years 1991-1994, 97 anovulatory infertile women with polycystic ovarian syndrome (PCOS) were treated with laparoscopic electrocautery of the ovarian surface after they had failed to ovulate under ovarian stimulation. To assess the endocrinological and clinical outcome and in an attempt to determine the mechanism of action, the serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), androstenedione, testosterone and dehydroepiandrosterone sulfate (DHEAS) were determined before and after laparoscopic ovarian cautery. Fifty regularly cycling women undergoing laparoscopy for investigation of infertility or tubal ligation served as controls. In patients with PCOS but not in controls, the reduction of androgen levels and normalization of cycle length were highly significant. In contrast, LH and FSH levels rose during the first 2 days after the operation. These results resemble those reported after ovarian wedge resection. Ovulation was obtained in 90% (81 of 90) and pregnancy in 81.1% (73 of 90) of the patients; that increased to 84.4%, including the non-responders (nine patients) treated with clomiphene citrate (CC), after electrocautery. The response to ovarian electrocautery was influenced by body weight, with an ovulation rate of 95-96% in the slim and moderately obese women, decreasing to 81-82% in the really obese ones. When ovulation was established, the pregnancy rate was independent of body weight. However, a striking relationship was detected between smoking habits and pregnancy rate subsequent to ovarian electrocautery, ranging from 24% in smokers to 92% in non-smoking couples. In 30 second-look operations, de novo adhesions were found in 23.3% of the patients (7 of 30). Therefore, ovarian electrocautery is an effective procedure to improve the intraovarian mechanism of selecting a dominant follicle for patients with PCOS in whom initial medical management fails, and it appears to be one of the possible treatments for this

  3. Prediction of over-response to ovarian stimulation in an intrauterine insemination programme.

    PubMed

    Lashen, H; Afnan, M; McDougall, L; Clark, P

    1999-11-01

    Prediction of poor-response is of equal importance to prediction of over-response in intrauterine insemination programmes. The gonadotrophin-releasing hormone agonist (GnRHa) stimulation test (GAST) was assessed as a predictor of over-response to ovarian stimulation in 81 patients. Blood samples were taken on cycle day 2 (before and 24 h after starting the GnRHa). Day 2 and 3 samples were assayed for oestradiol, follicle stimulating hormone (FSH) and luteinizing hormone (LH). Linear and logistic regression analyses were used to assess age, day 2 FSH, day 2 FSH/LH, oestradiol ratio (oestradiol on day 3/oestradiol on day 2) and FSH ratio (FSH on day 3/FSH on day 2) as predictors of the number of follicles (total and > or = 14 mm), oestradiol on HCG day, and clinical pregnancy rate as appropriate. Several parameters were also compared between the patients who produced < or = 3 (> or = 14 mm) follicles (group A) and those who produced >3 (> or = 14 mm) follicles (group B). The mean +/- SEM age of the patients in the study was 32 +/- 0.4 years. The mean total dose of recombinant FSH was 800 +/- 20 IU and the mean duration of stimulation was 7.6 +/- 0.2 days. Nine (11%) and 12 (15%) patients were cancelled for poor and over-response respectively. The oestradiol ratio was significantly positively correlated with oestradiol on HCG day (P < 0.001), and with the number of mature follicles (> or = 14 mm) (P = 0.01). Age, day 2 FSH and FSH ratio were not significantly correlated with oestradiol on HCG day, total follicles and follicles > or = 14 mm. None of the above-mentioned variables was correlated with clinical pregnancy rate. Group A had significantly lower oestradiol ratio (P = 0.007), longer duration of stimulation (P = 0.002), higher total FSH dose (P = 0.001), and lower oestradiol on HCG day (P = 0.001). GAST is therefore useful in predicting the high responders to gonadotrophin stimulation.

  4. DNA methylation changes in epithelial ovarian cancer histotypes

    PubMed Central

    Earp, Madalene A.; Cunningham, Julie M.

    2016-01-01

    Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There’s considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field. PMID:26363302

  5. Applying Quantitative CT Image Feature Analysis to Predict Response of Ovarian Cancer Patients to Chemotherapy.

    PubMed

    Danala, Gopichandh; Thai, Theresa; Gunderson, Camille C; Moxley, Katherine M; Moore, Kathleen; Mannel, Robert S; Liu, Hong; Zheng, Bin; Qiu, Yuchen

    2017-10-01

    The study aimed to investigate the role of applying quantitative image features computed from computed tomography (CT) images for early prediction of tumor response to chemotherapy in the clinical trials for treating ovarian cancer patients. A dataset involving 91 patients was retrospectively assembled. Each patient had two sets of pre- and post-therapy CT images. A computer-aided detection scheme was applied to segment metastatic tumors previously tracked by radiologists on CT images and computed image features. Two initial feature pools were built using image features computed from pre-therapy CT images only and image feature difference computed from both pre- and post-therapy images. A feature selection method was applied to select optimal features, and an equal-weighted fusion method was used to generate a new quantitative imaging marker from each pool to predict 6-month progression-free survival. The prediction accuracy between quantitative imaging markers and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria was also compared. The highest areas under the receiver operating characteristic curve are 0.684 ± 0.056 and 0.771 ± 0.050 when using a single image feature computed from pre-therapy CT images and feature difference computed from pre- and post-therapy CT images, respectively. Using two corresponding fusion-based image markers, the areas under the receiver operating characteristic curve significantly increased to 0.810 ± 0.045 and 0.829 ± 0.043 (P < 0.05), respectively. Overall prediction accuracy levels are 71.4%, 80.2%, and 74.7% when using two imaging markers and RECIST, respectively. This study demonstrated the feasibility of predicting patients' response to chemotherapy using quantitative imaging markers computed from pre-therapy CT images. However, using image feature difference computed between pre- and post-therapy CT images yielded higher prediction accuracy. Copyright © 2017 The Association of University

  6. Augmentation of Response to Chemotherapy by microRNA-506 Through Regulation of RAD51 in Serous Ovarian Cancers

    PubMed Central

    Liu, Guoyan; Yang, Da; Rupaimoole, Rajesha; Pecot, Chad V.; Sun, Yan; Mangala, Lingegowda S.; Li, Xia; Ji, Ping; Cogdell, David; Hu, Limei; Wang, Yingmei; Rodriguez-Aguayo, Cristian; Lopez-Berestein, Gabriel; Shmulevich, Ilya; De Cecco, Loris; Chen, Kexin; Mezzanzanica, Delia; Xue, Fengxia; Sood, Anil K.

    2015-01-01

    Background: Chemoresistance is a major challenge in cancer treatment. miR-506 is a potent inhibitor of the epithelial-to-mesenchymal transition (EMT), which is also associated with chemoresistance. We characterized the role of miR-506 in chemotherapy response in high-grade serous ovarian cancers. Methods: We used Kaplan-Meier and log-rank methods to analyze the relationship between miR-506 and progression-free and overall survival in The Cancer Genome Atlas (TCGA) (n = 468) and Bagnoli (n = 130) datasets, in vitro experiments to study whether miR-506 is associated with homologous recombination, and response to chemotherapy agents. We used an orthotopic ovarian cancer mouse model (n = 10 per group) to test the effect of miR-506 on cisplatin and PARP inhibitor sensitivity. All statistical tests were two-sided. Results: MiR-506 was associated with better response to therapy and longer progression-free and overall survival in two independent epithelial ovarian cancer patient cohorts (PFS: high vs low miR-506 expression; Bagnoli: hazard ratio [HR] = 3.06, 95% confidence interval [CI] = 1.90 to 4.70, P < .0001; TCGA: HR = 1.49, 95% CI = 1.00 to 2.25, P = 0.04). MiR-506 sensitized cells to DNA damage through directly targeting the double-strand DNA damage repair gene RAD51. Systemic delivery of miR-506 in 8–12 week old female athymic nude mice statistically significantly augmented the cisplatin and olaparib response (mean tumor weight ± SD, control miRNA plus cisplatin vs miR-506 plus cisplatin: 0.36±0.05g vs 0.07±0.02g, P < .001; control miRNA plus olaparib vs miR-506 plus olaparib: 0.32±0.13g vs 0.05±0.02g, P = .045, respectively), thus recapitulating the clinical observation. Conclusions: MiR-506 is a robust clinical marker for chemotherapy response and survival in serous ovarian cancers and has important therapeutic value in sensitizing cancer cells to chemotherapy. PMID:25995442

  7. Ovarian Fibrosis: A Phenomenon of Concern

    PubMed Central

    Zhou, Feng; Shi, Li-Bing; Zhang, Song-Ying

    2017-01-01

    Objective: Ovarian fibrosis is characterized by excessive proliferation of ovarian fibroblasts and deposition of extracellular matrix (ECM) and it is one of the principal reasons for ovarian dysfunction. This review aimed to investigate the pathogenetic mechanism of ovarian fibrosis and to clarify the relationship between ovarian diseases and fibrosis. Data Sources: We searched PubMed for English language articles published up to November 2016. The search terms included ovarian fibrosis OR fibrosis, ovarian chocolate cyst OR ovarian endometrioma, polycystic ovarian syndrome (PCOS), premature ovarian failure, ECM, matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), transforming growth factor-beta 1 (TGF-β1), connective tissue growth factor (CTGF), peroxisome proliferator-activated receptor gamma (PPAR-γ), vascular endothelial growth factor (VEGF), endothelin-1 (ET-1), and combinations of these terms. Study Selection: Articles were obtained and reviewed to analyze the pathogenic mechanism of ovarian fibrosis and related ovarian diseases. Results: Many cytokines, such as MMPs, TIMPs, TGF-β1, CTGF, PPAR-γ, VEGF, and ET-1, are involved in ovarian fibrogenesis. Ovarian fibrogenesis is associated with various ovarian diseases, including ovarian chocolate cyst, PCOS, and premature ovarian failure. One finding of particular interest is that fibrogenesis in peripheral tissues around an ovarian chocolate cyst commonly causes ovarian function diminution, and therefore, this medical problem should arouse widespread concern in clinicians worldwide. Conclusions: Patients with ovarian fibrosis are susceptible to infertility and tend to have decreased responses to assisted fertility treatment. Thus, protection of ovarian function should be a priority for women who wish to reproduce when making therapeutic decisions about ovarian fibrosis-related diseases. PMID:28139522

  8. Sialic acid-specific lectin participates in an immune response and ovarian development of the banana shrimp Fenneropenaeus merguiensis.

    PubMed

    Utarabhand, Prapaporn; Rittidach, Wanida; Rattanaporn, Onnicha; Runsaeng, Phanthipha; Hedrick, Jerry L

    2017-01-01

    A sialic acid-specific lectin was purified from the hemolymph of Fenneropenaeus merguiensis by repetitive affinity fetuin-agarose column chromatography. The purified F. merguiensis lectin (called FmL) consisted of two distinct 30.9 and 32kDa subunits with identical N-terminal amino acid sequences of ten residues. FmL was also composed of sugar moieties; glucosamine, glucose, mannose and N-acetyl neuraminic acid but not N-glycolyl neuraminic acid. It was postulated to be a glycoprotein as it was positively stained by glycoprotein staining kit and detected by some bionylated plant lectins. Deglycosylation by either peptide N-glycosidase F or trifluoromethanesulfonic acid turned both types of FmL subunits to 28kDa peptides. The internal peptide sequence of FmL was similar to a fibrinogen-related domain of human ficolin and the horseshoe crab lectin. Determination of the lectin concentrations in the hemolymph was performed by ELISA while its hemaglutinating activity (HA) was tested by hemagglutination. Both specific lectin concentrations and HA increased as shrimp developed ovarian maturation stages 2 to 4. Their constitutive levels were found in pre-vitellogenic females and higher than those of males. Both specific lectin concentrations and HA of FmL were inducible to the highest levels at 12h after F. merguiensis was challenged by pathogenic Vibrio harveyi. The FmL-induced agglutination of V. harveyi was specifically abolished by sialic acid, fetuin and bacterial cell wall components. These findings might indicate the implication in an immune response of FmL to protect the shrimp themselves or their spawning eggs towards pathogenic bacteria in surrounding environment. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Maternal obesity leads to an inflammatory response and insulin resistance in ovarian tissue

    USDA-ARS?s Scientific Manuscript database

    Maternal obesity during the pre-conception period may influence ovarian functions and affect embryo development. Lean and obese (OB) Sprague-Dawley dams were examined during the preimplantation period at dpc 4.5. Obesity was induced by controlled overfeeding (40% excess calories for 28 d) via total ...

  10. P18/Stathmin1 is regulated by miR-31 in ovarian cancer in response to taxane

    PubMed Central

    Hassan, Mohamed Kamel; Watari, Hidemichi; Mitamura, Takashi; Mohamed, Zainab; EL-khamisy, Sherif F.; Ohba, Yusuke; Sakuragi, Noriaki

    2015-01-01

    MicroRNAs (miRNAs) have been reported to regulate the development of chemoresistance in many tumors. Stathmin 1 (STMN1) is a microtubule-depolymerizing molecule, involved in chemo-response; however, the mechanism of its regulation is unknown. Herein, the immunohistochemical study indicated significant upregulation of the STMN1 in the ovarian cancer tissues defined as resistant tumors compared with those defined as responsive tumors. STMN1 level elevated in the chemoresistant ovarian cancer cells, KF-TX, compared with the parental, KF, ones. Targeting STMN1 by siRNA restored taxane-sensitivity of KF-TX cells. Screening miRNA profiles from KF/KF-TX cellular set followed by bioinformatics-based prediction, revealed that miR-31 could be a possible regulator of STMN1. Down-modulation of miR-31 was verified by quantitative RT-PCR in the cellular set used. Overexpression of miR-31 in KF-TX cells (KF-TX-miR-31) significantly restored chemo-response and reduced STMN1 expression as well. STMN1 reduction-associated cellular characteristics such as enhanced microtubule polymerization and stability, as indicated by acetylated tubulin quantification, confocal visualization, and G2 phase delay, were observed in KF-TX-miR-31 cells, indicating the functional reduction of STMN1. miR-31 suppressed the luciferase activity in reporter construct containing the STMN1 3′-untranslated region (3′-UTR), confirming that miR-31 directly targets STMN1. miR-31 has therapeutic potency when introduced into ovarian cancer, in combination with taxane. PMID:25897432

  11. P18/Stathmin1 is regulated by miR-31 in ovarian cancer in response to taxane.

    PubMed

    Hassan, Mohamed Kamel; Watari, Hidemichi; Mitamura, Takashi; Mohamed, Zainab; El-Khamisy, Sherif F; Ohba, Yusuke; Sakuragi, Noriaki

    2015-01-01

    MicroRNAs (miRNAs) have been reported to regulate the development of chemoresistance in many tumors. Stathmin 1 (STMN1) is a microtubule-depolymerizing molecule, involved in chemo-response; however, the mechanism of its regulation is unknown. Herein, the immunohistochemical study indicated significant upregulation of the STMN1 in the ovarian cancer tissues defined as resistant tumors compared with those defined as responsive tumors. STMN1 level elevated in the chemoresistant ovarian cancer cells, KF-TX, compared with the parental, KF, ones. Targeting STMN1 by siRNA restored taxane-sensitivity of KF-TX cells. Screening miRNA profiles from KF/KF-TX cellular set followed by bioinformatics-based prediction, revealed that miR-31 could be a possible regulator of STMN1. Down-modulation of miR-31 was verified by quantitative RT-PCR in the cellular set used. Overexpression of miR-31 in KF-TX cells (KF-TX-miR-31) significantly restored chemo-response and reduced STMN1 expression as well. STMN1 reduction-associated cellular characteristics such as enhanced microtubule polymerization and stability, as indicated by acetylated tubulin quantification, confocal visualization, and G2 phase delay, were observed in KF-TX-miR-31 cells, indicating the functional reduction of STMN1. miR-31 suppressed the luciferase activity in reporter construct containing the STMN1 3'-untranslated region (3'-UTR), confirming that miR-31 directly targets STMN1. miR-31 has therapeutic potency when introduced into ovarian cancer, in combination with taxane.

  12. CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer

    PubMed Central

    Devapatla, Bharat; Sharma, Ankur; Woo, Sukyung

    2015-01-01

    Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy

  13. The evaluation of risk factors for failed response to conservative treatment in tubo-ovarian abscesses

    PubMed Central

    Akkurt, Mehmet Özgür; Yalçın, Serenat Eris; Akkurt, İltaç; Tatar, Burak; Yavuz, And; Yalçın, Yakup; Akgül, Mehmet Akif; Kayıkçıoğlu, Fulya

    2015-01-01

    Objective The aim of our study is to assess the risk factors for medical treatment failure and to predict the patients who will require the surgical therapy as well as to predict the factors affecting treatment success. Material and Methods This was a cross-sectional study including 76 women with tubo-ovarian abscesses (TOA) who were either conservatively or surgically treated and were admitted to two gynecology units over a 4-year period. The demographic characteristics of the patients, gynecologic and obstetric histories, size and localization of abscesses were recorded. Gentamicin plus clindamycin treatment protocol was implemented for all patients. Ampicillin treatment was added in three patients with the positive culture of Actinomyces. Response to treatment was evaluated after 48–72 h. Patients who fail to respond to medical treatment required surgery or percutaneous drainage. We compared clinical and laboratory factors between the groups. Results In surgery group, patients were significantly older than the others (44.9±5.4 versus 39.1±7.6 years). Fifty-six patients (74%) responded to antibiotics and 20 of the patients required surgical intervention. Patients treated with antibiotics were hospitalized for an average of 6.32±2.8 days versus 12.75±5.6 days for those who required surgery (p=0.021). Patients who were surgically treated had a mean size of TOA of 67.9±11.2 mm versus 53.6±9.4 mm for those treated with antibiotics alone (p=0.036). There were no significant differences between groups in laboratory parameters, except for initial white blood cell (WBC) counts. The complications of surgery included in descending order of frequency blood transfusions, surgical wound infections, bowel injury, and bladder injury. Conclusion An increased size of pelvic mass, higher initial WBC counts, advanced age, and smoking were all associated with failed response to conservative treatment. It is important to identify the risk factors to distinguish patients who

  14. E-cadherin: A determinant molecule associated with ovarian cancer progression, dissemination and aggressiveness.

    PubMed

    Rosso, Marina; Majem, Blanca; Devis, Laura; Lapyckyj, Lara; Besso, María José; Llauradó, Marta; Abascal, María Florencia; Matos, María Laura; Lanau, Lucia; Castellví, Josep; Sánchez, José Luis; Pérez Benavente, Asunción; Gil-Moreno, Antonio; Reventós, Jaume; Santamaria Margalef, Anna; Rigau, Marina; Vazquez-Levin, Mónica Hebe

    2017-01-01

    Ovarian cancer (OC) is the fifth cancer death cause in women worldwide. The malignant nature of this disease stems from its unique dissemination pattern. Epithelial-to-mesenchymal transition (EMT) has been reported in OC and downregulation of Epithelial cadherin (E-cadherin) is a hallmark of this process. However, findings on the relationship between E-cadherin levels and OC progression, dissemination and aggressiveness are controversial. In this study, the evaluation of E-cadherin expression in an OC tissue microarray revealed its prognostic value to discriminate between advanced- and early-stage tumors, as well as serous tumors from other histologies. Moreover, E-cadherin, Neural cadherin (N-cadherin), cytokeratins and vimentin expression was assessed in TOV-112, SKOV-3, OAW-42 and OV-90 OC cell lines grown in monolayers and under anchorage-independent conditions to mimic ovarian tumor cell dissemination, and results were associated with cell aggressiveness. According to these EMT-related markers, cell lines were classified as mesenchymal (M; TOV-112), intermediate mesenchymal (IM; SKOV-3), intermediate epithelial (IE; OAW-42) and epithelial (E; OV-90). M- and IM-cells depicted the highest migration capacity when grown in monolayers, and aggregates derived from M- and IM-cell lines showed lower cell death, higher adhesion to extracellular matrices and higher invasion capacity than E- and IE-aggregates. The analysis of E-cadherin, N-cadherin, cytokeratin 19 and vimentin mRNA levels in 20 advanced-stage high-grade serous human OC ascites showed an IM phenotype in all cases, characterized by higher proportions of N- to E-cadherin and vimentin to cytokeratin 19. In particular, higher E-cadherin mRNA levels were associated with cancer antigen 125 levels more than 500 U/mL and platinum-free intervals less than 6 months. Altogether, E-cadherin expression levels were found relevant for the assessment of OC progression and aggressiveness.

  15. A New Approach to Evaluate Drug Treatment Response of Ovarian Cancer Patients Based on Deformable Image Registration

    PubMed Central

    Tan, Maxine; Li, Zheng; Qiu, Yuchen; McMeekin, Scott D.; Thai, Theresa C.; Ding, Kai; Moore, Kathleen N.; Liu, Hong; Zheng, Bin

    2016-01-01

    Although Response Evaluation Criteria in Solid Tumors (RECIST) is the current clinical guideline to assess size change of solid tumors after therapeutic treatment, it has a relatively lower association to the clinical outcome of progression free survival (PFS) of the patients. In this paper, we presented a new approach to assess responses of ovarian cancer patients to new chemotherapy drugs in clinical trials. We first developed and applied a multi-resolution B-spline based deformable image registration method to register two sets of computed tomography (CT) image data acquired pre- and post-treatment. The B-spline difference maps generated from the co-registered CT images highlight the regions related to the volumetric growth or shrinkage of the metastatic tumors, and density changes related to variation of necrosis inside the solid tumors. Using a testing dataset involving 19 ovarian cancer patients, we compared patients’ response to the treatment using the new image registration method and RECIST guideline. The results demonstrated that using the image registration method yielded higher association with the six-month PFS outcomes of the patients than using RECIST. The image registration results also provided a solid foundation of developing new computerized quantitative image feature analysis schemes in the future studies. PMID:26336119

  16. Visualizing photodynamic therapy response with time-lapse OCT in an in vitro model of metastatic ovarian cancer

    NASA Astrophysics Data System (ADS)

    Evans, Conor L.; Rizvi, Imran; Celli, Jonathan; Abu-Yousif, Adnan; de Boer, Johannes; Hasan, Tayyaba

    2010-02-01

    Ovarian epithelial cancer has a high morbidity due to its propensity to metastasize onto surfaces in the abdomen. In order to effectively treat these metastatic lesions with photodynamic therapy (PDT), it is critical to understand the detailed dynamics of the PDT response. 3D in vitro models of ovarian cancer are a promising system for studying the response to PDT of these lesions, as they replicate the size, appearance, and characteristics of metastatic disease observed in the clinic. An ideal approach capable of non-purturbative, 3D imaging of this model is optical coherence tomography (OCT). An ultrahigh resolution time-lapse OCT (TL-OCT) system was used to visualize the photodynamic therapeutic response in the hours and days following treatment. Tumor nodules were observed to experience rapid cell death within the first 24 hours post-treatment using benzophorphyrin derivative monoacid A (BPD), characterized by structural breakdown of the model nodules. Highly scattering bodies were observed with OCT contrast to form at the periphery of the tumor nodules. These highly scattering moieties were identified as apoptotic bodies, indicating that OCT is capable of tracking the PDT-induced apoptosis in real-time without the need for labels.

  17. Phosphoramide mustard exposure induces DNA adduct formation and the DNA damage repair response in rat ovarian granulosa cells.

    PubMed

    Ganesan, Shanthi; Keating, Aileen F

    2015-02-01

    Phosphoramide mustard (PM), the ovotoxic metabolite of the anti-cancer agent cyclophosphamide (CPA), destroys rapidly dividing cells by forming NOR-G-OH, NOR-G and G-NOR-G adducts with DNA, potentially leading to DNA damage. A previous study demonstrated that PM induces ovarian DNA damage in rat ovaries. To investigate whether PM induces DNA adduct formation, DNA damage and induction of the DNA repair response, rat spontaneously immortalized granulosa cells (SIGCs) were treated with vehicle control (1% DMSO) or PM (3 or 6μM) for 24 or 48h. Cell viability was reduced (P<0.05) after 48h of exposure to 3 or 6μM PM. The NOR-G-OH DNA adduct was detected after 24h of 6μM PM exposure, while the more cytotoxic G-NOR-G DNA adduct was formed after 48h by exposure to both PM concentrations. Phosphorylated H2AX (γH2AX), a marker of DNA double stranded break occurrence, was also increased by PM exposure, coincident with DNA adduct formation. Additionally, induction of genes (Atm, Parp1, Prkdc, Xrcc6, and Brca1) and proteins (ATM, γH2AX, PARP-1, PRKDC, XRCC6, and BRCA1) involved in DNA repair were observed in both a time- and dose-dependent manner. These data support that PM induces DNA adduct formation in ovarian granulosa cells, induces DNA damage and elicits the ovarian DNA repair response. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. A B-spline image registration based CAD scheme to evaluate drug treatment response of ovarian cancer patients

    NASA Astrophysics Data System (ADS)

    Tan, Maxine; Li, Zheng; Moore, Kathleen; Thai, Theresa; Ding, Kai; Liu, Hong; Zheng, Bin

    2016-03-01

    Ovarian cancer is the second most common cancer amongst gynecologic malignancies, and has the highest death rate. Since the majority of ovarian cancer patients (>75%) are diagnosed in the advanced stage with tumor metastasis, chemotherapy is often required after surgery to remove the primary ovarian tumors. In order to quickly assess patient response to the chemotherapy in the clinical trials, two sets of CT examinations are taken pre- and post-therapy (e.g., after 6 weeks). Treatment efficacy is then evaluated based on Response Evaluation Criteria in Solid Tumors (RECIST) guideline, whereby tumor size is measured by the longest diameter on one CT image slice and only a subset of selected tumors are tracked. However, this criterion cannot fully represent the volumetric changes of the tumors and might miss potentially problematic unmarked tumors. Thus, we developed a new CAD approach to measure and analyze volumetric tumor growth/shrinkage using a cubic B-spline deformable image registration method. In this initial study, on 14 sets of pre- and post-treatment CT scans, we registered the two consecutive scans using cubic B-spline registration in a multiresolution (from coarse to fine) framework. We used Mattes mutual information metric as the similarity criterion and the L-BFGS-B optimizer. The results show that our method can quantify volumetric changes in the tumors more accurately than RECIST, and also detect (highlight) potentially problematic regions that were not originally targeted by radiologists. Despite the encouraging results of this preliminary study, further validation of scheme performance is required using large and diverse datasets in future.

  19. The distribution of the apparent diffusion coefficient as an indicator of the response to chemotherapeutics in ovarian tumour xenografts

    NASA Astrophysics Data System (ADS)

    Tourell, Monique C.; Shokoohmand, Ali; Landgraf, Marietta; Holzapfel, Nina P.; Poh, Patrina S. P.; Loessner, Daniela; Momot, Konstantin I.

    2017-02-01

    Diffusion-weighted magnetic resonance imaging (DW-MRI) was used to evaluate the effects of single-agent and combination treatment regimens in a spheroid-based animal model of ovarian cancer. Ovarian tumour xenografts grown in non-obese diabetic/severe-combined-immunodeficiency (NOD/SCID) mice were treated with carboplatin or paclitaxel, or combination carboplatin/paclitaxel chemotherapy regimens. After 4 weeks of treatment, tumours were extracted and underwent DW-MRI, mechanical testing, immunohistochemical and gene expression analyses. The distribution of the apparent diffusion coefficient (ADC) exhibited an upward shift as a result of each treatment regimen. The 99-th percentile of the ADC distribution (“maximum ADC”) exhibited a strong correlation with the tumour size (r2 = 0.90) and with the inverse of the elastic modulus (r2 = 0.96). Single-agent paclitaxel (n = 5) and combination carboplatin/paclitaxel (n = 2) treatment regimens were more effective in inducing changes in regions of higher cell density than single-agent carboplatin (n = 3) or the no-treatment control (n = 5). The maximum ADC was a good indicator of treatment-induced cell death and changes in the extracellular matrix (ECM). Comparative analysis of the tumours’ ADC distribution, mechanical properties and ECM constituents provides insights into the molecular and cellular response of the ovarian tumour xenografts to chemotherapy. Increased sample sizes are recommended for future studies. We propose experimental approaches to evaluation of the timeline of the tumour’s response to treatment.

  20. The distribution of the apparent diffusion coefficient as an indicator of the response to chemotherapeutics in ovarian tumour xenografts

    PubMed Central

    Tourell, Monique C.; Shokoohmand, Ali; Landgraf, Marietta; Holzapfel, Nina P.; Poh, Patrina S. P.; Loessner, Daniela; Momot, Konstantin I.

    2017-01-01

    Diffusion-weighted magnetic resonance imaging (DW-MRI) was used to evaluate the effects of single-agent and combination treatment regimens in a spheroid-based animal model of ovarian cancer. Ovarian tumour xenografts grown in non-obese diabetic/severe-combined-immunodeficiency (NOD/SCID) mice were treated with carboplatin or paclitaxel, or combination carboplatin/paclitaxel chemotherapy regimens. After 4 weeks of treatment, tumours were extracted and underwent DW-MRI, mechanical testing, immunohistochemical and gene expression analyses. The distribution of the apparent diffusion coefficient (ADC) exhibited an upward shift as a result of each treatment regimen. The 99-th percentile of the ADC distribution (“maximum ADC”) exhibited a strong correlation with the tumour size (r2 = 0.90) and with the inverse of the elastic modulus (r2 = 0.96). Single-agent paclitaxel (n = 5) and combination carboplatin/paclitaxel (n = 2) treatment regimens were more effective in inducing changes in regions of higher cell density than single-agent carboplatin (n = 3) or the no-treatment control (n = 5). The maximum ADC was a good indicator of treatment-induced cell death and changes in the extracellular matrix (ECM). Comparative analysis of the tumours’ ADC distribution, mechanical properties and ECM constituents provides insights into the molecular and cellular response of the ovarian tumour xenografts to chemotherapy. Increased sample sizes are recommended for future studies. We propose experimental approaches to evaluation of the timeline of the tumour’s response to treatment. PMID:28220831

  1. The distribution of the apparent diffusion coefficient as an indicator of the response to chemotherapeutics in ovarian tumour xenografts.

    PubMed

    Tourell, Monique C; Shokoohmand, Ali; Landgraf, Marietta; Holzapfel, Nina P; Poh, Patrina S P; Loessner, Daniela; Momot, Konstantin I

    2017-02-21

    Diffusion-weighted magnetic resonance imaging (DW-MRI) was used to evaluate the effects of single-agent and combination treatment regimens in a spheroid-based animal model of ovarian cancer. Ovarian tumour xenografts grown in non-obese diabetic/severe-combined-immunodeficiency (NOD/SCID) mice were treated with carboplatin or paclitaxel, or combination carboplatin/paclitaxel chemotherapy regimens. After 4 weeks of treatment, tumours were extracted and underwent DW-MRI, mechanical testing, immunohistochemical and gene expression analyses. The distribution of the apparent diffusion coefficient (ADC) exhibited an upward shift as a result of each treatment regimen. The 99-th percentile of the ADC distribution ("maximum ADC") exhibited a strong correlation with the tumour size (r(2) = 0.90) and with the inverse of the elastic modulus (r(2) = 0.96). Single-agent paclitaxel (n = 5) and combination carboplatin/paclitaxel (n = 2) treatment regimens were more effective in inducing changes in regions of higher cell density than single-agent carboplatin (n = 3) or the no-treatment control (n = 5). The maximum ADC was a good indicator of treatment-induced cell death and changes in the extracellular matrix (ECM). Comparative analysis of the tumours' ADC distribution, mechanical properties and ECM constituents provides insights into the molecular and cellular response of the ovarian tumour xenografts to chemotherapy. Increased sample sizes are recommended for future studies. We propose experimental approaches to evaluation of the timeline of the tumour's response to treatment.

  2. Ovarian Cancer

    MedlinePlus

    OVARIAN CANCER Get the Facts About Gynecologic Cancer There are five main types of cancer that affect a ... rare fallopian tube cancer.) This fact sheet about ovarian cancer is part of the Centers for Disease Control ...

  3. Effects of momorcharins on ovarian response to gonadotropin-induced superovulation in mice.

    PubMed

    Ng, T B; Tam, P P; Hon, W K; Choi, H L; Yeung, H W

    1988-01-01

    Alpha- and beta-momorcharins, which are abortifacient proteins isolated from Momordica charantia seeds, were tested for a possible effect on ovulation and plasma levels of ovarian steroids in mice induced to superovulate by PMSG and hCG. The plant proteins did not affect follicular recruitment and maturation as evidenced by ovarian histology and serum 17 beta-estradiol level. Both proteins diminished the number of oocytes ovulated when given on the day prior to or on the day of PMSG treatment, but not when given after the gonadotropin injection; they also increased the incidence of follicular atresia. The number of corpora lutea was slightly reduced by treatment with the proteins, but there was no long-term suppression of the serum progesterone level. After mating, animals which have previously been treated with the plant proteins underwent pregnancy resulting in a litter size similar to that of controls.

  4. Prediction of Response to Therapy and Clinical Outcome through a Pilot Study of Complete Genetic Assessment of Ovarian Cancer

    DTIC Science & Technology

    2015-12-01

    important as nothing has been published on the molecular alternation of the different histological subtypes of ovarian cancer. 15. SUBJECT TERMS...Ovarian Cancer, histological subtypes, somatic mutations 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF...for ovarian cancer patients. Although once considered a single entity, ovarian cancer can be now subdivided into different histological subtypes

  5. Ovarian Response to Different Dose Levels of Follicle Stimulating Hormone (FSH) in Different Genotypes of Bangladeshi Cattle

    PubMed Central

    Ali, M. S.; Khandoker, M. A. M. Y.; Afroz, M. A.; Bhuiyan, A. K. F. H.

    2012-01-01

    The experiment was conducted under the Department of Animal Breeding and Genetics, Bangladesh Agricultural University (BAU), Mymensingh from June, 2001 to December, 2005 in two different locations (Central Cattle Breeding and Dairy Farm and Bangladesh Livestock Research Institute in Savar, Dhaka) to observe ovarian response to different doses of FSH in three different genotypes of cattle- indigenous Local, Pabna cattle and Friesian×Local cross. Five different dose levels used were 200, 240, 280, 320 and 360 mg. Ovarian response as corpus luteum (CL), recovered embryo (RE) and of transferable embryos (TE) count in Local were significant for 320, 280 and 280 mg respectively. In Pabna cattle CL, RE and TE count were found significant for 360, 320 and 320 mg respectively. In Friesian×Local cross CL, RE and TE count were found significant for 360, 320 and 320 mg respectively. The excellent quality embryos showed significantly the highest yield (1.80±0.20) in the 240 and 280 mg FSH levels in Local genotype. In Pabna cattle, the highest yield (2.00±0.32) was found at FSH level 320 mg. In Friesian×Local, the highest yield (2.20±0.20) was found at FSH level 280 mg. PMID:25049478

  6. Determination of ovarian cyclicity and pregnancy using fecal progesterone in forest musk deer (Moschus berezovskii).

    PubMed

    Wang, Yi-Hua; Liu, Shu-Qiang; Yang, Shuang; Zhang, Tian-Xiang; Wei, Yu-Ting; Zhou, Jun-Tong; Hu, De-Fu; Li, Lin-Hai

    2016-07-01

    The forest musk deer (FMD, Moschus berezovskii) is a threatened species in China. Although crucial for its artificial breeding management and thus protection, to date, gonadal steroidogenic activity data are unavailable in this species. Thus, the objectives of the present study were to characterize ovarian activity throughout the estrous cycle, non-pregnant luteal phase, and gestation in female FMD. These goals were accomplished using an enzyme immunoassay to measure fecal concentrations of estradiol (E2) and progesterone. Fecal samples were collected from female FMD (aged 3-4 years) for one year, including during breeding and non-breeding seasons. Non-pregnant estrous cycles were recorded in females, based on fecal progesterone concentrations, their overall estrous cycle length was (mean±SEM) 24.3±0.5 days, with 21.6±0.5 days in the luteal phase and 2.7±0.3 days in the inter-luteal phase. Fecal progesterone and E2 concentrations were also measured in females that became pregnant and gave birth after gestating approximately 6 months. Two weeks after becoming pregnant, the average fecal progesterone concentration was significantly greater than that during non-pregnancy. The average fecal progesterone concentrations during pregnancy increased 3.2-fold above non-pregnant concentrations, decreasing to non-pregnant concentrations only after parturition. By contrast, average fecal E2 concentrations during gestation and after parturition were not different from average non-pregnant concentration. In addition, no difference was observed between progesterone concentration in the first month after pregnancy and the value during the luteal phase. However, progesterone concentration during the second month of pregnancy was significantly higher than the value during the luteal phase. In conclusion, monitoring fecal progesterone is an effective method for assessing ovarian function in FMD and will be a useful tool for breeding management and development of assisted

  7. [Ovarian carcinoid tumor responsible of permanent facial erythrosis and flushings during sexual intercourse].

    PubMed

    Talvande, B; Dorange, A; Lecouflet, M; Le Nezet, M; Kianifard, B; Maillard, H; Duquenne, M

    2016-11-01

    Ovarian neuroendocrine tumors are extremely rare. In the ovary, the term of neuroendocrine tumor is usually related to carcinoid tumors although it may be sometimes applied to neuroendocrine carcinomas of non-small cells or small cells cancers usually occurring in the lungs. These carcinoid tumors may develop de novo or from other tumors including teratomas. We report a patient who presented with an ovarian carcinoid tumor developed, near or from a dermoid cyst, which was original by its mode of discovery in the dermatology department. Indeed, the patient consulted because of permanent facial erythrosis, with flushes but also facial telangiectasias. During medical examination, classic symptoms of carcinoid syndrome including heart disease were obvious. The occurrence of flushes during coitus should evoke pelvic tumor location. A carcinoid syndrome is naturally evoked in the presence of flushes but it must also be part of the differential diagnosis in a patient with facial erythrosis or telangiectasias, especially if they are associated with diarrhea or right heart failure. The prognosis of carcinoid heart disease is considerably better in case of ovarian location than when it is a primitive carcinoid tumor of lung or from gastrointestinal tract. Copyright © 2016 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  8. Identification of Anti-CA125 Antibody Responses in Ovarian Cancer Patients by a Novel Deep Sequence-Coupled Biopanning Platform.

    PubMed

    Frietze, Kathryn M; Roden, Richard B S; Lee, Ji-Hyun; Shi, Yang; Peabody, David S; Chackerian, Bryce

    2016-02-01

    High-grade epithelial ovarian cancer kills more women than any other gynecologic cancer and is rarely diagnosed at an early stage. We sought to identify tumor-associated antigens (TAA) as candidate diagnostic and/or immunotherapeutic targets by taking advantage of tumor autoantibody responses in individuals with ovarian cancer. Plasma-derived IgG from a pool of five patients with advanced ovarian cancer was subjected to iterative biopanning using a library of bacteriophage MS2 virus-like particles (MS2-VLPs) displaying diverse short random peptides. After two rounds of biopanning, we analyzed the selectant population of MS2-VLPs by Ion Torrent deep sequencing. One of the top 25 most abundant peptides identified (DISGTNTSRA) had sequence similarity to cancer antigen 125 (CA125/MUC16), a well-known ovarian cancer-associated antigen. Mice immunized with MS2-DISGTNTSRA generated antibodies that cross-reacted with purified soluble CA125 from ovarian cancer cells but not membrane-bound CA125, indicating that the DISGTNTSRA peptide was a CA125/MUC16 peptide mimic of soluble CA125. Preoperative ovarian cancer patient plasma (n = 100) was assessed for anti-DISGTNTSRA, anti-CA125, and CA125. Patients with normal CA125 (<35 IU/mL) at the time of diagnosis had significantly more antibodies to DISGTNTSRA and to CA125 than those patients who had high CA125 (>35 IU/mL). A statistically significant survival advantage was observed for patients who had either normal CA125 and/or higher concentrations of antibodies to CA125 at the time of diagnosis. These data show the feasibility of using deep sequence-coupled biopanning to identify TAA autoantibody responses from cancer patient plasma and suggest a possible antibody-mediated mechanism for low CA125 plasma concentrations in some ovarian cancer patients.

  9. Soft Determinism plus Awareness Equals Shared Responsibility

    ERIC Educational Resources Information Center

    Rousseve, Ronald J.

    1971-01-01

    This article seeks to present a viable resolution of one of the perennial ideological issues in counseling: determinism versus human freedom. The dilemma has bearing on the related professional issue of client and counselor responsibility. (Author)

  10. Oophorectomy versus radiation ablation of ovarian function in patients with metastatic carcinoma of the breast

    SciTech Connect

    Lees, A.W.; Giuffre, C.; Burns, P.E.; Hurlburt, M.E.; Jenkins, H.J.

    1980-12-01

    A retrospective study of two methods of ovarian ablation as primary therapy for metastatic carcinoma of the breast was carried out using records from this cancer institute. Sixty-one radiation and 97 surgical ovarian ablations, performed from 1972 to 1977, were assessed. Over-all response was similar for the surgical and irradiation groups. Survival from the time of ovarian ablation was greater in both groups in those who responded positively than in those who did not. Factors other than estrogen receptor status can determine the response of patients with metastatic carcinoma of the breast to ovarian ablation. The results indicate that clinical determinates and not the efficiency of one method over the other should be the main criteria for choosing between ovarian ablation by irradiation or by oophorectomy.

  11. Quantitative proteomics analysis integrated with microarray data reveals that extracellular matrix proteins, catenins, and p53 binding protein 1 are important for chemotherapy response in ovarian cancers.

    PubMed

    Pan, Sheng; Cheng, Lihua; White, James T; Lu, Wei; Utleg, Angelita G; Yan, Xiaowei; Urban, Nicole D; Drescher, Charles W; Hood, Leroy; Lin, Biaoyang

    2009-08-01

    Chemotherapy with carboplatin and paclitaxel is the standard treatment for ovarian cancer patients. Although most patients initially respond to this treatment, few are cured. Resistance to chemotherapy is the major cause of treatment failure. We applied a quantitative proteomic approach based on ICAT/MS/MS technology to analyze tissues harvested at primary debulking surgery before the initiation of combination chemotherapy in order to identify potential naive or intrinsic chemotherapy response proteins in ovarian cancers. We identified 44 proteins that are overexpressed, and 34 proteins that are underexpressed in the chemosensitive tissue compared to the chemoresistant tissue. The overexpressed proteins identified in the chemoresistant tissue include 10 proteins (25.6%) belonging to the extracellular matrix (ECM), including decorin, versican, basigin (CD147), fibulin-1, extracellular matrix protein 1, biglycan, fibronectin 1, dermatopontin, alpha-cardiac actin (smooth muscle actin), and an EGF-containing fibulin-like extracellular matrix protein 1. Interesting proteins identified as overexpressed in the chemosensitive tissue include gamma-catenin (junction plakoglobin) and delta-catenin, tumor suppressor p53-binding protein 1 (53BP1), insulin-like growth factor-binding protein 2 (IGFBP2), proliferating cell nuclear antigen (PCNA), annexin A11, and 53 kDa selenium binding protein 1. Integrative analysis with expression profiling data of eight chemoresistant tissues and 13 chemosensitive tissues revealed that 16 proteins showed consistent changes at both the protein and the RNA levels. These include P53 binding protein 1, catenin delta 1 and plakoglobin, EGF-containing fibulin-like extracellular matrix protein 1 and voltage-dependent anion-selective channel protein 1. Our results suggest that chemotherapy response may be determined by multiple and complex system properties involving extracellular-matrix, cell adhesion and junction proteins.

  12. NUCKS nuclear elevated expression indicates progression and prognosis of ovarian cancer.

    PubMed

    Shi, Ce; Qin, Ling; Gao, Hongyu; Gu, Lina; Yang, Chang; Liu, Hebing; Liu, Tianbo

    2017-09-01

    NUCKS (nuclear, casein kinase, and cyclin-dependent kinase substrate) is implicated in the tumorigenesis of several human malignancies, but its role in ovarian cancer remains unknown. We aim to investigate NUCKS expression and its clinical significance in ovarian cancer. The messenger RNA expression of NUCKS was determined in normal and malignant ovarian tissues using quantitative polymerase chain reaction assay. Immunohistochemistry was applied to detect the status of NUCKS protein expression in 121 ovarian cancer tissues. NUCKS protein high expression was detected in 52 (43.0%) of 121 patients. NUCKS messenger RNA expression was gradually upregulated in non-metastatic ovarian cancers ( n = 20), metastatic ovarian cancers ( n = 20), and its matched metastatic lesions ( n = 20) in comparison with that in normal ovarian tissues ( n = 10; p < 0.05). Elevated expression of NUCKS in ovarian cancer was associated significantly with the Federation of Gynecology and Obstetrics stage ( p = 0.037), histological grade ( p = 0.003), residual disease ( p = 0.013), lymph node metastasis ( p = 0.002), response to chemotherapy ( p < 0.001), and recurrence ( p = 0.013). In the multivariate Cox analysis, NUCKS expression was an independent prognostic marker for overall survival and disease-free survival in ovarian cancer with p values of <0.001 for both. Especially, NUCKS overexpression had prognostic potential for overall survival and disease-free survival ( p < 0.001 for both) in advanced ovarian cancers and only for disease-free survival in early ovarian cancers ( p = 0.017). Our data suggest that NUCKS overexpression may contribute to progression and poor prognosis in ovarian cancer especially in advanced ovarian cancer.

  13. Morphokinetic Characteristics and Developmental Potential of In Vitro Cultured Embryos from Natural Cycles in Patients with Poor Ovarian Response

    PubMed Central

    Hojnik, N.; Vlaisavljević, V.

    2016-01-01

    Background. Patients with poor ovarian response to ovarian hyperstimulation represent an interesting group for studying the impact of embryo cleavage irregularities on clinical outcome since all embryos, regardless of their quality, are usually transferred to the uterus. The aim of our study was to follow the morphokinetics of fertilized oocytes from natural cycles in poor responders. Methods. Zygotes from 53 cycles were cultured in vitro for 3 days. The morphokinetics of their development and transfer outcomes were retrospectively analyzed for the normally and irregularly cleaved embryos. Results. Of all embryos, 30.2% had single and 20.8% multiple cleavage irregularities with the following prevalence: developmental arrest 30.2%, direct cleavage to more than two cells 24.5%, chaotic cleavage 13.2%, and reverse cleavage 11.3%. These embryos had longer pronuclear phases, first cytokinesis, second embryo cell cycles, and less synchronized divisions. The transfer of normally developing embryos resulted in an implantation rate of 30.8% and a delivery rate of 23.1%, but irregularly cleaved embryos did not implant. Conclusions. The use of time-lapse microscopy in poor responder patients identified embryos with cleavage abnormalities that are related with no or extremely low implantation potential. Gained information about embryo quality is important for counselling patients about their expectations. PMID:28097133

  14. 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.

  15. Maternal obesity is associated with ovarian inflammation and upregulation of early growth response factor 1.

    PubMed

    Ruebel, Meghan; Shankar, Kartik; Gaddy, Dana; Lindsey, Forrest; Badger, Thomas; Andres, Aline

    2016-07-01

    Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a proinflammatory gene signature and upregulation of Egr-1 protein in ovaries from obese (OB; n = 7) compared with lean (LN; n = 10) female Sprague-Dawley rats during the peri-implantation period at 4.5 days postcoitus (dpc). Obesity was induced by overfeeding (40% excess calories for 28 days) via total enteral nutrition prior to mating. OB dams had higher body weight (P < 0.001), greater fat mass (P < 0.001), and reduced lean mass (P < 0.05) and developed metabolic dysfunction with elevated serum lipids, insulin, leptin, and CCL2 (P < 0.05) compared with LN dams. Microarray analyses identified 284 differentially expressed genes between ovaries from LN vs. OB dams (±1.3 fold, P < 0.05). RT-qPCR confirmed a decrease in expression of glucose transporters GLUT4 and GLUT9 and elevation of proinflammatory genes, including CCL2, CXCL10, CXCL11, CCR2, CXCR1, and TNFα in ovaries from OB compared with LN (P < 0.05). Protein levels of PI3K and phosphorylated Akt were significantly decreased (P < 0.05), whereas nuclear levels of Egr-1 (P < 0.05) were increased in OB compared with LN ovaries. Moreover, Egr-1 was localized to granulosa cells, with the highest expression in cumulus cells of preovulatory follicles. mRNA expression of VCAN, AURKB, and PLAT (P < 0.05) correlated with %visceral fat weight (r = 0.51, -0.77, and -0.57, respectively, P ≤ 0.05), suggesting alterations in ovarian function with obesity. In summary, maternal obesity led to an upregulation of inflammatory genes and Egr-1 expression in peri-implantation ovarian tissue and a concurrent downregulation of GLUTs and Akt and PI3K protein levels.

  16. 14-3-3 σ Expression Effects G2/M Response to Oxygen and Correlates with Ovarian Cancer Metastasis

    PubMed Central

    Ravi, Dashnamoorthy; Chen, Yidong; Karia, Bijal; Brown, Adam; Gu, Ting Ting; Li, Jie; Carey, Mark S.; Hennessy, Bryan T.; Bishop, Alexander J. R.

    2011-01-01

    Background In vitro cell culture experiments with primary cells have reported that cell proliferation is retarded in the presence of ambient compared to physiological O2 levels. Cancer is primarily a disease of aberrant cell proliferation, therefore, studying cancer cells grown under ambient O2 may be undesirable. To understand better the impact of O2 on the propagation of cancer cells in vitro, we compared the growth potential of a panel of ovarian cancer cell lines under ambient (21%) or physiological (3%) O2. Principal Findings Our observations demonstrate that similar to primary cells, many cancer cells maintain an inherent sensitivity to O2, but some display insensitivity to changes in O2 concentration. Further analysis revealed an association between defective G2/M cell cycle transition regulation and O2 insensitivity resultant from overexpression of 14-3-3 σ. Targeting 14-3-3 σ overexpression with RNAi restored O2 sensitivity in these cell lines. Additionally, we found that metastatic ovarian tumors frequently overexpress 14-3-3 σ, which in conjunction with phosphorylated RB, results in poor prognosis. Conclusions Cancer cells show differential proliferative sensitivity to changes in O2 concentration. Although a direct link between O2 insensitivity and metastasis was not determined, this investigation showed that an O2 insensitive phenotype in cancer cells to correlate with metastatic tumor progression. PMID:21249227

  17. 14-3-3 σ expression effects G2/M response to oxygen and correlates with ovarian cancer metastasis.

    PubMed

    Ravi, Dashnamoorthy; Chen, Yidong; Karia, Bijal; Brown, Adam; Gu, Ting Ting; Li, Jie; Carey, Mark S; Hennessy, Bryan T; Bishop, Alexander J R

    2011-01-10

    In vitro cell culture experiments with primary cells have reported that cell proliferation is retarded in the presence of ambient compared to physiological O₂ levels. Cancer is primarily a disease of aberrant cell proliferation, therefore, studying cancer cells grown under ambient O₂ may be undesirable. To understand better the impact of O₂ on the propagation of cancer cells in vitro, we compared the growth potential of a panel of ovarian cancer cell lines under ambient (21%) or physiological (3%) O₂. Our observations demonstrate that similar to primary cells, many cancer cells maintain an inherent sensitivity to O₂, but some display insensitivity to changes in O₂ concentration. Further analysis revealed an association between defective G2/M cell cycle transition regulation and O₂ insensitivity resultant from overexpression of 14-3-3 σ. Targeting 14-3-3 σ overexpression with RNAi restored O₂ sensitivity in these cell lines. Additionally, we found that metastatic ovarian tumors frequently overexpress 14-3-3 σ, which in conjunction with phosphorylated RB, results in poor prognosis. Cancer cells show differential proliferative sensitivity to changes in O₂ concentration. Although a direct link between O₂ insensitivity and metastasis was not determined, this investigation showed that an O₂ insensitive phenotype in cancer cells to correlate with metastatic tumor progression.

  18. Reproductive responses of dairy cows with ovarian cysts to simultaneous human chorionic gonadotropin or gonadotropin-releasing hormone and cloprostenol compared to gonadotropin-releasing hormone alone treatment

    PubMed Central

    Taktaz, T.; Kafi, M.; Mokhtari, Adel; Heidari, M.

    2015-01-01

    Aim: Bovine ovarian cysts are a common cause of economic loss in modern dairy herds. The objective of the present study was to evaluate the reproductive responses to three protocols using hCG, GnRH and cloprostenol when the definite diagnosis of the type of ovarian cyst is/is not possible in dairy cows. Materials and Methods: A total of 144 lactating dairy cows with ovarian cysts were divided into three groups. At diagnosis (Day 0), cows in Group 1 (the conventional method, n=47) were injected with 0.02 mg of a GnRH analogue i.m. (Buserelin); cows in Group 2 (n=47) were intramuscularly treated with 0.02 mg Buserelin plus 500 µg cloprostenol; and cows in Group 3 (n=50) were intramuscularly treated with 1500 IU hCG plus 500 µg cloprostenol. All cows received 500 µg cloprostenol intramuscularly on Day 10. Results: No statistically significant differences were found in the recovery time, interval to conception, conception rate at first AI, and pregnancy rates by Days 70 and 100 after treatment among the three groups. Conclusions: Simultaneous treatment of ovarian cysts with hCG or GnRH and cloprostenol appeared to have no advantage over the conventional method, GnRH alone, in dairy cows. Furthermore, hCG and GnRH have an equal therapeutic effect in cows with ovarian cysts. PMID:27047149

  19. Mumps virus induces innate immune responses in mouse ovarian granulosa cells through the activation of Toll-like receptor 2 and retinoic acid-inducible gene I.

    PubMed

    Wang, Qing; Wu, Han; Cheng, Lijing; Yan, Keqin; Shi, Lili; Zhao, Xiang; Jiang, Qian; Wang, Fei; Chen, Yongmei; Li, Qihan; Han, Daishu

    2016-11-15

    Mumps virus (MuV) infection may lead to oophoritis and perturb ovarian function. However, the mechanisms underlying the activation of innate immune responses to MuV infection in the ovary have not been investigated. This study showed that Toll-like receptor 2 (TLR2) and retinoic acid-inducible gene I (RIG-I) cooperatively initiate innate immune responses to MuV infection in mouse ovarian granulosa cells. Ovarian granulosa cells infected with MuV significantly produced pro-inflammatory cytokines and chemokines, including interleukin-1β (IL-1β), tumor necrosis factor α (TNF-α), monocyte chemotactic protein 1 (MCP-1), and type 1 interferons (IFN-α and IFN-β). Knockdown of RIG-I significantly decreased MuV-induced cytokine expression. TLR2 deficiency reduced the expression of IL-1β, TNF-α, and MCP-1 but did not affect the expression of IFN-α and IFN-β in granulosa cells after infection with MuV. Intraperitoneal injection of MuV induced the ovarian innate immune responses in vivo, which suppressed estradiol synthesis and induced granulosa cell apoptosis. The results provide novel insights into the mechanisms underlying MuV-induced innate immune responses in the mouse ovary. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Genetic Variants in MicroRNA Biosynthesis Pathways and Binding Sites Modify Ovarian Cancer Risk, Survival, and Treatment Response

    PubMed Central

    Liang, Dong; Meyer, Larissa; Chang, David W.; Lin, Jie; Pu, Xia; Ye, Yuanqing; Gu, Jian; Wu, Xifeng; Lu, Karen

    2017-01-01

    MicroRNAs (miRNA) play important roles in tumorigenesis. Genetic variations in miRNA processing genes and miRNA binding sites may affect the biogenesis of miRNA and the regulatory effect of miRNAs to their target genes, hence promoting tumorigenesis. This study analyzed 226 single nucleotide polymorphisms (SNP) in miRNA processing genes and miRNA binding sites in 339 ovarian cancer cases and 349 healthy controls to assess association with cancer risk, overall survival, and treatment response. Thirteen polymorphisms were found to have significant association with risk. The most significant were 2 linked SNPs (r2 = 0.99), rs2740351 and rs7813 in GEMIN4 [odds ratio (OR) = 0.71; 95% confidence interval (CI), 0.57–0.87 and OR = 0.71; 95% CI, 0.57–0.88, respectively]. Unfavorable genotype analysis showed the cumulative effect of these 13 SNPs on risk (P for trend < 0.0001). Potential higher order gene–gene interactions were identified, which categorized patients into different risk groups according to their genotypic signatures. In the clinical outcome study, 24 SNPs exhibited significant association with overall survival and 17 SNPs with treatment response. Notably, patients carrying a rare homozygous genotype of rs1425486 in PDGFC had poorer overall survival [hazard ratio (HR) = 2.69; 95% CI, 1.67–4.33] and worse treatment response (OR = 3.38; 95% CI, 1.39–8.19), compared to carriers of common homozygous and heterozygous genotypes. Unfavorable genotype analyses also showed a strong gene-dosage effect with decreased survival and increased risk of treatment nonresponse in patients with greater number of unfavorable genotypes (P for trend < 0.0001). Taken together, miRNA-related genetic polymorphisms may impact ovarian cancer predisposition and clinical outcome both individually and jointly. PMID:21118967

  1. Retinoblastoma pathway deregulatory mechanisms determine clinical outcome in high-grade serous ovarian carcinoma.

    PubMed

    Milea, Anca; George, Sophia H L; Matevski, Donco; Jiang, Haiyan; Madunic, Mary; Berman, Hal K; Gauthier, Mona L; Gallie, Brenda; Shaw, Patricia A

    2014-07-01

    Alterations in the retinoblastoma pathway are frequent in ovarian/tubal high-grade serous cancers, but the mechanism of deregulation and the impact on patient outcome are poorly understood. A cohort of 334 high-grade serous carcinomas was studied by immunohistochemical analysis of RB1, p16, cyclin D1, cyclin E1, and Ki67. Additional detailed analyses including RB1 allelic deletion (n=42), mutation (n=75), methylation (n=31), and SNP array analyses (n=75) were performed on cases with clinical parameters, including age, debulking status, treatment, and clinical outcome. p16/RB1 expression results yielded three distinct clinically relevant subgroups upon multivariable analysis controlling for stage, debulking status, and treatment types: p16 homogeneous/RB1+ with the shortest progression-free survival (median 15 months (95% CI: 13-18); P=0.016) compared with the p16 heterogeneous/RB1+ subgroup (median 22 months (95% CI: 16-32)) and the p16 homogeneous/RB1- subgroup (median 20 months (95% CI: 15-24)). Patients in the p16 homo/RB1- subgroup showed a significant increase in overall survival (>60 months; P=0.013), which suggests an increase in sensitivity to cytotoxic agents. Analyses of Rb pathway mechanistic differences among these groups revealed frequent RB1 genomic alterations such as RB1 allelic loss and/or large spanning deletions (83%) in the p16 homo/RB1- subgroups, also indicating that RB1 deletions are frequent in high-grade serous carcinoma. CCNE1 gene gains/amplifications were frequent in the p16 homogeneous/RB1+ subgroup (68%) and cyclin D1 protein overexpression was predominantly characteristic of the p16 heterogeneous/RB1+ subgroup. These subcategories occur early in tumor progression and are seen with similar frequency in the cancer precursor lesion, serous tubal intra-epithelial carcinoma. Overall, this study uniquely identifies multiple non-synonymous mechanisms of retinoblastoma pathway deregulation that correlate with significantly different clinical

  2. Current Approaches and Challenges in Managing and Monitoring Treatment Response in Ovarian Cancer

    PubMed Central

    Marcus, Charlotte S; Maxwell, G Larry; Darcy, Kathleen M; Hamilton, Chad A; McGuire, William P

    2014-01-01

    Epithelial ovarian cancer is the leading cause of death among gynecologic malignancies. Treatment of recurrent ovarian cancer remains a challenge despite advances in surgical and chemotherapeutic options. A goal of many providers is to detect recurrences as early as possible and initiate treatment though there is controversy as to whether this impacts outcome. Elevations in CA125 and radiological findings may precede symptoms of recurrence by several months. While detection of recurrences by physical exam alone is unusual, a thorough exam in conjunction with reported symptoms and elevated CA125 is sufficient to detect 80-90% of recurrences. A spiral CT scan may be used to confirm recurrence in the setting of asymptomatic CA125 elevation and a PET/CT can yield additional insight if the CT is inconclusive. Initiating chemotherapy prior to the development of symptoms, even in the setting of elevated CA125, does not impact overall survival primarily because the efficacy of available treatments in the recurrent setting is poor. More information about tumor biology and ways to predict which patients will benefit from available treatment options is required. Consequently, the approach to post-treatment surveillance should be individualized taking into account the clinical benefit of the second-line therapy, versus the costs and morbidity of the surveillance method. PMID:24396495

  3. Ovarian responses in Bos indicus heifers treated to synchronise ovulation with intravaginal progesterone releasing devices, oestradiol benzoate, prostaglandin F(2α) and equine chorionic gonadotrophin.

    PubMed

    Butler, S A A; Phillips, N J; Boe-Hansen, G B; Bo, G A; Burns, B M; Dawson, K; McGowan, M R

    2011-12-01

    The objectives were: (i) improve understanding of the ovarian responses of Bos indicus heifers treated with different ovulation synchronisation protocols, (ii) compare ovarian responses of B. indicus heifers treated with intravaginal progesterone releasing device (IPRD)+oestradiol benzoate (ODB) versus a conventional prostaglandin F(2α) (PGF(2α)) protocol and (iii) investigate whether reducing the amount of progesterone (P(4)) in the IPRD, and treatment with equine chorionic gonadotrophin (eCG) would increase the proportion of heifers with normal ovarian function during the synchronised and return cycles. Two-year-old Brahman (n=30) and Brahman-cross (n=34) heifers were randomly allocated to three IPRD-treatment groups: (i) standard-dose IPRD (Cue-Mate(®) 1.56g P(4); n=17); (ii) half-dose IPRD (Cue-Mate(®) 0.78g P(4); n=15); (iii) half-dose IPRD+300IU eCG at IPRD removal (n=14), and a non-IPRD control group (iv) 2×PGF(2α) (500μg cloprostenol) on Days -16 and -2 (n=18). IPRD-treated heifers received 250μg cloprostenol at IPRD insertion (Day -10) and IPRD removal (Day -2) and 1mg ODB on Days -10 and -1. Ovarian function was evaluated by ultrasonography and plasma P(4) throughout the synchronised and return cycles. The mean diameter of the dominant follicle observed at 54-56h after IPRD removal, was greater for heifers which ovulated than heifers which did not ovulate (P<0.001; 14.5±1.1 vs. 9.3±0.6mm, respectively). The prevalence of IPRD-treated heifers with ovarian dysfunction (persistent CL, failure to re-ovulate, shortened luteal phase) was 39%. This relatively high prevalence of ovarian dysfunction may explain the commonly reported, lower than expected pregnancy rates to FTAI in B. indicus heifers treated to synchronise ovulation.

  4. Family History of Breast Cancer as a Determinant of the Risk of Developing Endometrial and Ovarian Cancers: A Nationwide Cohort Study

    DTIC Science & Technology

    2002-01-01

    associated with reduced risk. Aside from its association with hereditary nonpolyposis colorectal cancer (HNPCC), and probably Cowden=s syndrome , the...HBOC) syndrome (Lynch et al., 1981; Prior and Waterhouse, 1981). Inherited mutations in the genes BRCA1 and BRCA2 are responsible for most (80-90...addressed familial aggregations of breast cancer and ovarian cancer and, in the context of the HBOC syndrome , a shared genetic etiology has been

  5. Ovarian Tumor (OTU)-domain Containing Viral Proteases Evade Ubiquitin- and ISG15-dependent Innate Immune Responses

    PubMed Central

    Frias-Staheli, Natalia; Giannakopoulos, Nadia V.; Kikkert, Marjolein; Taylor, Shannon L.; Bridgen, Anne; Paragas, Jason J.; Richt, Juergen A.; Rowland, Raymond R.; Schmaljohn, Connie S.; Lenschow, Deborah J.; Snijder, Eric J.; García-Sastre, Adolfo; Virgin, Herbert Whiting

    2007-01-01

    Summary Ubiquitin (Ub) and interferon stimulated gene product 15 (ISG15) reversibly conjugate to proteins via a conserved LRLRGG C-terminal motif, mediating important innate antiviral responses. The ovarian tumor (OTU) domain represents a superfamily of predicted proteases found in eukaryotic, bacterial and viral proteins, some of which have Ub-deconjugating activity. We show that the OTU domain-containing proteases of nairoviruses and arteriviruses hydrolyze Ub and ISG15 from cellular target proteins. This broad activity contrasts with the target specificity of known mammalian OTU domain-containing proteins. The biological significance of this activity of viral OTU domain-containing proteases was evidenced by their capacity to inhibit NF-κB dependent signaling and to antagonize the antiviral effects of ISG15 during Sindbis virus infection in vivo. The deconjugating activity of viral OTU proteases represents a novel viral immune evasion mechanism that inhibits Ub-and ISG15-dependent antiviral pathways. PMID:18078692

  6. Increased cell survival by inhibition of BRCA1 using an antisense approach in an estrogen responsive ovarian carcinoma cell line

    PubMed Central

    Annab, Lois A; Hawkins, Rebecca E; Solomon, Greg; Barrett, J Carl; Afshari, Cynthia A

    2000-01-01

    Introduction: Germline mutations in the breast and ovarian cancer susceptibility gene BRCA1, which is located on chromosome 17q21, are associated with a predisposition to the development of cancer in these organs [1,2]. No mutations in the BRCA1 gene have been detected in sporadic breast cancer cases, but mutations have been detected in sporadic cases of ovarian cancer [3,4]. Although there is debate regarding the level of cancer risk associated with mutations in BRCA1 and the significance of the lack of mutations in sporadic tumors, it is possible that alterations in the function of BRCA1 may occur by mechanisms other than mutation, leading to an underestimation of risk when it is calculated solely on the basis of mutational analysis. Such alterations cannot be identified until the function and regulation of BRCA1 are better understood. The BRCA1 gene encodes a 220-kDa nuclear phosphoprotein that is regulated in response to DNA damaging agents [5,6,7] and in response to estrogen-induced growth [8,9,10,11]. Germline mutations that cause breast and ovarian cancer predisposition frequently result in truncated and presumably inactive BRCA1 protein [12]. BG-1 cells were derived from a patient with stage III, poorly differentiated ovarian adenocarcinoma [13]. This cell line, which expresses wild-type BRCA1, is estrogen responsive and withdrawal of estrogen results in eventual cell death. Previous studies suggest that BRCA1 is stimulated as a result of estrogen treatment [8,9,10,11], and also that BRCA1 may be involved in the cell death process [14]. Therefore, we examined the effect of reduction of BRCA1 levels in BG-1 cells on the cellular response to hormone depletion as well as estrogen stimulation. The results suggest that reduced levels of BRCA1 correlates with a survival advantage when BG-1 cells are placed under growth-restrictive and hormone-depleted conditions. In optimum growth conditions, significantly reduced levels of BRCA1 correlates with enhanced growth

  7. The effect of age on the ovarian response to gonadotropin and on pregnancy rate in polycystic ovary syndrome.

    PubMed

    Guido, M; Belosi, C; Selvaggi, L; Lattanzi, F; Apa, R; Fulghesu, A M; Lanzone, A

    2003-06-01

    Recent studies have proposed that, in women affected by the polycystic ovary syndrome (PCOS), aging is able to regularize the menstrual cyclicity. To evaluate the ovarian response in PCOS patients according to their age, we studied 33 PCOS patients, 20 of whom with an age ranging from 28 to 34 years (younger PCOS) and 13 ranging from 35 to 45 years (older PCOS). All patients underwent an ovulation induction therapeutic protocol with low-dose recombinant follicle stimulating hormone, for a total of 80 cycles (44 cycles for the younger PCOS group and 36 cycles for the older PCOS group). No significant difference was found between the days of therapy (12.3 +/- 5.4 vs. 13.5 +/- 5.6 days), total amount of drugs (980.7 +/- 568.9 IU vs. 1063.9 +/- 469.5 IU) or ovulation rate (93% vs. 89%) in the two groups. The two groups showed a significant difference in the maximum estradiol level (2053.5 +/- 1497.2 vs. 1269.0 +/- 911.5 pmol/l, p < 0.01), the number of the recruited and preovulatory follicles (1.7 +/- 2.5 vs. 0.64 +/- 0.9, p < 0.05 and 1.7 +/- 1.1 vs. 1.2 +/- 0.5, p < 0.01, respectively) and the pregnancy rate (36% vs. 14%, p < 0.05). In conclusion, our data clearly showed that, also in PCOS, advanced age is a negative prognostic factor in the ovarian response to ovulation induction therapies.

  8. 48 CFR 370.505 - Responsibility determinations.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 48 Federal Acquisition Regulations System 4 2014-10-01 2014-10-01 false Responsibility determinations. 370.505 Section 370.505 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES HHS SUPPLEMENTATIONS SPECIAL PROGRAMS AFFECTING ACQUISITION Acquisitions Under the Buy Indian Act...

  9. 48 CFR 370.505 - Responsibility determinations.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 48 Federal Acquisition Regulations System 4 2013-10-01 2013-10-01 false Responsibility determinations. 370.505 Section 370.505 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES HHS SUPPLEMENTATIONS SPECIAL PROGRAMS AFFECTING ACQUISITION Acquisitions Under the Buy Indian Act...

  10. 48 CFR 370.505 - Responsibility determinations.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 48 Federal Acquisition Regulations System 4 2010-10-01 2010-10-01 false Responsibility determinations. 370.505 Section 370.505 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES HHS SUPPLEMENTATIONS SPECIAL PROGRAMS AFFECTING ACQUISITION Acquisitions Under the Buy Indian Act...

  11. 48 CFR 370.505 - Responsibility determinations.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 4 2011-10-01 2011-10-01 false Responsibility determinations. 370.505 Section 370.505 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES HHS SUPPLEMENTATIONS SPECIAL PROGRAMS AFFECTING ACQUISITION Acquisitions Under the Buy Indian Act...

  12. 48 CFR 370.505 - Responsibility determinations.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 48 Federal Acquisition Regulations System 4 2012-10-01 2012-10-01 false Responsibility determinations. 370.505 Section 370.505 Federal Acquisition Regulations System HEALTH AND HUMAN SERVICES HHS SUPPLEMENTATIONS SPECIAL PROGRAMS AFFECTING ACQUISITION Acquisitions Under the Buy Indian Act...

  13. Reducing the dose of gonadotrophin-releasing hormone agonist on starting ovarian stimulation: effect on ovarian response and in-vitro fertilization outcome.

    PubMed

    Elgendy, M; Afnan, M; Holder, R; Lashen, H; Afifi, Y; Lenton, W; Sharif, K

    1998-09-01

    The aim of this study was to examine if lowering the dose of gonadotrophin-releasing hormone agonist (GnRHa) on starting ovarian stimulation could be beneficial in in-vitro fertilization (IVF) programmes. A total of 64 normally ovulating patients entering an IVF programme were randomized to receive GnRHa (nafarelin acetate/Synarel) as an intranasal spray commencing in the midluteal phase, either at a dosage of 200 microg three times daily until the day of human chorionic gonadotrophin (HCG) administration, or to be reduced to 200 microg twice daily as ovarian stimulation was initiated. Patients in both groups were below 35 years with a body mass index below 30. All patients received three ampoules of Metrodin HP per day. Blood samples were taken on the day of HCG administration to measure luteinizing hormone (LH), oestradiol, and progesterone. LH and oestradiol were found to be significantly higher in the lower Synarel dose group. Our results show that reducing the GnRHa dose during ovarian stimulation in IVF might be beneficial in terms of significantly more oocytes recovered, and significantly greater number of embryos available for transfer and freezing, with no incidence of premature luteinization.

  14. Accommodation stimulus and response determinations with autorefractors.

    PubMed

    Atchison, David A; Varnas, Saulius R

    2017-01-01

    To develop equations for accommodation stimulus and accommodation response with autorefractors when the accommodation stimulus is produced by combinations of object distances and lenses placed in front of eyes, and to give worked examples using these equations. Simple ray tracing was used to determine stimulus and response equations, taking into account the reference positions for targets, for refraction, and for autorefractor readings. Several examples applying equations are provided. Features of these examples include evaluating approximate calculations that have been used previously, demonstrating which equations should be used in different circumstances, how to substitute numbers into equations, how to deal with discrepancies between subjective and objective refraction, and how to deal with astigmatism. Problems associated with measuring accommodation response by placing lenses in front of the eye are discussed. Accurate equations for accommodation stimulus and accommodation response for a range of accommodation stimuli in different setups have been developed. © 2016 The Authors Ophthalmic & Physiological Optics © 2016 The College of Optometrists.

  15. Targeting Ovarian Carcinoma Stem Cells

    DTIC Science & Technology

    2012-05-01

    expertise with expertise in gynecologic oncology /ovarian carcinoma and in animal models of cancer this proposal will: 1) Identify, isolate, and...more numerous differentiated progeny characterizing the malignancy . Although the clinical significance of these cancer stem cells (CSC) has been...the dramatic initial response rates in ovarian carcinoma represent therapeutic effectiveness against the differentiated cancer cells making up the

  16. Molecular Subtyping of Serous Ovarian Tumors Reveals Multiple Connections to Intrinsic Breast Cancer Subtypes

    PubMed Central

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Objective Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Methods Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. Results 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. Conclusions These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast

  17. Molecular subtyping of serous ovarian tumors reveals multiple connections to intrinsic breast cancer subtypes.

    PubMed

    Jönsson, Jenny-Maria; Johansson, Ida; Dominguez-Valentin, Mev; Kimbung, Siker; Jönsson, Mats; Bonde, Jesper Hansen; Kannisto, Päivi; Måsbäck, Anna; Malander, Susanne; Nilbert, Mef; Hedenfalk, Ingrid

    2014-01-01

    Transcriptional profiling of epithelial ovarian cancer has revealed molecular subtypes correlating to biological and clinical features. We aimed to determine gene expression differences between malignant, benign and borderline serous ovarian tumors, and investigate similarities with the well-established intrinsic molecular subtypes of breast cancer. Global gene expression profiling using Illumina's HT12 Bead Arrays was applied to 59 fresh-frozen serous ovarian malignant, benign and borderline tumors. Nearest centroid classification was performed applying previously published gene profiles for the ovarian and breast cancer subtypes. Correlations to gene expression modules representing key biological breast cancer features were also sought. Validation was performed using an independent, publicly available dataset. 5,944 genes were significantly differentially expressed between benign and malignant serous ovarian tumors, with cell cycle processes enriched in the malignant subgroup. Borderline tumors were split between the two clusters. Significant correlations between the malignant serous tumors and the highly aggressive ovarian cancer signatures, and the basal-like breast cancer subtype were found. The benign and borderline serous tumors together were significantly correlated to the normal-like breast cancer subtype and the ovarian cancer signature derived from borderline tumors. The borderline tumors in the study dataset, in addition, also correlated significantly to the luminal A breast cancer subtype. These findings remained when analyzed in an independent dataset, supporting links between the molecular subtypes of ovarian cancer and breast cancer beyond those recently acknowledged. These data link the transcriptional profiles of serous ovarian cancer to the intrinsic molecular subtypes of breast cancer, in line with the shared clinical and molecular features between high-grade serous ovarian cancer and basal-like breast cancer, and suggest that biomarkers and

  18. DcR3 binds to ovarian cancer via heparan sulfate proteoglycans and modulates tumor cells response to platinum with corresponding alteration in the expression of BRCA1

    PubMed Central

    2012-01-01

    Background Overcoming platinum resistance is a major obstacle in the treatment of Epithelial Ovarian Cancer (EOC). In our previous work Decoy Receptor 3 (DcR3) was found to be related to platinum resistance. The major objective of this work was to define the cellular interaction of DcR3 with EOC and to explore its effects on platinum responsiveness. Methods We studied cell lines and primary cultures for the expression of and the cells ability to bind DcR3. Cells were cultured with DcR3 and then exposed to platinum. Cell viability was determined by MTT assay. Finally, the cells molecular response to DcR3 was studied using real time RT-PCR based differential expression arrays, standard RT-PCR, and Western blot. Results High DcR3 in the peritoneal cavity of women with EOC is associated with significantly shorter time to first recurrence after platinum based therapy (p = 0.02). None-malignant cells contribute DcR3 in the peritoneal cavity. The cell lines studied do not secrete DcR3; however they all bind exogenous DcR3 to their surface implying that they can be effected by DcR3 from other sources. DcR3s protein binding partners are minimally expressed or negative, however, all cells expressed the DcR3 binding Heparan Sulfate Proteoglycans (HSPGs) Syndecans-2, and CD44v3. DcR3 binding was inhibited by heparin and heparinase. After DcR3 exposure both SKOV-3 and OVCAR-3 became more resistant to platinum with 15% more cells surviving at high doses. On the contrary CaOV3 became more sensitive to platinum with 20–25% more cell death. PCR array analysis showed increase expression of BRCA1 mRNA in SKOV-3 and OVCAR-3 and decreased BRCA1 expression in CaOV-3 after exposure to DcR3. This was confirmed by gene specific real time PCR and Western blot analysis. Conclusions Non-malignant cells contribute to the high levels of DcR3 in ovarian cancer. DcR3 binds readily to EOC cells via HSPGs and alter their responsiveness to platinum chemotherapy. The paradoxical responses seen

  19. Determination of the spectral dependence of reduced scattering and quantitative second-harmonic generation imaging for detection of fibrillary changes in ovarian cancer

    NASA Astrophysics Data System (ADS)

    Campbell, Kirby R.; Tilbury, Karissa B.; Campagnola, Paul J.

    2015-03-01

    Here, we examine ovarian cancer extracellular matrix (ECM) modification by measuring the wavelength dependence of optical scattering measurements and quantitative second-harmonic generation (SHG) imaging metrics in the range of 800-1100 nm in order to determine fibrillary changes in ex vivo normal ovary, type I, and type II ovarian cancer. Mass fractals of the collagen fiber structure is analyzed based on a power law correlation function using spectral dependence measurements of the reduced scattering coefficient μs' where the mass fractal dimension is related to the power. Values of μs' are measured using independent methods of determining the values of μs and g by on-axis attenuation measurements using the Beer-Lambert Law and by fitting the angular distribution of scattering to the Henyey-Greenstein phase function, respectively. Quantitativespectral SHG imaging on the same tissues determines FSHG/BSHG creation ratios related to size and harmonophore distributions. Both techniques probe fibril packing order, but the optical scattering probes structures of sizes from about 50-2000 nm where SHG imaging - although only able to resolve individual fibers - builds contrast from the assembly of fibrils. Our findings suggest that type I ovarian tumor structure has the most ordered collagen fibers followed by normal ovary then type II tumors showing the least order.

  20. Levels of Distress in Women at Risk for Ovarian Cancer

    DTIC Science & Technology

    2008-01-01

    subjective risk status, their knowledge of ovarian cancer and risk factors, uncertainty about ovarian cancer, levels of anxiety and depression ...behaviors, anxiety, depression 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF RESPONSIBLE PERSON...their subjective risk status, their knowledge of ovarian cancer and risk factors, uncertainty about ovarian cancer, levels of anxiety and depression

  1. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    2000-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...potent apoptotic effect on ovarian epithelial cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women...A chemoprevention trial is ongoing in chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

  2. Ovarian response to gonadotropin treatment initiated relative to wave emergence in ultrasonographically monitored ewes.

    PubMed

    Rubianes, E; Ungerfeld, R; Viñoles, C; Rivero, A; Adams, G P

    1997-06-01

    Follicular recruitment and luteal response to superovulatory treatment initiated relative to the status of the first wave of the ovine estrous cycle (Wave 1) were studied. All ewes (n = 25) received an intravaginal progestagen sponge to synchronize estrous cycles, and ewes were monitored daily by transrectal ultrasonography. Multiple-dose FSH treatment (total dose = 100 mg NIH-FSH-P1) was initiated on the day of ovulation (Day 0 group) in 16 ewes. In the remaining 9 ewes, FSH treatment was started 3 d after emergence of the largest follicle of Wave 1 (Day 3 group). Ewes received PGF(2alpha) with the last 2 FSH treatments to induce luteolysis. Daily blood samples were taken to determine progesterone profiles and to evaluate the luteal response subsequent to superovulation. The ovulation rate was determined by ultrasonography and correlated with direct observation of the ovaries during laparotomy 5 to 6 d after superovulatory estrus when the uterus was flushed to collect embryos. Results confirmed that follicular recruitment was suppressed by the presence of a large, growing follicle. In the Day 0 and Day 3 groups, respectively, mean numbers (+/- SEM) of large follicles (>/= 4 mm) recruited were 6.4 +/- 0.6 and 2.7 +/- 0.7 (P < 0.01) at 48 h after the onset of treatment, and 6.7 +/- 0.5 and 5.1 +/- 0.6 (P = 0.08) at 72 h after the onset of treatment. Ovulation rates were 5.6 +/- 0.8 and 3.3 +/- 0.8 in the respective groups (P < 0.05). The number of transferable embryos was 1.8 +/- 0.5 and 0.3 +/- 0.2 in the respective groups (P < 0.05). Short luteal phases (response in ewes. Response was influenced by the status of the follicular wave. The presence of a large growing follicle

  3. Non-monotonic dose-response effect of bisphenol A on rare minnow Gobiocypris rarus ovarian development.

    PubMed

    Zhang, Yingying; Tao, Shiyu; Yuan, Cong; Liu, Yan; Wang, Zaizhao

    2016-02-01

    Bisphenol A (BPA) is widely spread in the environment, and can cause various reproductive disrupting effects on different organisms, including fish. Our previous published study showed that BPA has non-monotonic (inverted U-shaped) dose-response effect on rare minnow Gobiocypris rarus ovarian weight at different concentrations. To investigate the potential mechanism, we exposed female rare minnow to 1, 15 and 225 µg L(-1) BPA for 7 days in the present study. The levels of vitellogenin (Vtg), sex hormones, hydrogen peroxide (H2O2), glutathione (GSH) and triglyceride (TG) were measured. RNA-seq of ovary tissues was also performed. Result showed that Vtg, sex hormone and TG levels showed an inverted U-shaped increased response, while H2O2 and GSH levels showed a U-shaped inhibited response. RNA-seq data showed that many genes involved in lipid metabolism, oxidative stress, and proteolysis processes were altered. The change of Vtg, H2O2, GSH and TG levels was possibly related to the altered sex hormone levels. Sex hormone's direct effect, Vtg accumulation, TG accumulation and oxidative stress induced proteolysis may contribute to the change of ovary weight.

  4. Development of persistent ovarian follicles during synchronization of estrus influences the superovulatory response to FSH treatment in cattle.

    PubMed

    Wehrman, M E; Fike, K E; Kojima, F N; Bergfeld, E G; Cupp, A S; Mariscal, V; Sanchez, T; Kinder, J E

    1996-02-01

    The synchronization of estrus with synthetic progestins or progesterone (P(4)) results in the development of a large, persistent ovarian follicle. The objectives of the present study were to determine if development of a persistent ovarian follicle during synchronization of estrus suppresses recruitment of additional follicles during FSH treatment. On Day 5 of the estrous cycle (estrus = Day 0), beef cows were treated with 0.5 or 2.0 P(4) releasing intravaginal devices (PRIDs) for 8 d (Experiment 1, n = 20), 5 or 2 d (Experiment 2, n = 44) before initiation of FSH treatment. Prostaglandin F(2alpha) (25 mg) was administered on Days 5 and 6. Superovulation was induced with 24 mg of recombinant bovine FSH (rbFSH, Experiment 1) or 28 mg of FSH-P (Experiment 2) over a 3- or 4-d period, respectively. The PRIDs were removed concurrently with the 5th injection of rbFSH or FSH-P. There was a treatment-by-day interaction (P < 0.001) for the concentration of 17beta-estradiol in cows treated for 8, 5 or 2 d before FSH treatment. In Experiment 1, FSH treatment initiated 8 d after insertion of a 0.5 PRID did not affect the number of CL (6.9 +/- 1.4 vs 6.7 +/- 1.6), ova/embryos (3.7 +/-1.3 vs 3.0 +/- 1.3) and transferable embryos (2.4 +/- 0.9 vs 3.0 +/- 0.9) compared with that of the 2.0 PRIDs. In Experiment 2, FSH treatment initiated 5 d after insertion of a 0.5 PRID decreased the number of CL (4.0 +/- 0.5 vs 8.3 +/- 0.8; P < 0.001), ova/embryos (3.0 +/- 0.6 vs 5.9 +/- 1.2; P < 0.03) and transferable embryos (2.3 +/- 0.6 vs 5.1 +/- 1.0; P < 0.03) compared with that of a 2.0 PRID, respectively. Initiation of FSH treatment 2 d after insertion of a 0.5 PRID compared with a 2.0 PRID had no affect on the number of CL (8.0 +/- 2.1 vs 8.7 +/- 1.2), total ova (4.8 +/- 1.4 vs 6.9 +/- 1.4) and transferable embryos (2.9 +/- 1.2 vs 6.1 +/- 1.7). In conclusion, treatment with low doses of P(4) (0.5 PRID) for 5 d but not for 2 or 8 d before initiation of FSH treatment results in the

  5. Trophinin is a potent prognostic marker of ovarian cancer involved in platinum sensitivity.

    PubMed

    Baba, Tsukasa; Mori, Seiichi; Matsumura, Noriomi; Kariya, Masatoshi; Murphy, Susan K; Kondoh, Eiji; Kusakari, Takashi; Kuroda, Hideki; Mandai, Masaki; Higuchi, Toshihiro; Takakura, Kenji; Fukuda, Michiko N; Fujii, Shingo

    2007-08-24

    Ovarian cancer is the leading cause of death in women with gynecological malignancies, with prognosis of advanced stage tumors determined by chemotherapeutic response and the success of tumor resection. Since aberrant RAS pathway activation is frequent in ovarian cancer, study of in vitro RAS-induced transformation and accompanying genomic expression changes in ovarian surface epithelial cells is imperative for development of new therapeutic modalities and for understanding tumorigenesis. cDNA microarray analysis revealed TROPHONIN (TRO), a homophilic adhesion molecule involved in blastocyst implantation, was among the genes most downregulated by RAS induction. TRO expression is higher in cisplatin-sensitive cancer cell lines and positively correlates with prognoses in ovarian cancers. TRO knockdown by RNA interference conferred cisplatin resistance and led to increased invasiveness of cultured ovarian cancer cells. These findings underscore the importance of TRO in tumorigenesis, and suggest that TRO may be a useful biomarker for cisplatin sensitivity and invasive potential.

  6. Pulmonary papillary serous adenocarcinoma with intraperitoneal and ovarian tumors: identification of primary site. A case report.

    PubMed

    Chen, M-Y; Jung, S-M; Ng, K-K; Chang, T-C

    2006-01-01

    Papillary serous adenocarcinoma has been recognized as a highly malignant ovarian cancer and is also not uncommonly seen in primary lung cancer. Difficulty may exist in determining the origin of the primary tumor in women with synchronous pulmonary and ovarian tumors. We present a patient who was initially diagnosed and treated as stage IV papillary serous ovarian cancer with diffuse pulmonary metastases. Only transient symptomatic improvement was achieved after standard chemotherapy for ovarian cancer, and then she died of respiratory distress during treatment. Poor tumor response to chemotherapy prompted us to reevaluate the previous bronchoscopic biopsy, and immunohistochemical studies, which were cytokeratin (CK) 7 positive, CK20 negative, and thyroid transcription factor-1 (TTF-1)-positive, provided irrefutable evidences for the diagnosis of primary lung cancer. We suggest that in dealing with coexistence of ovarian and pulmonary tumors, immunohistochemical study by using CK7, CK20, and TTF-1 may be helpful in the differentiation of the primary origin.

  7. Validation of Electrochemiluminiscence Immunoassay for Ovarian Steroid Determination in Rhinella arenarum.

    PubMed

    Arias Torres, Ana Josefina; Páez, José Bernardino; Zelarayán, Liliana Isabel

    2016-04-01

    In this work, we describe the validation of an electrochemiluminescence immunoassay (ECLIA) that allowed us for the first time to determine the levels of progesterone (P4 ) and testosterone (T) secreted by Rhinella arenarum follicles during the preovulatory (POP) and reproductive (RP) periods. We also verified the relation between P4 and T levels and oocyte maturation. Moreover, we demonstrated that the extraction protocol developed for the determinations of P4 and T by ECLIA proved to be efficient and reproducible since the efficacy of the extraction was above 95% in all assays conducted. The results indicate that in the validation process the variation coefficient (CV) between assays is compatible with the analytical procedures based on automated immunoassays (CV < 8%) and that the adaptation proposed for the samples allows the determination of T and P4 with the Cobas e-411 analyzer. Our results indicate that in basal conditions the levels of T released by R. arenarum follicles were higher than those of P4 during POP and RP. In these conditions, steroid secretion failed to induce germinal vesicle break down (GVBD) in the follicles. Under gonadotropin stimulation, steroidogenesis showed a remarkable increase in both periods, especially during POP. This increase was correlated with a high maturation percentage in the follicles incubated in vitro (GVBD = 72 ± 16%) during POP. During RP, human Chorionic Gonadotropin (hCG) induced 81.75 ± 9.1% GVBD. This study is the first report of the seasonal steroidogenic activity in the ovary of R. arenarum in situ using an ECLIA-modified protocol developed in our laboratory.

  8. UCA1 overexpression predicts clinical outcome of patients with ovarian cancer receiving adjuvant chemotherapy.

    PubMed

    Zhang, Ling; Cao, Xili; Zhang, Liqian; Zhang, Xuelin; Sheng, Haihui; Tao, Kun

    2016-03-01

    Urothelial carcinoma associated 1 (UCA1) functions as an oncogene, which promotes cancer cell proliferation, invasion, and metastasis, and is responsible for drug resistance. This study aimed to determine the expression level of UCA1 in ovarian cancer and to further investigate its clinical significance. The expression levels of UCA1 in ovarian cancer and normal ovaries were determined by quantitative real-time PCR. The relationship between UCA1 expression and clinical features and the prognostic value of UCA1 for overall survival were examined. UCA1 expression in ovarian cancer tissues was significantly upregulated compared with normal ovarian tissues. High UCA1 expression was related to lymph node metastasis, FIGO stage, and response to chemotherapy. Kaplan-Meier analysis demonstrated that high UCA1 expression was associated with poorer overall survival in patients with ovarian cancer. Cox proportional hazards analysis showed that high UCA1 expression was an independent prognostic marker of poor outcome. This effect remained significant in the further stratification analysis. Our findings provided the first evidence that UCA1 may serve as an indicator of response to chemotherapy and prognosis of ovarian cancer. UCA1 may play an important role in the progression of ovarian cancer.

  9. Ovarian blood flow responses to electroacupuncture stimulation depend on estrous cycle and on site and frequency of stimulation in anesthetized rats.

    PubMed

    Stener-Victorin, Elisabet; Fujisawa, Shigeko; Kurosawa, Mieko

    2006-07-01

    Electroacupuncture (EA) applied to the abdomen and hindlimb modulates the ovarian blood flow (OBF) response. The present study aimed to further elucidate the role of the site and the frequency of short-term EA stimulation and the influence of the estrous cycle on the OBF response using anesthetized rats. EA stimulation was applied to the abdominal or the hindlimb muscles at three different frequencies (2, 10, and 80 Hz) during the estrus or diestrus phase. Involvement of spinal and supraspinal reflexes in OBF responses to EA stimulation was investigated by spinal cord transection. Abdominal EA stimulation at 10 Hz increased the OBF response, whereas hindlimb EA stimulation at 10 Hz and abdominal and hindlimb stimulation at 80 Hz decreased the OBF response; 2-Hz EA caused no OBF response. The OBF response to abdominal EA was more pronounced in the estrus than the diestrus phase. The OBF response to abdominal and hindlimb EA stimulation at both 10 and 80 Hz was almost abolished, both after severance of the sympathetic nerves and after spinal cord transection. In conclusion, the OBF response to both abdominal and hindlimb EA stimulation was mediated as a reflex response via the ovarian sympathetic nerves, and the response was controlled via supraspinal pathways. Furthermore, the OBF response to segmental abdominal EA stimulation was frequency dependent and amplified in the estrous phase.

  10. High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.

    PubMed

    Gorodnova, Tatiana V; Sokolenko, Anna P; Ivantsov, Alexandr O; Iyevleva, Aglaya G; Suspitsin, Evgeny N; Aleksakhina, Svetlana N; Yanus, Grigory A; Togo, Alexandr V; Maximov, Sergey Ya; Imyanitov, Evgeny N

    2015-12-28

    Preoperative therapy provides an advantage for clinical drug assessment, as it involves yet untreated patients and facilitates access to the post-treatment biological material. Testing for Slavic founder BRCA mutations was performed for 225 ovarian cancer (OC) patients, who were treated by platinum-based neoadjuvant therapy. 34 BRCA1 and 1 BRCA2 mutation carriers were identified. Complete clinical response was documented in 12/35 (34%) mutation carriers and 8/190 (4%) non-carriers (P = 0.000002). Histopathologic response was observed in 16/35 (46%) women with the germ-line mutation versus 42/169 (25%) patients with the wild-type genotype (P = 0.02). Somatic loss of heterozygosity (LOH) for the remaining wild-type BRCA1 allele was detected only in 7/24 (29%) post-neoadjuvant therapy residual tumor tissues as compared to 9/11 (82%) BRCA1-associated OC, which were not exposed to systemic treatment before the surgery (P = 0.009). Furthermore, comparison of pre- and post-treatment tumor material obtained from the same patients revealed restoration of BRCA1 heterozygosity in 2 out of 3 sample pairs presenting with LOH at diagnosis. The obtained data confirm high sensitivity of BRCA-driven OC to platinating agents and provide evidence for a rapid selection of tumor cell clones without LOH during the course of therapy.

  11. Emergency response determinants confirm situation status

    SciTech Connect

    Wray, T.K.

    1993-08-01

    Since introducing the Hazardous Waste Operations and Emergency Response (HAZWOPER) standard in December 1986, OSHA has received hundreds of letters requesting clarification of emergency response.'' To facilitate more efficient access to policy interpretations, the agency's Directorate of Compliance Programs has created interpretive quips (IQs), which are abstracted from OSHA letters and memoranda, and, therefore, represent agency policy. IQ language can be incorporated into new letters of interpretation or provided as technical guidance during telephone inquiries. However, IQs are no substitute for provisions of the 1970 OSHAct. To maintain consistency, OSHA prepares a compliance guidance document (CPL) on particular standards. The agency usually prepares CPLs for performance-oriented standards, such as hazard communication, lockout/tagout, confined space entry and, of course, HAZWOPER. CPLs are detailed documents delineating how OSHA determines whether a company is in compliance with the provisions of a particular standard. The agency has developed several CPLs but only recently has created IQs.

  12. Ovarian dynamics in response to two modified intravaginal progesterone releasing device and oestradiol benzoate based ovulation synchronisation protocols designed for use in Brahman heifers.

    PubMed

    Edwards, S A A; Atkinson, P C; Satake, N; Boe-Hansen, G; McGowan, M R

    2014-07-01

    The objective was to investigate the ovarian response of Brahman heifers to two modified ovulation synchronisation protocols developed to increase the proportion of normal synchronous ovulations. Experiment 1 characterised the growth of the ovulatory follicle in heifers (n=19) treated with an intravaginal progesterone releasing device (IPRD) and oestradiol benzoate (ODB), to determine the optimal time to induce ovulation. Using the findings from Experiment 1, Experiment 2 investigated the effect of reducing the duration of IPRD insertion and increasing the interval from IPRD removal to ODB treatment (modified protocol 1 - OPO-6; n=20), and omitting ODB treatment at the time of IPRD insertion (modified protocol 2 - PO-6; n=20). An IPRD (0.78 g progesterone) was inserted at Day 0 (OPO-8) or Day 2 (OPO-6 and PO-6) and all heifers also received 1 mg ODB i.m. Day 8: IPRD removed + 500 μg cloprostenol i.m. At 24 h (OPO-8) and 36 h (OPO-6 and PO-6) post IPRD removal: 1 mg ODB i.m. Fixed-time AI (FTAI) occurred at 54 h for OPO-8 and 72 h for OPO-6 and PO-6, post IPRD removal. After IPRD treatment all OPO-6 and OPO-8 heifers initiated a new follicular wave whereas 25% of PO-6 heifers failed. Diameter of the dominant follicle was larger at FTAI in the PO-6 (11.34 ± 0.50 mm) compared to the OPO-8 protocol (9.74 ± 0.51 mm; P<0.05), but similar to the OPO-6 protocol (10.52 ± 0.51 mm). Proportion of ovulations occurring 12 h prior and 24 h post FTAI was similar for the PO-6 (80%) and OPO-6 (75%) protocols but numerically lower in the OPO-8 heifers (60%). The apparent improvement in ovarian response in heifers treated with the modified protocols needs to be confirmed in larger field studies. Copyright © 2014 Elsevier B.V. All rights reserved.

  13. Plasma concentrations of PGFM and uterine and ovarian responses in early lactation dairy cows fed omega-3 and omega-6 fatty acids.

    PubMed

    Dirandeh, E; Towhidi, A; Pirsaraei, Z Ansari; Hashemi, F Adib; Ganjkhanlou, M; Zeinoaldini, S; Roodbari, A Rezaei; Saberifar, T; Petit, H V

    2013-07-15

    A total of 120 dairy cows were assigned randomly to three diets to determine the effects of omega-6 or omega-3 fatty acid (FA) supplementation on uterine diseases, ovarian responses, and blood concentrations of estradiol, progesterone, and PGFM in lactating Holstein dairy cows. Diets contained either protected palm oil (C), extruded linseed (L), or roasted whole soybeans (S), and they were fed from calving to Day 70 postpartum. Estrous cycles were synchronized and ovarian follicular development was monitored daily for an entire cycle. There were no differences among diets in the incidence of lameness, mastitis, or metritis, but the incidence of clinical endometritis was lower (P < 0.05) in cows fed S (0%) compared with cows fed C (28.2%) and L (20.5%). Uterine involution in cows fed S occurred 3.77 and 2.78 days earlier, respectively, than in those fed C and L. The PGFM response 60 minutes after an oxytocin challenge was highest for cows fed S and lowest for cows fed L. Mean plasma progesterone concentration on Day 15 of the synchronized cycle was higher in cows fed S (14.5 ng/mL) and L (15.0 ng/mL) than in those fed C (12.0 ng/mL). The ovulatory follicle on Day 21 of the estrous cycle (estrous = Day 0) was larger in cows fed S (16.1 ± 0.9 mm) and L (15.7 ± 0.7 mm) compared with cows fed C (13.2 ± 0.87 mm; P = 0.02) but there were no significant differences between cows fed diets S and L. The mean number of small and medium follicles and diameter of subordinate follicle were similar among diets. In conclusion, feeding a source of omega-6 FA can be a strategy to improve uterine health after calving, although a source of omega-3 FA such as L should be fed after uterine involution to decrease PGF2α secretion.

  14. Does thalassemia influence ovarian response? An analysis of 127 cycles involving pre-implantation genetic diagnosis of thalassemia in southern China.

    PubMed

    Yuan, Yuan; Yuan, Xi; Zhou, Canquan

    2016-08-01

    To evaluate the impact of thalassemia carrier status on the response to controlled ovarian stimulation (COS) and outcome of intracytoplasmic sperm injection (ICSI). Seventy couples that both carried a mutation attributed to thalassemia (PGD group) and 57 couples in which only the father was a thalassemia carrier (CON group) were enrolled. All female subjects received long protocol GnRH agonist stimulation and received equivalent doses of recombinant follicle-stimulating hormone and the number of retrieved oocytes and utilisable embryos did not differ significantly. The endometrial thickness at human chorionic gonadotropin (hCG) administration day and the number of transferable embryos was lower in the PGD groups. However, pregnancy outcomes, including the clinical pregnancy rate and ongoing pregnancy rate, did not differ significantly between the two groups per cycle. Ovarian response to COS is not impaired by maternal thalassemia carrier status and embryo biopsy did not impair preimplantation embryo development or pregnancy outcomes.

  15. Steroid Signaling and Temperature-Dependent Sex Determination – Reviewing the Evidence for Early Action of Estrogen during Ovarian Determination in the Red-Eared Slider Turtle (Trachemys scripta elegans)

    PubMed Central

    Ramsey, Mary; Crews, David

    2009-01-01

    The developmental processes underlying gonadal differentiation are conserved across vertebrates, but the triggers initiating these trajectories are extremely variable. The red-eared slider turtle (Trachemys scripta elegans) exhibits temperature-dependent sex determination (TSD), a system where incubation temperature during a temperature-sensitive period of development determines offspring sex. However, gonadal sex is sensitive to both temperature and hormones during this period – particularly estrogen. We present a model for temperature-based differences in aromatase expression as a critical step in ovarian determination. Localized estrogen production facilitates ovarian development while inhibiting male-specific gene expression. At male-producing temperatures aromatase is not upregulated, thereby allowing testis development. PMID:18992835

  16. Role of ghrelin in regulating rabbit ovarian function and the response to LH and IGF-I.

    PubMed

    Sirotkin, Alexander V; Rafay, Ján; Kotwica, Ján; Darlak, Krzysztof; Valenzuela, Francisco

    2009-04-01

    The aim of these in vivo and in vitro studies was to examine the role of ghrelin in the control of plasma hormone concentrations, the proliferation, apoptosis and secretory activity of ovarian granulosa cells and the response of these cells to hormonal treatments. Female rabbits were injected with ghrelin (10 microg/animal/day for one week before ovulation induced by 25IU PMSG and 0.25IU LHRH). On the day of ovulation, blood samples were collected and analyzed for concentrations of progesterone (P(4)), testosterone (T), estradiol (E(2)), estrone-sulphate (ES), insulin-like growth factor I (IGF-I) and leptin (L) by RIA. Some control and ghrelin-treated animals were killed in the periovulatory period, their ovaries were weighed and granulosa cells were isolated and cultured for 2d. Cell proliferation (expression of PCNA) and apoptosis (expression of TdT) were evaluated by immunocytochemistry and TUNEL respectively. Secretion of P(4), T, E(2), IGF-I, and prostaglandin F (PGF) by granulosa cells cultured with and without LH or IGF-I (1, 10 or 100 ng/ml medium) was assessed by RIA. The remaining control and treated animals were kept until parturition, while the number, viability and body weight of pups were recorded. Ghrelin treatment increased rabbit plasma T and decreased ES concentrations but did not influence P(4), E(2), IGF-I or L. Granulosa cells from ghrelin-treated animals showed higher expression of PCNA and lower expression of TdT, than those from control animals. They also secreted less P(4), T, E(2), IGF-I and PGF than granulosa cells from untreated animals. Treatment of cultured granulosa cells with ghrelin (1, 10 or 100 ng/ml medium) either increased (at 1 ng/ml) or decreased (at 10 ng/ml) P(4) secretion, increased (at 100 ng/ml) or decreased (at 10 ng/ml) IGF-I secretion, decreased T (at 1 and 10 ng/ml) and OT (at 1 ng/ml) secretion, and increased (at 100 ng/ml) PGF secretion. LH treatment of cells from control animals stimulated P(4) (at 1 and 10 ng

  17. High-Resolution Mapping of Genomic Imbalance and Identification of Gene Expression Profiles Associated with Differential Chemotherapy Response in Serous Epithelial Ovarian Cancer1*

    PubMed Central

    Bernardini, Marcus; Lee, Chung-Hae; Beheshti, Ben; Prasad, Mona; Albert, Monique; Marrano, Paula; Begley, Heather; Shaw, Patricia; Covens, Al; Murphy, Joan; Rosen, Barry; Minkin, Salomon; Squire, Jeremy A; Macgregor, Pascale F

    2005-01-01

    Abstract Array comparative genomic hybridization (aCGH) and microarray expression profiling were used to subclassify DNA and RNA alterations associated with differential response to chemotherapy in ovarian cancer. Two to 4 Mb interval arrays were used to map genomic imbalances in 26 sporadic serous ovarian tumors. Cytobands 1p36, 1q42-44, 6p22.1-p21.2, 7q32.1-q34 9q33.3-q34.3, 11p15.2, 13q12.2-q13.1, 13q21.31, 17q11.2, 17q24.2-q25.3, 18q12.2, and 21q21.2-q21.3 were found to be statistically associated with chemotherapy response, and novel regions of loss at 15q11.2-q15.1 and 17q21.32-q21.33 were identified. Gene expression profiles were obtained from a subset of these tumors and identified a group of genes whose differential expression was significantly associated with drug resistance. Within this group, five genes (GAPD, HMGB2, HSC70, GRP58, and HMGB1), previously shown to form a nuclear complex associated with resistance to DNA conformation-altering chemotherapeutic drugs in in vitro systems, may represent a novel class of genes associated with in vivo drug response in ovarian cancer patients. Although RNA expression change indicated only weak DNA copy number dependence, these data illustrate the value of molecular profiling at both the RNA and DNA levels to identify small genomic regions and gene subsets that could be associated with differential chemotherapy response in ovarian cancer. PMID:16036111

  18. Differential cellular responses induced by dorsomorphin and LDN-193189 in chemotherapy-sensitive and chemotherapy-resistant human epithelial ovarian cancer cells.

    PubMed

    Ali, Jennifer L; Lagasse, Brittany J; Minuk, Ainsley J; Love, Allison J; Moraya, Amani I; Lam, Linda; Arthur, Gilbert; Gibson, Spencer B; Morrison, Ludivine Coudière; Werbowetski-Ogilvie, Tamra E; Fu, Yangxin; Nachtigal, Mark W

    2015-03-01

    Inherent or acquired drug resistance is a major contributor to epithelial ovarian cancer (EOC) mortality. Novel drugs or drug combinations that produce EOC cell death or resensitize drug resistant cells to standard chemotherapy may improve patient treatment. After conducting drug tolerability studies for the multikinase inhibitors dorsomorphin (DM) and it is structural analogue LDN-193189 (LDN), these drugs were tested in a mouse intraperitoneal xenograft model of EOC. DM significantly increased survival, whereas LDN showed a trend toward increased survival. In vitro experiments using cisplatin (CP)-resistant EOC cell lines, A2780-cp or SKOV3, we determined that pretreatment or cotreatment with DM or LDN resensitized cells to the killing effect of CP or carboplatin (CB). DM was capable of blocking EOC cell cycle and migration, whereas LDN produced a less pronounced effect on cell cycle and no effect on migration. Subsequent analyses using primary human EOC cell samples or additional established EOC cells lines showed that DM or LDN induced a dose-dependent autophagic or cell death response, respectively. DM induced a characteristic morphological change with the appearance of numerous LC3B-containing acidic vacuoles and an increase in LC3BII levels. This was coincident with a decrease in cell growth and the altered cell cycle consistent with DM-induced cytostasis. By contrast, LDN produced a caspase 3-independent, reactive oxygen species-dependent cell death. Overall, DM and LDN possess drug characteristics suitable for adjuvant agents used to treat chemotherapy-sensitive and -resistant EOC.

  19. Oncolytic virotherapy for ovarian cancer.

    PubMed

    Li, Shoudong; Tong, Jessica; Rahman, Masmudur M; Shepherd, Trevor G; McFadden, Grant

    2012-08-01

    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.

  20. 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

  1. 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.

  2. 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 ...

  3. Ovarian Cancer

    MedlinePlus

    ... and getting enough rest can help combat the stress and fatigue of cancer. There's no sure way to prevent ovarian cancer. But certain factors are associated with lower risk: Use of oral contraceptives, especially for more than 10 years Previous ...

  4. Ovarian Cysts

    MedlinePlus

    ... ovarian cysts develop as a result of your menstrual cycle (functional cysts). Other types of cysts are much ... cysts: Follicular cyst. Around the midpoint of your menstrual cycle, an egg bursts out of its follicle and ...

  5. What Determines the Response: Test or Reference?

    NASA Technical Reports Server (NTRS)

    Chukova, S. V.; Ahumada, A. J., Jr.; Null, Cynthia (Technical Monitor)

    1998-01-01

    The stability of sensory memory has been studied by presenting a reference stimulus, a delay, and a test stimulus. As has been pointed out by Lages and Treisman (1998 Vision Research 38 557-572), the usual measure of performance depends only on the effect of test variations on the responses. The Weber fraction characterizing performance is more properly called the test stimulus Weber fraction. We measure the relative contribution of the test and reference to the response by the ratio of the test Weber fraction to the reference Weber fraction. The stimuli were two dark lines on a bright background. Seven reference separations, varying from 9.5 to 16.7 arc min, were intermixed in each run. Interstimulus intervals (ISI) of 50, 200 and 2000 msec and intertrial intervals (ITI) of 500 and 2500 msec were investigated. When the ISI was short (50 or 200 msec), for both ITIs, responses were determined equally by the test and reference. For the long ISI (2000 msec), the reference stimulus contributed less. However, only for the 500 msec ITI (and not for all observers) was the contribution of the reference stimulus negligible, as Treisman's criterion setting theory might suggest.

  6. Baseline clinical predictors of antitumor response to the PARP inhibitor olaparib in germline BRCA1/2 mutated patients with advanced ovarian cancer.

    PubMed

    Rafii, Saeed; Gourley, Charlie; Kumar, Rajiv; Geuna, Elena; Ern Ang, Joo; Rye, Tzyvia; Chen, Lee-May; Shapira-Frommer, Ronnie; Friedlander, Michael; Matulonis, Ursula; De Greve, Jacques; Oza, Amit M; Banerjee, Susana; Molife, L Rhoda; Gore, Martin E; Kaye, Stan B; Yap, Timothy A

    2017-07-18

    The PARP inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP inhibitors, patients with platinum-resistant disease still respond to olaparib. 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib. We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib. PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.

  7. Death by bleomycin pulmonary toxicity in ovarian dysgerminoma with pathologic complete response to chemotherapy. A case report.

    PubMed

    Calzas Rodríguez, Julia; Carmen Juarez Morales, María Del; Casero, Miguel Angel Racionero

    2016-01-01

    With cisplatin-based chemotherapy, most patients with ovarian dysgerminoma will survive long-term. Bleomycin is an important part of ovarian germ cell tumors (OGCT) treatment, and its dose-limiting toxicity is the development of pulmonary toxicity and it is increased in patients older than 40 years. We report the case of an elderly patient with an unresectable ovarian dysgerminoma who received neoadjuvant chemotherapy and who developed fatal bleomycin pulmonary toxicity (BPT) after surgery. A monitoring of pulmonary function is not routinely recommended for detecting BPT, although together with carefully assessment for symptoms or signs suggestive of pulmonary toxicity is the best way to reduce the risk of BPT. The frequency of pulmonary events in older patients makes us to think about the possibility of either reduce the dose of bleomycin or removing it from the BEP in ovarian GCT.

  8. Relationship between the ovarian follicular response at the start of an Ovsynch-TAI program and pregnancy outcome in the Mediterranean river buffalo.

    PubMed

    Neglia, Gianluca; Gasparrini, Bianca; Salzano, Angela; Vecchio, Domenico; De Carlo, Esterina; Cimmino, Roberta; Balestrieri, Anna; D'Occhio, Michael J; Campanile, Giuseppe

    2016-12-01

    The aim of this study was to evaluate the relationship between the ovarian follicular response at the start of the OVsynch-fixed-time artificial insemination (TAI) program and pregnancy outcome in the Mediterranean river buffalo. The study involved 116 pluriparous buffaloes at 118 ± 65 days in milk maintained under commercial conditions on a buffalo dairy enterprise in southern Italy. Synchronization of the stage of the estrous cycle in the Ovsynch-TAI program involves an injection of GnRH on Day 0 (GnRH1), PGF2α on Day 7, and GnRH on Day 9 (GnRH2). Timed artificial insemination is carried out on Day 10. Ovarian ultrasound examinations were undertaken on days 0, 2, 7, 9, 10, and 11 to record total follicles, the dimensions of follicles greater than 0.75 cm, dimensions of the corpus luteum (CL), and the occurrence of ovulation. Blood concentrations of P4 were measured on days 0 and 10 and 10 days after TAI. Pregnancy status was determined on days 27 and 45 after TAI to calculate late embryonic mortality. The data were analyzed by ANOVA and multiple logistic regression. A total of 70 of 116 (60.4%) buffaloes showed ovulation after GnRH1. Buffaloes that ovulated after GnRH1 had a smaller (P < 0.05) area of the ovulatory follicle on Day 0 compared with buffaloes that did not ovulate (1.08 ± 0.1 and 1.29 ± 0.1 cm(2), respectively). The former buffaloes also had a larger (P < 0.05) CL area (1.81 ± 0.1 and 1.51 ± 0.1 cm(2), respectively) and greater (P < 0.05) blood concentrations of P4 (1.84 ± 0.2 and 1.34 ± 0.2 ng/mL, respectively) on Day 0. A larger (P < 0.05) proportion of buffaloes that ovulated after GnRH1 showed regression of the CL after the injection of PGF2α on Day 7 compared with buffaloes that did not ovulate (68 of 69 [98.6%] and 27 of 32 [84.4%], respectively). Buffaloes that ovulated after GnRH1 also had a greater (P < 0.05) ovulation rate after GnRH2 than buffaloes that did not ovulate (65 of 70 [92.8%] and 37 of 46

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

    PubMed

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

    2014-03-18

    The main objective of the present study was to establish the relationships between CA-125 kinetics and tumour size changes during treatment. 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. 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%). 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.

  10. Methamphetamine and Ovarian Steroid Responsive Cells in the Posteriodorsal Medial Amygdala are Required for Methamphetamine-enhanced Proceptive Behaviors

    PubMed Central

    Williams, Katrina M.; Mong, Jessica A.

    2017-01-01

    Methamphetamine (Meth) is a psychomotor stimulant strongly associated with increases in sexual drive and impulse in both men and women. These changes in sexual motivation have a greater impact on women due to their likelihood of facing the greater burden of unplanned pregnancies, as well as increased risk for psychiatric co-morbidities such as depression. We have previously established a rodent model of Meth-induced increases in sexual motivation. Using this model, we have identified the posteriodorsal medial amygdala (MePD) via excitotoxic lesion studies as a necessary nucleus in Meth-facilitated female sexual motivation. While lesion studies give us insight into key nuclei that may be targets of Meth action, such an approach does not give insight into the identity of the specific MePD neurons or neural circuitry involved in Meth-induced increases in proceptive behaviors. Using the DAUN02 inactivation method, a recently established technique for removing behaviorally relevant cell populations, we present evidence that the ovarian steroid/Meth responsive cells in the MePD are necessary for Meth-induced facilitation of proceptive behaviors. These findings form the basis for future work that will allow for the classification of neuronal subtypes involved in the MePD’s modulation of proceptive behavior as well as a stronger understanding of the neurocircuitry of female sexual motivation. PMID:28045134

  11. The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma.

    PubMed

    Stronach, Euan A; Cunnea, Paula; Turner, Christina; Guney, Tankut; Aiyappa, Radhika; Jeyapalan, Senthuran; de Sousa, Camila H; Browne, Alacoque; Magdy, Nesreen; Studd, James B; Sriraksa, Ruethairat; Gabra, Hani; El-Bahrawy, Mona

    2015-10-13

    Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease.

  12. The role of interleukin-8 (IL-8) and IL-8 receptors in platinum response in high grade serous ovarian carcinoma

    PubMed Central

    Stronach, Euan A.; Cunnea, Paula; Turner, Christina; Guney, Tankut; Aiyappa, Radhika; Jeyapalan, Senthuran; de Sousa, Camila H.; Browne, Alacoque; Magdy, Nesreen; Studd, James B.; Sriraksa, Ruethairat; Gabra, Hani; El-Bahrawy, Mona

    2015-01-01

    Platinum based drugs are the cornerstone of chemotherapy for ovarian cancer, however the development of chemoresistance hinders its success. IL-8 is involved in regulating several pro-survival pathways in cancer. We studied the expression of IL-8 and IL-8 receptors in platinum sensitive and resistant cell lines. Using qRT-PCR and immunohistochemistry, both platinum sensitive (PEA1, PEO14) and resistant (PEA2, PEO23) show increased expression of IL-8 and IL-8 receptors. IL-8RA shows nuclear and cytoplasmic expression, whilst IL-8RB is present solely in the cytoplasm. Knockdown of IL-8 increased sensitivity to cisplatin in platinum sensitive and reversed platinum resistance in resistant cell lines, decreased the expression of anti-apoptotic Bcl-2 and decreased inhibitory phosphorylation of pro-apoptotic Bad. IL-8 receptor antagonist treatment also enhanced platinum sensitivity. Nuclear localisation of IL-8RA was only detected in platinum resistant tumours. Inhibition of IL-8 signalling can enhance response in platinum sensitive and resistant disease. Nuclear IL-8RA may have potential as a biomarker of resistant disease. PMID:26267317

  13. The prognostic significance of optimal debulking in the setting of a complete clinical response for advanced ovarian carcinoma patients receiving maintenance chemotherapy.

    PubMed

    Abaid, Lisa N; Goldstein, Bram H; Lopez, Katrina L; Micha, John P; Brown, John V; Rettenmaier, Mark A; Markman, Maurie

    2011-05-01

    We investigated if optimal surgical debulking increases tumor responsiveness to maintenance chemotherapy and improves survival in advanced ovarian cancer patients who previously attained a clinical complete response (CCR) to primary chemotherapy. We retrospectively reviewed 75 advanced ovarian cancer patients, of whom 43 and 32 underwent optimal versus suboptimal cytoreduction, respectively. All patients exhibited a CCR following 6 cycles of paclitaxel and carboplatin and subsequently received maintenance chemotherapy (paclitaxel 135 mg/m(2); q21 days). The median progression free survival (PFS) for the optimally debulked patients was 35 months, compared to 20 months for the suboptimal population (P = 0.003). Moreover, a Cox model analysis revealed that an increased number of maintenance chemotherapy cycles and optimal surgical reduction significantly correlated with favorable patient PFS (P < 0.001). In regard to overall survival (OS), the patients who had optimal cytoreductive surgery exhibited improved OS results compared to the sub-optimal surgery group (42 vs. 27 months; P < 0.001). However, a Cox model analysis indicated that a greater number of maintenance chemotherapy cycles was a surrogate marker for improved OS (P < 0.001), but surgery type was not (P > 0.05). Duration of overall patient follow-up exceeds 41 months. In advanced ovarian cancer patients who achieve a CCR following induction chemotherapy, optimal cytoreduction may confer a greater clinical benefit from a maintenance approach compared to suboptimal cytoreduction.

  14. Predictive values of anti-müllerian hormone, antral follicle count and ovarian response prediction index (ORPI) for assisted reproductive technology outcomes.

    PubMed

    Ashrafi, Mahnaz; Hemat, Mandana; Arabipoor, Arezoo; Salman Yazdi, Reza; Bahman-Abadi, Akram; Cheraghi, Rezvaneh

    2017-01-01

    This prospective study was performed from June 2012 to June 2014 at Royan Institute to compare the predictive values of serum anti-müllerian hormone (AMH), antral follicle count (AFC) and ovarian response prediction index (ORPI) ([AFC × AMH]/age) for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle outcomes. Five hundred and fifty women included in the study with male factor and unexplained infertility were the first candidates for IVF/ICSI cycles. Serum AMH level was measured by a commercial ELISA kit and AFC was calculated by a transvaginal ultrasonography on day 2-3 of the menstrual cycle before starting ovarian stimulation. All women underwent IVF/ICSI cycles using a long standard protocol with gonadotropin-releasing hormone agonist. The receiver operating characteristic curves (ROC) analysis showed that both AMH and AFC were good predictors of ovarian response with an area under the curves (AUC) > 0.75; even it seems that AFC was being a better predictor. Combining these variables is necessary as ORPI will not improve the prediction value. All the variables had poor predictive ability (AUC <0.60) for clinical pregnancy and live birth rates. Logistic regression analysis showed the AMH less than 0.4 ng/ml and quality of transferred embryos were significant predictors for clinical pregnancy rate.

  15. Evaluation of results obtained with corifollitropin alfa after poor ovarian response in previous cycle using recombinant follicular stimulating hormone in the long-term protocol

    PubMed Central

    Salgueiro, Lister L.; Rolim, Juliana R.; Moura, Bernardo R. L.; Machado, Suelen P. P.; Haddad, Carolina

    2016-01-01

    Objective This study evaluated the use of Corifollitropin alfa in patients with previous poor response to recombinant follicle stimulating hormone in long-term protocols using gonadotropin-releasing hormone. Methods Twenty-seven poor responders to previous treatment with the long term protocol using the recombinant follicle stimulating hormone (Group 1) were selected and then submitted to a second attempt using the same long term protocol with Corifollitropin alfa instead of the recombinant follicle stimulating hormone (Group 2). Ovarian down-regulation was achieved using subcutaneous administration of Leuprolide Acetate. Ovarian stimulation was performed with recombinant follicle stimulating hormone until the administration of human chorionic gonadotropin, followed by follicular aspiration (Group 1). Group 2 was submitted to this same protocol using Corifollitropin alfa instead of recombinant follicle stimulating hormone. Results There were significant differences in the number of aspirated oocytes, percentage of mature oocytes, amount of injected oocytes and transferred embryos - with all of these parameters being increased in the Corifollitropin alfa group. In addition, the rates of pregnancy and ongoing pregnancy were also significantly higher in the Corifollitropin alfa group. Conclusion The present study demonstrated that the use of Corifollitropin alfa in the long-term protocol could be a highly effective alternative for patients with poor ovarian response, who were unsuccessful in a previous treatment with In Vitro Fertilization - Intracytoplasmic Sperm Injection. PMID:27584604

  16. Secreted ovarian stromal substance inhibits ovarian epithelial cell proliferation.

    PubMed

    Karlan, B Y; Baldwin, R L; Cirisano, F D; Mamula, P W; Jones, J; Lagasse, L D

    1995-10-01

    Determine the effects of factors secreted by normal human ovarian stroma on the proliferation of benign and malignant ovarian epithelia, in vitro. Primary cultures of normal human ovarian surface epithelium (HOSE), human ovarian stromal tissue (HOST), and epithelial ovarian carcinomas (CSOC) were established from surgical specimens and characterized immunohistochemically using anti-cytokeratin, vimentin, and Factor VIII antibodies. Stroma-conditioned media (SCM) were collected over 3 days from confluent HOST cultures. The SCM were dialyzed, lyophilized, resuspended, and added to HOSE, CSOC, SKOV-3, and Caov-3 ovarian cancer cell cultures and growth inhibitory effects were assayed by MTS and [3H]thymidine uptake. SCM inhibited the growth and DNA synthesis of normal HOSE cells and cancer cells by 79-99% in > 10-cell lines studied to date. The inhibitory effect was rapid in onset with 31-82% reduction in DNA synthesis at 1 hr and approximately 50% return of activity by 23 hr following a 1-hr SCM pulse treatment. The SCM inhibitory activity was not abolished by boiling or by absorption with heparin-agarose. Size exclusion filtration places the molecular weight of the inhibitory substance between 1 and 3 kDa. Neither trypsin nor proteinase K treatments altered the inhibitory activity of SCM, while a Bligh-Dyer organic extraction placed the activity in the aqueous phase. A heat-stable, non-heparin-binding, low-molecular-weight, water-soluble substance secreted by normal ovarian stroma significantly inhibits HOSE and ovarian cancer cell proliferation. Derangements in normal ovarian stroma-epithelial interactions may contribute to growth dysregulation of the surface epithelia and result in ovarian carcinogenesis.

  17. Ovarian biopsy: a non-terminal method to determine reproductive status in giant kokopu, Galaxias argenteus (Gmelin 1789).

    PubMed

    Wylie, M J; Forbes, E L; Lokman, P M

    2013-09-01

    To establish a method of gonad biopsy for ovarian tissue collection in the declining giant kokopu Galaxias argenteus (Gmelin 1789) as an alternative to lethal sampling in order to understand the species' reproductive biology. Six female giant kokopu weighing between 200 and 350 g were caught from the wild in early December of 2009 and transferred to a holding facility (Department of Zoology, University of Otago, Dunedin) where they were kept under a simulated natural photo-thermal regime for 10 months. Fish were repeatedly biopsied for ovarian tissue at near-monthly intervals (mean number of days between biopsies = 33) until ovulation. Ovarian samples were successfully collected from giant kokopu by biopsy for use in downstream analyses. Among a total of 23 biopsy events, a single death occurred when a two-layered suturing approach was used, highlighting the value of this method for study of the reproductive biology of valuable fish. This biopsy method may have implications for veterinary research on fish physiology, pathology, conservation and development, when repeated tissue samples need to be collected over a prolonged period of time or for general surgical manipulations on fish when accessing the coelom. Furthermore, this approach allows the implementation of a more powerful experimental design, as repeated measures reduces the variability of estimates due to the removal of inherent stage differences among individuals.

  18. The pattern of LH secretion and the ovarian response to the 'ram effect' in the anoestrous ewe is influenced by body condition but not by short-term nutritional supplementation.

    PubMed

    Scaramuzzi, R J; Oujagir, L; Menassol, J-B; Freret, S; Piezel, A; Brown, H M; Cognié, J; Fabre Nys, C

    2014-10-01

    In sheep, the 'ram effect' induces out-of-season fertility and good nutrition increases prolificacy. This experiment determined if fatness or short-term nutritional supplementation modified the response to the 'ram effect'. A group of 48 Île-de-France ewes were fed diets that produced groups with body-condition scores (BCS) of >3.0 and <2.0. Within each BCS group animals were supplemented daily with 500g of lupins from Day -5 to Day 0 (ram introduction) resulting in four groups: low BCS, supplemented (n=7) and non-supplemented (n=8) and high BCS, supplemented (n=12) and non-supplemented (n=11). The blood concentrations of glucose and insulin and the LH response to gonadotrophin-releasing hormone (GnRH) were determined. After the 'ram effect' the pattern of LH pulsatility, the LH surge and ovarian responses were analysed. Low BCS ewes had lower glucose and insulin (P<0.001) and supplementation increased both (P≤0.001). The increase in LH induced by GnRH was reduced in low BCS ewes (P=0.015) but it was not affected by supplementation. Similarly, LH pulsatility was reduced in low BCS ewes (P<0.05). The LH surge and ovarian cyclicity were not affected but the follow-up cycle was delayed (P=0.034) and progesterone was reduced (P=0.029) in low BCS ewes. There was an effect of BCS on ovulation rate (P<0.05). These results show that the BCS can modify the response to the 'ram effect' and that supplementation has little effect on this response.

  19. Neoadjuvant Chemotherapy of Ovarian Cancer Results in Three Patterns of Tumor-Infiltrating Lymphocyte Response with Distinct Implications for Immunotherapy.

    PubMed

    Lo, Charlotte S; Sanii, Sanaz; Kroeger, David R; Milne, Katy; Talhouk, Aline; Chiu, Derek S; Rahimi, Kurosh; Shaw, Patricia A; Clarke, Blaise A; Nelson, Brad H

    2017-02-15

    Purpose: Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.Experimental Design: Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (n = 90).Results: Neoadjuvant chemotherapy was associated with increased densities of CD3(+), CD8(+), CD8(+) TIA-1(+), PD-1(+) and CD20(+) TIL. Other immune subsets and factors were unchanged, including CD79a(+) CD138(+) plasma cells, CD68(+) macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3(+) PD-1(+) cells (putative regulatory T cells), IDO-1(+) cells, and PD-L1(+) cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TIL(high) tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL(low) tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL(negative) cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.Conclusions: Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment. Clin Cancer Res; 23(4); 925-34. ©2016 AACR.

  20. [Ovarian carcinoma antigen (CA 125) and ovarian cancer (clinical follow-up and prognostic studies)].

    PubMed

    Göcze, P; Vahrson, H

    1993-04-25

    Serum concentrations of ovarian carcinoma antigen (CA 125) were determined by Abbot CA 125-EIA Monoclonal kit from 66 patients with malignant ovarian tumor. The preoperative serum levels of CA 125 were elevated (> 35.0 IU/ml) in 93% (27/29). After the laparotomy and before the irradiation or chemotherapy in 36% (24/36) of patients had elevated levels. No significant correlation was seen between elevated levels and histology, tumor grade and clinical stage. However, the rate of positive cases were significantly higher in advanced stages than in the 1st stage (p < 0.05). No significant correlation was found between the preoperative levels of CA 125 and the clinical course. The postoperative elevated levels indicated bad prognosis. Good conformity was found between CA 125 levels and the therapy response. Serological follow up revealed a correlation with the clinical course of ovarian carcinoma in 84% (44/52). In patients with tumor progression the CA 125 levels increased before clinical signs of progression with median lead time of 97 days. The second look laparotomy proved, that residual tumor larger than 2 cm of diameter cause elevated levels. Smaller tumors remained marker negatives. CA 125 determination before operation, during and after therapy provide a useful tool in detecting progression and persistence of ovarian carcinoma.

  1. Recurrent ovarian dysgerminoma after laparoscopy.

    PubMed

    Prado, S; Yazigi, R; Garrido, J; Gonzalez, M; Torres, R; Oddo, D

    2006-01-01

    To our knowledge, recurrent dysgerminoma at the site of tumor removal by laparoscopy in a patient with stage IA disease has not been previously reported. A woman with ovarian dysgerminoma treated by laparoscopy and tumor removed through the cul-de-sac recurred the 17 months later at the site of tumor removal. She was successfully treated with etoposide, bleomycin, and cisplatin chemotherapy with complete response. This case illustrates the potential for surgical site implant of an ovarian dysgerminoma; surgeons should follow strict guidelines when performing laparoscopic procedures for ovarian malignancies in order to prevent this type of incident.

  2. Clinical response to antiestrogen therapy in platinum-resistant ovarian cancer patients and the role of tumor estrogen receptor expression status.

    PubMed

    Stasenko, Marina; Plegue, Melissa; Sciallis, Andrew P; McLean, Karen

    2015-02-01

    This study aimed to determine the progression-free interval (PFI) for patients with platinum-resistant ovarian cancer on antiestrogen therapy (AET), and to correlate PFI with tumor estrogen receptor (ER) expression status. This single-institution retrospective cohort study investigated platinum-resistant epithelial ovarian, fallopian tube, and primary peritoneal cancers treated with tamoxifen or an aromatase inhibitor from January 1999 to January 2012. Median PFI was calculated and a 95% confidence interval was constructed by bootstrapping. Relationships of PFI with disease characteristics were examined using 1-way analysis of variance or Pearson correlation. Estrogen receptor status of tumor specimens was assessed by immunohistochemistry. Progression-free interval was compared between ER groups with the Mann-Whitney test. Kaplan-Meier estimate was used to determine overall survival. Ninety-nine patients met inclusion criteria: 77 (78%) received tamoxifen and 22 (22%) an aromatase inhibitor. Patients had a mean of 4 prior chemotherapy regimens (range, 1-14). Median PFI for any AET was 4.0 months (range, 1-49; 95% confidence interval, 3.0-5.0). Progression-free interval was independent of the number of prior treatments and type of AET, but longer with earlier stage at diagnosis. Estrogen receptor status was obtained for 63 patients, 44 were positive and 19 were negative. Progression-free interval was not statistically significant between ER-positive (median, 4.0 months) and ER-negative (median, 2.0 months) tumor status (P = 0.36). This is the largest study to date investigating AET in heavily pretreated, platinum-resistant ovarian cancer patients. The median PFI of 4.0 months is comparable to standard cytotoxic therapies, and some patients with PFI greater than this median interval had ER-negative tumors. Given the limited adverse effects of AET, as well as low cost including oral administration, this treatment should be considered in all patients with platinum

  3. Review: Puberty as a time of remodeling the adult response to ovarian hormones

    PubMed Central

    Blaustein, Jeffrey D.; Ismail, Nafissa; Holder, Mary K.

    2015-01-01

    During pubertal development an animal's response to stress changes and sexual differentiation of the brain and behavior continue. We discovered that particular stressors, shipping from suppliers or an immune challenge with lipopolysaccharide, during the prolonged pubertal period of female mice result in long-term changes in behavioral responsiveness of the brain to estradiol assessed in adulthood. All behaviors influenced by estradiol and/or progesterone that we have studied are compromised by a stressor during pubertal development. Depending on the behavior, immune challenge or shipping from suppliers during pubertal development decreases, eliminates, or even reverses the effects of estradiol. Shipping during this period causes changes in the number of estrogen receptor-immunoreactive cells in key brain areas suggesting one cellular mechanism for this remodeling of the brain's response to hormones. We suggest that particular adverse experiences in girls may cause long-term alterations in the brain's response to estradiol and/or progesterone via activation of the immune system. This in turn could lead to an alteration in any aspect of mental health that is influenced by estradiol. PMID:26004504

  4. Granulosa cell responsiveness to follicle stimulating hormone during early growth of hen ovarian follicles.

    PubMed

    Johnson, A L; Lee, Jeeyoung

    2016-01-01

    In the laying hen ovary, the cyclic recruitment of a follicle represents a process in which a single follicle is selected to enter the rapid growth phase and undergo final maturation prior to ovulation. Published data support the proposal that final differentiation of the granulosa cell (GC) layer commences at the time of follicle selection. This process is characterized by the enhanced capacity for FSH-induced cell signaling via the protein kinase A/cyclic adenosine monophosphate (cAMP) pathway. One consequence of such signaling within the GC layer is the initial capacity for steroidogenesis (predominantly progesterone production) mediated by increased expression of mRNA encoding steroidogenic acute regulatory protein (STAR) and the cholesterol side-chain cleavage enzyme (CYP11A). Prior to selection, the GC layer remains minimally responsive to a 3 h challenge with FSH (10 ng/mL), in vitro, compared to that from the most recently selected 9- to 12-mm follicle. By comparison, when the duration of the cell culture prior to FSH challenge is increased to 18 h, GCs collected from 1- to 2-mm, 3- to 5-mm, and 6- to 8-mm follicles respond to a 3 h FSH challenge by increasing STAR expression and progesterone production, with the greatest response from GCs collected from 6- to 8-mm follicles. Culture with Bone Morphogenetic Protein 6 (BMP6) enhances both CYP11A expression and FSH responsiveness at each stage of development, with the greatest response again occurring in GCs from 6- to 8-mm follicles. Significantly, factors that activate mitogen activated protein kinase (MAPK) or protein kinase C (PKC) signaling prevent the ability of prolonged culture or culture with BMP6 to induce FSH-responsiveness and the initiation of GC differentiation at each stage of development. Collectively, these results provide further support for the hypothesis that prior to follicle selection, inhibitory cell signaling (e.g., MAPK, PKC) maintains the GC layer in an undifferentiated state in

  5. The addition of anti-Müllerian hormone in an algorithm for individualized hormone dosage did not improve the prediction of ovarian response-a randomized, controlled trial.

    PubMed

    Magnusson, Å; Nilsson, L; Oleröd, G; Thurin-Kjellberg, A; Bergh, C

    2017-04-01

    Does the addition of anti-Müllerian hormone (AMH) to a conventional dosage regimen, including age, antral follicle count (AFC) and BMI, improve the rate of targeted ovarian response, defined as 5-12 oocytes after IVF? The addition of AMH did not alter the rate of targeted ovarian response, 5-12 oocytes, or decreased the rate of ovarian hyperstimulation syndrome (OHSS) or cancelled cycles due to poor ovarian response. Controlled ovarian hyperstimulation (COH) in connection with IVF is sometimes associated with poor ovarian response resulting in low pregnancy and live birth rates or leading to cycle cancellations, but also associated with excessive ovarian response, causing an increased risk of OHSS. Even though it is well-established that both AMH and AFC are strong predictors of ovarian response in IVF, few randomized trials have investigated their impact on achieving an optimal number of oocytes. Between January 2013 and May 2016, 308 patients starting their first IVF treatment were randomly assigned, using a computerized randomization program with concealed allocation of patients and in the proportions of 1:1, to one of two dosage algorithms for decisions on hormone starting dose, an algorithm, including AMH, AFC, age and BMI (intervention group), or an algorithm, including only AFC, age and BMI (control group). The study was blinded to patients and treating physicians. Women aged >18 and <40 years, with a BMI above 18.0 and below 35.0 kg/m2 starting their first IVF cycle where standard IVF was planned, were eligible. All patients were treated with a GnRH agonist protocol and recombinant FSH was used for stimulation. The study was performed as a single-centre study at a large IVF unit at a university hospital. The rate of patients having the targeted number of oocytes retrieved was 81/152 (53.3%) in the intervention group versus 96/155 (61.9%) in the control group (P = 0.16, difference: -8.6, 95% CI: -20.3; 3.0). Cycles with poor response (<5 oocytes) were more

  6. The postpartum period in dromedary camels: uterine involution, ovarian activity, hormonal changes, and response to GnRH treatment.

    PubMed

    Derar, R; Ali, A; Al-Sobayil, F A

    2014-12-30

    The aim of the present study was to investigate the time for complete uterine involution and resumption of ovarian activity in postpartum dromedary camels, relative to hormonal changes. A total of six females were examined by ultrasonography twice weekly starting 3d after parturition. GnRH was administered when the follicles reached ≥0.9cm diameter. Blood samples were collected for hormonal analysis. Results revealed that the mean intervals for complete involution of the previously gravid horn, non-gravid horn, and cervix were 34.33±3.9, 29.01±0.81, and 28.71±1.51d, respectively. After GnRH treatment (Days 17-34), five of the six camels had ovulated. The corpus luteum was detected by Day 4.1±1.6 after GnRH treatment and lasted for 6±1.1d. Serum progesterone (P4) was basal and increased only after GnRH treatment. Serum estradiol 17-β (E2) peaked twice: when a large follicle was detected and 8.5±2.8d post-GnRH treatment. The serum FSH pattern was biphasic, with two peaks just before the recruitment of small follicles and 4.67±4.1d after GnRH treatment. The five ovulating females were mated; two conceived after the first service and three after the second service. The interval from calving to conception was 78.16±3.71d. It was concluded that in dromedary camels, involution of the uterus is completed by the 5th week postpartum, these camels are highly responsive to early GnRH treatment, and they can be mated between the 5th and 6th week after parturition with encouraging conception rates.

  7. Human anti-murine antibody responses in ovarian cancer patients undergoing radioimmunotherapy with the murine monoclonal antibody OC-125

    SciTech Connect

    Muto, M.G.; Finkler, N.J.; Kassis, A.I.; Lepisto, E.M.; Knapp, R.C. )

    1990-08-01

    Human anti-murine antibody (HAMA) responses were monitored in 23 patients with recurrent or persistent epithelial ovarian carcinoma undergoing single-dose intraperitoneal radioimmunotherapy (RIT) with the murine monoclonal antibody OC-125. Sera of patients receiving escalating doses of OC-125 F(ab')2 (10-70 mg) radiolabeled with 18 to 141 mCi of iodine-131 were assayed for HAMA by a protein A-based radioimmunoassay. Overall, 70% of patients (16/23) developed HAMA within 10 to 46 days (median = 29) postinfusion, with peak values (23 +/- 6 to 325 +/- 10 micrograms/ml) at 32 to 102 days (median = 38). HAMA was undetectable prior to infusion in all cases and persisted up to 76 weeks. Of patients receiving a dose of 123 mCi or less, 80% (16/20) developed HAMA, whereas in the 140-mCi group, none of the three patients had detectable levels. Two patients in the 140-mCi group demonstrated dose-limiting bone marrow toxicity (severe thrombocytopenia and neutropenia). It is concluded that a single intraperitoneal dose of monoclonal antibody leads to a high incidence of HAMA production. The results also suggest that the likelihood of HAMA formation in patients who either had undergone recent chemotherapy or had received the highest dose of the radioimmunoconjugate is reduced. These observations may be of significance in designing multiple-dose therapy trials as HAMA has been demonstrated to decrease antibody-to-tumor binding and may potentially increase renal, hepatic, and hematologic toxicity associated with radioimmunotherapy.

  8. Characterization and expression profile of the ovarian cytochrome P-450 aromatase (cyp19A1) gene during thermolabile sex determination in pejerrey, Odontesthes bonariensis.

    PubMed

    Karube, Makiko; Fernandino, Juan Ignacio; Strobl-Mazzulla, Pablo; Strüssmann, Carlos Augusto; Yoshizaki, Goro; Somoza, Gustavo Manuel; Patiño, Reynaldo

    2007-11-01

    Cytochrome P450 aromatase (cyp19) is an enzyme that catalyzes the conversion of androgens to estrogens and may play a role in temperature-dependent sex determination (TSD) of reptiles, amphibians, and fishes. In this study, the ovarian P450 aromatase form (cyp19A1) of pejerrey Odontesthes bonariensis, a teleost with marked TSD, was cloned and its expression profile evaluated during gonadal differentiation at feminizing (17 degrees C, 100% females), mixed-sex producing (24 and 25 degrees C, 73.3 and 26.7% females, respectively), and masculinizing (29 degrees C, 0% females) temperatures. The deduced cyp19A1 amino acid sequence shared high identity (>77.8%) with that from other teleosts but had low identity (<61.8%) with brain forms (cyp19A2), including that of pejerrey itself. The tissue distribution analysis of cyp19A1 mRNA in adult fish revealed high expression in the ovary. Semi-quantitative reverse transcription polymerase chain reaction analysis of the bodies of larvae revealed that cyp19A1 expression increased before the appearance of the first histological signs of ovarian differentiation at the feminizing temperature but remained low at the masculinizing temperature. The expression levels at mixed-sex producing temperatures were bimodal rather than intermediate, showing low and high modal values similar to those at the feminizing and masculinizing temperatures, respectively. The population percentages of high and low expression levels at intermediate temperatures were proportional to the percentage of females and males, respectively, and high levels were first observed at about the time of sex differentiation of females. These results suggest that cyp19A1 is involved in the process of ovarian formation and possibly also in the TSD of pejerrey. (c) 2007 Wiley-Liss, Inc.

  9. Characterization and expression profile of the ovarian cytochrome P-450 aromatase (cyp19A1) gene during thermolabile sex determination in Pejerrey, Odontesthes bonariensis

    USGS Publications Warehouse

    Karube, M.; Fernandino, J.I.; Strobl-Mazzulla, P.; Strussmann, C.A.; Yoshizaki, G.; Somoza, G.M.; Patino, R.

    2007-01-01

    Cytochrome P450 aromatase (cyp19) is an enzyme that catalyzes the conversion of androgens to estrogens and may play a role in temperature- dependent sex determination (TSD) of reptiles, amphibians, and fishes. In this study, the ovarian P450 aromatase form (cyp19A1) of pejerrey Odontesthes bonariensis, a teleost with marked TSD, was cloned and its expression profile evaluated during gonadal differentiation at feminizing (17??C, 100% females), mixed-sex producing (24 and 25??C, 73.3 and 26.7% females, respectively), and masculinizing (29??C, 0% females) temperatures. The deduced cyp19A1 amino acid sequence shared high identity (>77.8%) with that from other teleosts but had low identity (<61.8%) with brain forms (cyp19A2), including that of pejerrey itself. The tissue distribution analysis of cyp19A1 mRNA in adult fish revealed high expression in the ovary. Semi-quantitative reverse transcription polymerase chain reaction analysis of the bodies of larvae revealed that cyp19A1 expression increased before the appearance of the first histological signs of ovarian differentiation at the feminizing temperature but remained low at the masculinizing temperature. The expression levels at mixed-sex producing temperatures were bimodal rather than intermediate, showing low and high modal values similar to those at the feminizing and masculinizing temperatures, respectively. The population percentages of high and low expression levels at intermediate temperatures were proportional to the percentage of females and males, respectively, and high levels were first observed at about the time of sex differentiation of females. These results suggest that cyp19A1 is involved in the process of ovarian formation and possibly also in the TSD of pejerrey. ?? 2007 Wiley-Liss, Inc.

  10. MRI in predicting the response of ovarian endometriomas to hormone therapy

    SciTech Connect

    Sugimura, Kazuro; Okizuka, Hiromi; Kaji, Yasushi

    1996-01-01

    Our goal was to investigate the usefulness of MRI in predicting the response of endometriomas to hormone therapy. MRI and laparoscopy at the onset of treatment and follow-up MRI after 6 months of hormone therapy were performed in 21 patients with 49 endometriomas. T1- and T2-weighted images were obtained with a 1.5 T apparatus using a body coil. The lesions were divided into a responder group and a nonresponder group according to whether the lesion size decreased by 50% or not. With MRI, shading was seen in 25 of 27 lesions (93%) from the nonresponder group, but in only 6 of 22 (27%) from the responder group. Low SI rim was seen in 59% of the responders and 89% of the nonresponders. Multiplicity in 68% of the responders and in 85% of the nonresponders and irregularity in 41% of the responders and in 78% of the nonresponders were shown. Multiple logistic analysis revealed shading was the most important factor in prediction of the response to hormone therapy. Shading was an important sign in evaluating the response of endometriomas to hormone therapy. MRI may assist in selecting the appropriate therapy for endometriomas. 16 refs., 3 figs., 2 tabs.

  11. Ovarian responses of dairy buffalo cows to timed artificial insemination protocol, using new or used progesterone devices, during the breeding season (autumn-winter).

    PubMed

    Monteiro, Bruno Moura; de Souza, Diego Cavalcante; Vasconcellos, Guilherme Souza Floriano Machado; Corrêa, Thalita Bueno; Vecchio, Domenico; de Sá Filho, Manoel Francisco; de Carvalho, Nelcio Antonio Tonizza; Baruselli, Pietro Sampaio

    2016-01-01

    This study evaluated the effect of new or used P4 devices on the ovarian responses of dairy buffalo that were administered an estradiol (E2) plus progesterone (P4)-based timed artificial insemination (TAI) protocol during the breeding season. On the first day of the TAI protocol, 142 cows were randomly assigned to receive one of the following: a new device (New; 1.0 g of P4; n = 48); a device that had previously been used for 9 days (Used1x, n = 47); or a device that had previously been used for 18 days (Used2x, n = 47). Ultrasound was used to evaluate the following: the presence of a corpus luteum (CL); the diameter of the dominant follicle (ØDF) during protocol; ovulatory response; and pregnancies per AI (P/AI). Despite similar responses among the treatments, there was a significant positive association of the ØDF during TAI protocol with ovulatory responses and number of pregnancies. In conclusion, satisfactory ovarian responses and a satisfactory pregnancy rate were achieved when grazing dairy buffalo were subjected to the TAI protocol in breeding season, independent of whether a new or used P4 device was used. Furthermore, the presence of the larger follicle was associated with a higher ovulation rate and higher P/AI following TAI.

  12. Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

    PubMed

    Stiff, P J; McKenzie, R S; Alberts, D S; Sosman, J A; Dolan, J R; Rad, N; McCloskey, T

    1994-01-01

    To develop an active high-dose chemotherapy regimen for the treatment of ovarian carcinoma. Due to the rapid development a drug resistance, conventional chemotherapy cures only 20% of patients with advanced disease. However, in vitro data demonstrate a steep dose-response curve to a variety of agents, most notably mitoxantrone. A phase I study of escalated bolus mitoxantrone (10 to 25 mg/m2 x 3) and cyclophosphamide (30 to 50 mg/kg x 3) with a 5-day infusion of carboplatin (1,500 mg/m2) and an autologous bone marrow transplant (ABMT) was performed. Mitoxantrone pharmacokinetics were performed to document levels required to kill platinum-resistant ovarian carcinoma in vitro. We treated 25 patients; the maximum-tolerated total doses (MTD) were 75 mg/m2 for mitoxantrone, 120 mg/kg for cyclophosphamide, and 1,500 mg/m2 for carboplatin. The dose-limiting toxicity was gastrointestinal, with severe diarrhea, ileus, and resulting sepsis. Transient partial deafness was seen in four patients, and acute renal failure (ARF) occurred in one patient at the first dose level, but was eliminated in subsequent patients with aggressive hydration. There were four early deaths due to ARF (n = 1), Legionella pneumonia (n = 1), and sepsis (n = 2). Peak mitoxantrone levels at the MTD were 623 to 2,810 ng/mL, and the area under the curve (AUC) values of the concentration versus time measurements were 560 to 1,700 ng/mL/h. Of 20 assessable patients, 65% responded, with a 45% complete remission (CR) rate. All six of the assessable patients with ovarian cancer responded: CR in five (83%) and partial remission (PR) in one (17%); the CRs have lasted 7 to 30+ months. Responses were also seen in testicular and breast carcinoma. This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

  13. Modulators of Response to Tumor Necrosis-Factor-Related Apoptosis Inducing Ligand (TRAIL) Therapy in Ovarian Cancer

    DTIC Science & Technology

    2010-04-01

    antibody, MORAb-003. Methods: FRα expression was examined in ovarian cell lines (SKOV3ip1, IGROV, HeyA8, A2780-par, and HIO -180) with fluorescence...IGROVand SKOV3ip1 cell lines both expressed high levels of FRα compared with the non-transformed ( HIO -180) cells. HeyA8 and A2780-par cell lines lacked

  14. Maternal obesity is associated with ovarian inflammation and up-regulation of early growth response factor 1

    USDA-ARS?s Scientific Manuscript database

    Obesity impairs reproductive functions through multiple mechanisms, possibly through disruption of ovarian function. We hypothesized that increased adiposity will lead to a pro-inflammatory gene signature and up-regulation of Egr-1 protein in ovaries from obese (OB, n=7) compared to lean (LN, n=10) ...

  15. 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).

  16. Inhibition of Phospho-S6 Kinase, a Protein Involved in the Compensatory Adaptive Response, Increases the Efficacy of Paclitaxel in Reducing the Viability of Matrix-Attached Ovarian Cancer Cells.

    PubMed

    Choi, Jeong In; Park, Sang Hi; Lee, Hee-Jin; Lee, Dae Woo; Lee, Hae Nam

    2016-01-01

    To identify the proteins involved the compensatory adaptive response to paclitaxel in ovarian cancer cells and to determine whether inhibition of the compensatory adaptive response increases the efficacy of paclitaxel in decreasing the viability of cancer cells. We used a reverse-phase protein array and western blot analysis to identify the proteins involved in the compensatory mechanism induced by paclitaxel in HeyA8 and SKOV3 ovarian cancer cells. We used a cell viability assay to examine whether inhibition of the proteins involved in the compensatory adaptive response influenced the effects of paclitaxel on cancer cell viability. All experiments were performed in three-dimensional cell cultures. Paclitaxel induced the upregulation of pS6 (S240/S244) and pS6 (S235/S236) in HeyA8 and SKOV3 cells, and pPRAS40 (T246) in HeyA8 cells. BX795 and CCT128930 were chosen as inhibitors of pS6 (S240/S244), pS6 (S235/S236), and pPRAS40 (T246). BX795 and CCT128930 decreased pS6 (S240/S244) and pS6 (S235/S236) expression in HeyA8 and SKOV3 cells. However, pPRAS40 (T246) expression was inhibited only by BX795 and not by CCT128930 in HeyA8 cells. Compared with paclitaxel alone, addition of BX795 or CCT128930 to paclitaxel was more effective in decreasing the viability of HeyA8 and SKOV3 cells. Addition of BX795 or CCT128930 to inhibit pS6 (S240/S244) or pS6 (S235/S236) restricted the compensatory adaptive response to paclitaxel in HeyA8 and SKOV3 cells. These inhibitors increased the efficacy of paclitaxel in reducing cancer cell viability.

  17. Identification and Functional Characterization of Somatic Mutations in Human MicroRNAs and their Responsive Elements in Target Genes in Ovarian Tumor Tissues

    DTIC Science & Technology

    2009-05-01

    sequenced 50 microRNAs in 75 OC tumor tissues . So far, seven novel somatic mutations were observed in seven primary or precursor miRNA genes. WE...f miRNA m ay be a hallmark of h uman cancers . M iRNA m isexpression m ight be due t o genetic mutations i n miRNA ge nes an d t heir responsive...15. SUBJECT TERMS microRNA ovarian cancer 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME OF

  18. Long-Term Moderate Oxidative Stress Decreased Ovarian Reproductive Function by Reducing Follicle Quality and Progesterone Production

    PubMed Central

    Lai, Zhiwen; Tian, Yong; Fang, Li; Wu, Meng; Xiong, Jiaqiang; Qin, Xian; Luo, Aiyue; Wang, Shixuan

    2016-01-01

    Ovarian aging is a long-term and complex process associated with a decrease in follicular quantity and quality. The damaging effects of reactive oxygen species (ROS) in ovarian aging and ovarian aging-associated disorders have received relatively little attention. Thus, we assessed if the oxidative stress induced by long-term (defined by the Environmental Protection Agency as at least 30 days in duration) moderate ozone inhalation reduced ovarian reserves, decreased ovarian function and induced ovarian aging-associated disorders. The expression of oxidative stress markers and antioxidant enzymes was used to determine the degree of oxidative stress. Ultrastructural changes in ovarian cells were examined via electron microscopy. The ovarian reserve was assessed by measuring multiple parameters, such as the size of the primordial follicle pool and anti-Müllerian hormone (AMH) expression. The estrous cycle, hormone levels and fertility status were investigated to assess ovarian function. To investigate ovarian aging-associated disorders, we utilized bone density and cardiovascular ultrasonography in mice. The levels of oxidized metabolites, such as 8-hydroxy-2´-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE) and nitrotyrosine (NTY), significantly increased in ovarian cells in response to increased oxidative stress. The ultrastructural analysis indicated that lipid droplet formation and the proportion of mitochondria with damaged membranes in granulosa cells were markedly increased in ozone-exposed mice when compared with the control group. Ozone exposure did not change the size of the primordial follicle pool or anti-Müllerian hormone (AMH) expression. The estrogen concentration remained normal; however, progesterone and testosterone levels decreased. The mice exposed to ozone inhalation exhibited a substantial decrease in fertility and fecundity. No differences were revealed by the bone density or cardiovascular ultrasounds. These findings suggest that the

  19. Estrus response and fertility after a single cloprostenol treatment in dairy cows with various ovarian structures

    PubMed Central

    Hatvani, Csilla; Balogh, Orsolya G.; Endrődi, Tamás; Abonyi-Tóth, Zsolt; Holló, István; Kastelic, John P.; Gábor, György

    2013-01-01

    The objective of this study was to determine rates of estrus and conception in lactating multiparous Holstein cows given 500 μg of cloprostenol intramuscularly after detection of the following ≥ 60 d after parturition: a solid corpus luteum (CL), a CL with a nonechodense cavity ≤ 20 mm in diameter (CLcav), a luteal cyst (cavity > 20 mm in diameter and a luteinized wall > 3 mm in diameter), or a follicular cyst (cavity > 20 mm and a luteinized wall ≤ 3 mm in diameter). The estrus rates were 335/419 (80.0%), 183/223 (82.1%), 170/182 (93.4%), and 44/87 (50.6%), respectively (P < 0.0001), and the conception rates 30 to 36 d after insemination among the estrous cows with an apparently normal mucus discharge were 130/285 (45.6%), 44/141 (31.2%), 39/79 (49.4%), and 19/30 (63.3%), respectively (P < 0.002). Compared with a solid CL, a CLcav did not affect the estrus rate but significantly reduced the conception rate (P < 0.05), and the estrus rates were significantly higher and lower in cows with a luteal or follicular cyst, respectively (P < 0.05). PMID:24101799

  20. Estrus response and fertility after a single cloprostenol treatment in dairy cows with various ovarian structures.

    PubMed

    Hatvani, Csilla; Balogh, Orsolya G; Endrődi, Tamás; Abonyi-Tóth, Zsolt; Holló, István; Kastelic, John P; Gábor, György

    2013-07-01

    The objective of this study was to determine rates of estrus and conception in lactating multiparous Holstein cows given 500 μg of cloprostenol intramuscularly after detection of the following ≥ 60 d after parturition: a solid corpus luteum (CL), a CL with a nonechodense cavity ≤ 20 mm in diameter (CLcav), a luteal cyst (cavity > 20 mm in diameter and a luteinized wall > 3 mm in diameter), or a follicular cyst (cavity > 20 mm and a luteinized wall ≤ 3 mm in diameter). The estrus rates were 335/419 (80.0%), 183/223 (82.1%), 170/182 (93.4%), and 44/87 (50.6%), respectively (P < 0.0001), and the conception rates 30 to 36 d after insemination among the estrous cows with an apparently normal mucus discharge were 130/285 (45.6%), 44/141 (31.2%), 39/79 (49.4%), and 19/30 (63.3%), respectively (P < 0.002). Compared with a solid CL, a CLcav did not affect the estrus rate but significantly reduced the conception rate (P < 0.05), and the estrus rates were significantly higher and lower in cows with a luteal or follicular cyst, respectively (P < 0.05).

  1. Investigational Agents in Development for the Treatment of Ovarian Cancer

    PubMed Central

    Westin, Shannon N.; Herzog, Thomas J.; Coleman, Robert L.

    2014-01-01

    Although significant success has been achieved in the treatment of advanced and recurrent ovarian cancer, there is clearly room for improvement. The use of targeted agents in this patient population has the promise to provide improved survival and quality of life. There are a myriad of relevant pathways under exploration in all settings of ovarian cancer. Clinical trial data are accumulating for antiangiogenic therapy, including vascular endothelial growth factor (VEGF)-specific inhibitors and multiple angiogenic signaling target inhibitors, as well as poly-ADP-ribose polymerase (PARP) inhibitors. Other types of tumorigenic pathway inhibitors, including those that target phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR), protein kinase B (AKT), Src, folate receptor alpha, and insulin-like growth factor-1 receptor (IGF-1R) pathways are in earlier phases of development for ovarian cancer. Attempts to target the epidermal growth factor receptor (EGFR) of ovarian tumors have been met with limited success; however, newer agents that inhibit this pathway show promise. Finally, with recognition of the role of Wee-1 in p53-deficient tumors, an inhibitor of this tyrosine kinase is being evaluated in recurrent ovarian cancer. The logistical challenge is to determine the optimal timing and proper combinations of novel agents independently as well as concomitantly with conventional chemotherapeutics. Reported results have been modest; however, our growing understanding of these pathways will be potentially reflected in greater impact on response and survival. PMID:22661305

  2. Ovarian reserve testing: A user's guide.

    PubMed

    Tal, Reshef; Seifer, David B

    2017-02-21

    Ovarian reserve is a complex clinical phenomenon that is influenced by age, genetics and environmental variables. Although it is challenging to predict the rate of an individual's ovarian reserve decline, clinicians are often asked for advice about fertility potential and/or recommendations regarding the pursuit of fertility treatment options. The purpose of this review is to summarize the state-of-the-art of ovarian reserve testing (ORT), providing a guide for the Ob/Gyn generalist and reproductive endocrinologist. The ideal ovarian reserve test should be convenient, reproducible, display little if any intra- and inter-cycle variability and demonstrate high specificity to minimize the risk of wrongly diagnosing women as having diminished ovarian reserve and accurately identify those at greatest risk of developing ovarian hyperstimulation prior to fertility treatment. Evaluation of ovarian reserve can help to identify patients who will have poor response or hyper-response to ovarian stimulation for assisted reproductive technology (ART). Ovarian reserve testing should allow individualization of treatment protocols to achieve optimal response while minimizing safety risks. Ovarian reserve testing may inform patients regarding their reproductive lifespan and menopausal timing as well as aid in the counselling and selection of treatment for female cancer patients of reproductive age who receive gonadotoxic therapy. In addition, it may aid in establishing the diagnosis of polycystic ovary syndrome (PCOS) and provide insight into its severity. While there is currently no perfect ovarian reserve test, both antral follicular count (AFC) and antimullerian hormone (AMH) have good predictive value and are superior to day 3 FSH. The convenience of untimed sampling, age-specific values, availability of an automated platform and potential standardization of AMH assay, make this test the preferred biomarker for the evaluation of ovarian reserve in women.

  3. Biological Basis for Chemoprevention of Ovarian Cancer

    DTIC Science & Technology

    1999-10-01

    Since reduction of ovulation is protective against ovarian cancer, prevention may represent a feasible approach to decreasing mortality . To achieve a...cells, the use of levonorgestrel in chemoprevention of ovarian cancer is being explored in chickens and women. A chernoprevention trial is ongoing in...chickens and we will begin a trial to determine whether levonorgestrel induces apoptosis in the ovarian epithelium of women undergoing oophorectomy.

  4. Sex Reversal in C57BL/6J XY Mice Caused by Increased Expression of Ovarian Genes and Insufficient Activation of the Testis Determining Pathway

    PubMed Central

    Correa, Stephanie M.; Washburn, Linda L.; Kahlon, Ravi S.; Musson, Michelle C.; Bouma, Gerrit J.; Eicher, Eva M.; Albrecht, Kenneth H.

    2012-01-01

    Sex reversal can occur in XY humans with only a single functional WT1 or SF1 allele or a duplication of the chromosome region containing WNT4. In contrast, XY mice with only a single functional Wt1, Sf1, or Wnt4 allele, or mice that over-express Wnt4 from a transgene, reportedly are not sex-reversed. Because genetic background plays a critical role in testis differentiation, particularly in C57BL/6J (B6) mice, we tested the hypothesis that Wt1, Sf1, and Wnt4 are dosage sensitive in B6 XY mice. We found that reduced Wt1 or Sf1 dosage in B6 XYB6 mice impaired testis differentiation, but no ovarian tissue developed. If, however, a YAKR chromosome replaced the YB6 chromosome, these otherwise genetically identical B6 XY mice developed ovarian tissue. In contrast, reduced Wnt4 dosage increased the amount of testicular tissue present in Sf1+/− B6 XYAKR, Wt1+/− B6 XYAKR, B6 XYPOS, and B6 XYAKR fetuses. We propose that Wt1B6 and Sf1B6 are hypomorphic alleles of testis-determining pathway genes and that Wnt4B6 is a hypermorphic allele of an ovary-determining pathway gene. The latter hypothesis is supported by the finding that expression of Wnt4 and four other genes in the ovary-determining pathway are elevated in normal B6 XX E12.5 ovaries. We propose that B6 mice are sensitive to XY sex reversal, at least in part, because they carry Wt1B6 and/or Sf1B6 alleles that compromise testis differentiation and a Wnt4B6 allele that promotes ovary differentiation and thereby antagonizes testis differentiation. Addition of a “weak” Sry allele, such as the one on the YPOS chromosome, to the sensitized B6 background results in inappropriate development of ovarian tissue. We conclude that Wt1, Sf1, and Wnt4 are dosage-sensitive in mice, this dosage-sensitivity is genetic background-dependant, and the mouse strains described here are good models for the investigation of human dosage-sensitive XY sex reversal. PMID:22496664

  5. Endocrine and Ovarian Changes in Response to the Ram Effect in Medroxyprogesterone Acetate-primed Corriedale Ewes During the Breeding and Nonbreeding Season

    PubMed Central

    Ungerfeld, R; Carbajal, B; Rubianes, E; Forsberg, M

    2005-01-01

    Two experiments were performed to determine the endocrine and ovarian changes in medroxyprogesterone acetate (MAP)-primed ewes after ram introduction. Experiment 1 was performed during the mid-breeding season with 71 ewes primed with an intravaginal MAP sponge for 12 days. While the control (C) ewes (n = 35) were in permanent contact with rams, the ram effect (RE) ewes (n = 36) were isolated for 34 days prior to contact with rams. At sponge withdrawal, all ewes were joined with eight sexually experienced marking Corriedale rams and estrus was recorded over the next 4 days. The ovaries were observed by laparoscopy 4–6 days after estrus. Four weeks later, pregnancy was determined by transrectal ultrasonography. In eight ewes from each group, ovaries were ultrasonographically scanned; FSH, LH, and estradiol-17β were measured every 12 hours until ovulation or 96 hours after estrus. The response to the rams was not affected by the fact that ewes had been kept or not in close contact with males before teasing. No differences were found in FSH, LH, estradiol-17β concentrations, growth of the ovulatory follicle, onset of estrus, ovulation rate, or pregnancy rate. Experiment 2 was performed with 14 ewes during the nonbreeding season. Ewes were isolated from rams for 1 month, and received a 6-day MAP priming. Ovaries were ultrasonographically scanned every 12 hours, and FSH, LH, estradiol-17β, and progesterone were measured. Ewes that ovulated and came into estrus had higher FSH and estradiol-17β levels before introduction of the rams than did ewes that had a silent ovulation. The endocrine pattern of the induced follicular phase of ewes that came into estrus was more similar to a normal follicular phase, than in ewes that had a silent ovulation. The follicle that finally ovulated tended to emerge earlier and in a more synchronized fashion in those ewes that did come into estrus. All ewes that ovulated had an LH surge and reached higher maximum FSH levels than ewes

  6. Functional Proteomic Analysis of Advanced Serous Ovarian Cancer using Reverse Phase Protein Array: TGFβ Pathway Signaling Indicates Response to Primary Chemotherapy

    PubMed Central

    Carey, Mark S.; Agarwal, Roshan; Gilks, Blake; Swenerton, Kenneth; Kalloger, Steve; Santos, Jennifer; Ju, Zhenlin; Lu, Yiling; Zhang, Fan; Coombes, Kevin; Miller, Dianne; Huntsman, David; Mills, Gordon B.; Hennessy, Bryan T

    2010-01-01

    Purpose: Using Reverse Phase Protein Array (RPPA) we measured protein expression associated with response to primary chemotherapy in patients with advanced-stage high-grade serous ovarian cancer. Experimental Design: Tumor samples were obtained from forty-five patients with advanced high-grade serous cancers from the Gynecology Tumor Bank at the British Columbia Cancer Agency. Treatment consisted of platinum-based chemotherapy following debulking surgery. Protein lysates were prepared from fresh frozen tumor samples and 80 validated proteins from signaling pathways implicated in ovarian carcinogenesis were measured by RPPA. Normalization of Ca-125 by the 3rd cycle of chemotherapy was chosen as the primary outcome measure of chemotherapy response. Logistic regression was used for multivariate analysis to identify protein predictors of Ca-125 normalization, and Cox regression to test for the association between protein expression and PFS. A significance level of p ≤ 0.05 was used. Results: The mean age at diagnosis was 56.8 years. EGFR, YKL-40 and several TGFβ pathway proteins (c-Jun N-terminal kinase JNK, JNK phosphorylated at residues 183 and 185, PAI-1, Smad3, TAZ) showed significant associations with Ca-125 normalization on univariate testing. On multivariate analysis, EGFR (p < 0.02), JNK (p < 0.01), and Smad3 (p < 0.04) were significantly associated with normalization of Ca-125. Contingency table analysis of pathway-classified proteins revealed that the selection of TGFβ pathway proteins was unlikely due to false discovery (p < 0.007, Bonferroni-adjusted). Conclusion: TGFβ pathway signaling likely plays an important role as a marker or mediator of chemoresistance in advanced serous ovarian cancer. On this basis, future studies to develop and validate a useful predictor of treatment failure are warranted. PMID:20460476

  7. Effects of eCG and FSH on ovarian response, recovery rate and number and quality of oocytes obtained by ovum pick-up in Holstein cows.

    PubMed

    Sendag, Sait; Cetin, Yunus; Alan, Muhammet; Hadeler, Klaus-Gerd; Niemann, Heiner

    2008-06-01

    The goal of the present study was to compare the ovarian response, oocyte yields per animal, and the morphological quality of oocytes collected by ultrasound guided follicular aspiration from Holstein cows treated either with FSH or eCG. Twenty four normal cyclic, German Holstein cows were randomly divided into two groups. Fourteen cows received 3000 IU eCG on day-4 prior to ovum pick-up (OPU) (day 0), 2 days later (day-2), 625 microg cloprostenol was administered. On day-1 GnRH was administered i.m. and 24h later OPU (day 0) was performed. In ten cows a total dose of 500 IU follicle stimulating hormone (Pluset) was administered intramuscularly in a constant dosage for 4 days with intervals of 12h, starting on day-5. Luteolysis was induced by application of 625 microg cloprostenol on day-2. On day-1 (24h after the last FSH treatment) GnRH was administered i.m. and 24h later OPU (day 0) was performed. Ovarian follicles were visualized on the ultrasound monitor, counted and recorded. All visible antral follicles were punctured. Recovered oocytes were graded morphologically based on the cumulus investment. Average follicle number in ovaries was higher in FSH group than eCG group (p<0.05). Oocyte yields per animal did not differ between FSH and eCG groups. The proportion of grade A oocytes was higher in the FSH group in the than eCG group (p<0.05). Likewise, rate of grade C oocytes in FSH group were lower than eCG group (p<0.05). In conclusion, these results suggest that ovarian response, follicle number in ovaries and oocyte quality are affected by the type of gonadotropin and FSH is better alternative than eCG for OPU treatment.

  8. Olaparib monotherapy in patients with advanced relapsed ovarian cancer and a germline BRCA1/2 mutation: a multistudy analysis of response rates and safety.

    PubMed

    Matulonis, U A; Penson, R T; Domchek, S M; Kaufman, B; Shapira-Frommer, R; Audeh, M W; Kaye, S; Molife, L R; Gelmon, K A; Robertson, J D; Mann, H; Ho, T W; Coleman, R L

    2016-06-01

    The PARP inhibitor olaparib (Lynparza™) demonstrates antitumor activity in women with relapsed ovarian cancer and a germline BRCA1/2 mutation (gBRCAm). Data from olaparib monotherapy trials were used to explore the treatment effect of olaparib in patients with gBRCAm ovarian cancer who had received multiple lines of prior chemotherapy. This analysis evaluated pooled data from two phase I trials [NCT00516373 (study 2); NCT00777582 (study 24)] and four phase II trials [NCT00494442 (study 9); NCT00628251 (study 12); NCT00679783 (study 20); NCT01078662 (study 42)] that recruited women with relapsed ovarian, fallopian tube or peritoneal cancer. All patients had a documented gBRCAm and were receiving olaparib 400 mg monotherapy twice daily (capsule formulation) at the time of relapse. Objective response rate (ORR) and duration of response (DoR) were evaluated using original patient outcomes data for patients with measurable disease at baseline. Of the 300 patients in the pooled population, 273 had measurable disease at baseline, of whom 205 (75%) had received ≥3 lines of prior chemotherapy. In the pooled population, the ORR was 36% [95% confidence interval (CI) 30-42] and the median DoR was 7.4 months (95% CI 5.7-9.1). The ORR among patients who had received ≥3 lines of prior chemotherapy was 31% (95% CI 25-38), with a DoR of 7.8 months (95% CI 5.6-9.5). The safety profile of olaparib was similar in patients who had received ≥3 lines of prior chemotherapy compared with the pooled population; grade ≥3 adverse events were reported in 54% and 50% of patients, respectively. Durable responses to olaparib were observed in patients with relapsed gBRCAm ovarian cancer who had received ≥3 lines of prior chemotherapy. NCT00516373; NCT00494442; NCT00628251; NCT00679783; NCT00777582; NCT01078662. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  9. Ovarian cancer immunotherapy: opportunities, progresses and challenges

    PubMed Central

    2010-01-01

    Due to the low survival rates from invasive ovarian cancer, new effective treatment modalities are urgently needed. Compelling evidence indicates that the immune response against ovarian cancer may play an important role in controlling this disease. We herein summarize multiple immune-based strategies that have been proposed and tested for potential therapeutic benefit against advanced stage ovarian cancer. We will examine the evidence for the premise that an effective therapeutic vaccine against ovarian cancer is useful not only for inducing remission of the disease but also for preventing disease relapse. We will also highlight the questions and challenges in the development of ovarian cancer vaccines, and critically discuss the limitations of some of the existing immunotherapeutic strategies. Finally, we will summarize our own experience on the use of patient-specific tumor-derived heat shock protein-peptide complex for the treatment of advanced ovarian cancer. PMID:20146807

  10. Evaluation of Feasibility for a Case-Control Study of Pituitary-Ovarian Function in Premenopausal Women With Breast Cancer

    DTIC Science & Technology

    2006-07-01

    case-control study that uses gonadotropin releasing hormone (GnRH) agonist stimulation tests to compare pituitary -ovarian function in premenopausal women...in responsiveness of ovarian hormones to gonadotropin releasing hormone (GnRH) stimulation in healthy premenopausal women. GnRH stimulation was...determine the safety and feasibility of conducting a case-control study that uses gonadotropin releasing hormone (GnRH) stimulation tests to evaluate

  11. [Ovarian tumors of low malignant potential (borderline ovarian tumors)].

    PubMed

    Luchian, Alina-Mihaela; Pricop, M

    2011-01-01

    Ovarian borderline tumors are rare, their good prognosis depending on their stage at the time of diagnosis, and the presence of invasive implants. There is little information on tumor type identified intra-surgically, as well as on the most favorable treatment in borderline ovarian tumors. To determine the criteria of identification and presurgery and intra-surgery differentiation of the ovarian borderline tumors from the invasive carcinoma and benign ovarian tumors. This study included 54 patients with TPMS (ovarian borderline tumors) surgically treated in the past 22 years (January 1988-December 2009) at the 4th Gynecological Clinic of the lasi "Gr. T. Popa" University of Medicine and Pharmacy. In this interval 1,107 ovarian tumors: 575 benign, 478 malignant, and 54 TPMS (4.87%) were recorded. The age of the patients with borderline tumors ranged between 20 and 78 years, mean age 46 years, and the histological types were: mucinous (27 cases), serous (18 cases), mixed (8 cases), and Brenner tumor (1 case). We have analyzed the distribution of these cases according to the time when surgical treatment was performed. The frequency of borderline ovarian tumors in our study is 4.87%, lower than in the literature. We believe that this low percentage in our study is due to missing the microscopic data in some macroscopic benign tumors. By this research we aimed at elaborating a therapeutic strategy for each case using with discernment the modern treatment (surgery, chemotherapy, radiotherapy), as well as new chemical drugs with the goal of obtaining better results and longer survival. There are no tumor markers which could predict the progression of a borderline ovarian tumor to invasive tumors, but the invasive course is only 0.7%.

  12. Premature Progesterone Rise Positively Correlates with Clinical Pregnancy Rate in In Vitro Fertilization (IVF) and Intracytoplasmic Sperm Injection (ICSI) Patients with good Ovarian Response.

    PubMed

    Cui, Na; Zhang, Jie; Xu, Yueming; Jiang, Lei; Yang, Aimin; Hao, Guimin

    2017-03-28

    Infertility affects millions of couples worldwide resulting in distress and depression. In the past several decades, in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have been developed with high efficiency and success rate. The possible effects of gonadotropin administration on follicular metabolism have been discussed but the outcomes remain controversial. The aim of this study was to identify whether serum progesterone on the day of human chorionic gonadotropin (hCG) administration and the ratio of serum progesterone and the number of oocyte retrieved (P/O) had a predictive role for the outcomes of IVF/ICSI. Eight hundred and twenty-five patients were enrolled between January 2012 and December 2012. A positive correlation between progesterone and IVF/ICSI outcomes were found in patients with good ovarian response using receiver operating characteristic (ROC) curve. We found that when progesterone level was higher than 1.04 ng/ml in good ovarian responses, the implantation rate and clinical pregnancy rate were both reduced compared to the rates in patients exhibiting lower progesterone level (progesterone≤1.04 ng/ml). Moreover, the rise of serum progesterone on the day of hCG was negatively correlated with luteinizing hormone (LH) level. This study used 1.04 ng/ml as a definition of progesterone elevation and an adverse effect of serum progesterone rise was observed on clinical pregnancy rate.

  13. 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.

  14. A controlled comparison of ovarian response to controlled stimulation in first generation Asian women compared with white Caucasians undergoing in vitro fertilisation.

    PubMed

    Lashen, H; Afnan, M; Sharif, K

    1999-05-01

    To compare ovarian response to controlled stimulation among Asian women from the Indian sub-continent and white Caucasian women undergoing in vitro fertilisation (IVF). Nested case-control study. Assisted Conception Unit, Birmingham Women's Hospital. One hundred and eight first generation Asian patients (born in the Indian sub-continent) and 216 white Caucasian controls, all of whom received IVF treatment in the period 1994 to 1997, were selected for the study. The two groups were matched for age to within one year, early follicular phase follicle stimulating hormone, indication for treatment, gonadotrophin dose and year of treatment. The outcome of treatment was not known when the controls were selected. There was no statistically significant difference between the two groups in the duration of stimulation, egg number, number of embryos produced, fertilisation rate, clinical pregnancy rate, miscarriage rate, cycle cancellation rate and implantation rate. Under the same IVF protocol Asian women's response to controlled ovarian stimulation and IVF outcome are comparable to their white Caucasian peers.

  15. Does pre-treatment with micronized progesterone affect the ovarian response to a gonadotropin releasing hormone agonist flare-up protocol?

    PubMed

    Loutradis, D; Stefanidis, K; Drakakis, P; Kallianidis, K; El Sheikh, A; Milingos, S; Siskos, K; Michalas, S

    2003-04-01

    The purpose of this study was to investigate the ovarian response and the receptivity of the endometrium in women pre-treated with micronized progesterone. Eighty-two normogonodotropic women undergoing in vitro fertilization were studied. Thirty received micronized progesterone 1500 mg/day from day 21 of the cycle for a minimum of 2 weeks, and 52 did not receive micronized progesterone (control group). A gonadotropin releasing hormone agonist (GnRH-a) was administered to all the patients in the follicular phase (flare-up). Twenty-five cycles were cancelled for fertilization failure due to male factor, 12 (40%) in the progesterone group and 13 (25%) in the control group (p = 0.271). There was no difference in the number of oocytes retrieved (7.3 +/- 5 vs. 8.2 +/- 4), fertilization rate (50.8% vs. 65%), clinical pregnancy rate (16.6% vs. 25%) or implantation rate (8% vs. 14%). In the progesterone group cases without fertilization, we performed two biopsies to evaluate the receptivity of the endometrium. Pinopode expression was noted 7 days after oocyte retrieval. It seems that the administration of micronized progesterone in the previous cycle does not affect the ovarian response to the combination of follicular phase GnRH-a and gonadotropins, nor the receptivity of the endometrium.

  16. Metabolic Regulation of Ovarian Cancer Cell Death

    DTIC Science & Technology

    2012-07-01

    Following treatment with chemotherapeutic agents, responsive ovarian cancer cells undergo apoptotic cell death . Several groups have shown that the...apoptotic protease, caspase 2 (C2), is an essential activator of cell death in ovarian cancer cells treated with cisplatin and we have found, by knock

  17. Possibilities and limits of ovarian reserve testing in ART.

    PubMed

    La Marca, Antonio; Argento, Cindy; Sighinolfi, Giovanna; Grisendi, Valentina; Carbone, Marilena; D'Ippolito, Giovanni; Artenisio, Alfredo Carducci; Stabile, Gaspare; Volpe, Annibale

    2012-03-01

    Markers of ovarian reserve are associated with ovarian aging as they decline with chronologic age, and hence may predict stages of reproductive aging including the menopause transition. Assessment of ovarian reserve include measurement of serum follicle stimulating hormone (FSH), anti-M�llerian hormone (AMH), and inhibin-B. Ultrasound determination of antral follicle count (AFC), ovarian vascularity and ovarian volume also can have a role. The clomiphene citrate challenge test (CCCT), exogenous FSH ovarian reserve test (EFORT), and GnRH-agonist stimulation test (GAST) are dynamic methods that have been used in the past to assess ovarian reserve. In infertile women, ovarian reserve markers can be used to predict low and high oocyte yield and treatment failure in women undergoing in vitro fertilization. However the markers may have limitations when an in depth analysis of their accuracy, cost, convenience, and utility is performed. As ovarian reserve markers may permit the identification of both the extremes of ovarian stimulation, a possible role for their measurement may be in the individualization of treatment strategies in order to reduce the clinical risk of ART along with optimized treatment burden. It is fundamental to clarify the cost/benefit of its use in the ovarian reserve testing before initiation of an IVF cycle and whether the ovarian reserve markers-determined strategy of ovarian stimulation for assisted conception may be associated to improved live birth rate.

  18. Nasal immunization with inhibin DNA vaccine delivered by attenuated Salmonella choleraesuis for improving ovarian responses and fertility in cross-bred buffaloes.

    PubMed

    Liu, Q; Rehman, Z U; Liu, J J; Han, L; Liu, X R; Yang, L G

    2017-04-01

    This study was conducted to determine the effect of immunization with inhibin DNA vaccine delivered by attenuated Salmonella choleraesuis on ovarian responses and fertility in cross-bred buffaloes. A total of 134 cross-bred buffaloes were divided into four groups: groups T1 (n = 34), T2 (n = 35) and T3 (n = 31) were nasal immunized twice a day with 10 ml of 1 × 10(10)  CFU/ml of the C501 (pVAX-asd-IS) vaccine for 5, 3 and 1 day, respectively. Group C (n = 34) was nasal immunized with 10 ml PBS for 5 days. All animals were immunized twice with an interval of 14 days and administered with 200 μg of a GnRH analogue on day 28, 0.5 mg PGF2α on day 35 and 200 μg of the same GnRH analogue on day 37. TAI was performed at 18 and 24 hr after the second GnRH treatment. Fourteen days after primary immunization, C501 (pVAX-asd-IS) elicited significant immune responses, and anti-inhibin IgG antibody titres in group T1 were significantly higher (p < .01) than groups T3 and C. After the second GnRH treatment, the growth speed of the dominant follicles in group T1 was significantly faster (p < .05) than groups T3 and C. The number and diameter of large follicles (≥10 mm) as well as ovulatory follicles in group T1 were the greatest in all groups, resulting in a greater conception rate in buffaloes with positive anti-inhibin antibodies. These results demonstrate that immunization with the C501 (pVAX-asd-IS) vaccine, coupled with the Ovsynch protocol, could be used as an alternative approach to improve reproductive performance in cross-bred buffaloes.

  19. Relative spectral responsivity determination of photometric detectors

    NASA Astrophysics Data System (ADS)

    Molina, J. C.; Bermudez, J. C.; Hernández-López, J. E.

    2006-02-01

    The experimental evaluation of the relative spectral response of a standard photometer is presented; the measurements were carried out by the substitution method by means a double monochromator in the range of 405 nm to 730 nm with 5 nm resolution wavelength. The experimental uncertainty and its mismatching factor f I' are evaluated as part of the routine procedure to realize the candela unit with trazability to an absolute cryogenic radiometer which is the national standard of radiant flux at CENAM (National Center of Metrology of Mexico).

  20. Associations between hormone receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study

    PubMed Central

    Sieh, Weiva; Köbel, Martin; Longacre, Teri A.; Bowtell, David D.; deFazio, Anna; Goodman, Marc T.; Høgdall, Estrid; Deen, Suha; Wentzensen, Nicolas; Moysich, Kirsten B.; Brenton, James D.; Clarke, Blaise; Menon, Usha; Gilks, C. Blake; Kim, Andre; Madore, Jason; Fereday, Sian; George, Joshy; Galletta, Laura; Lurie, Galina; Wilkens, Lynne R.; Carney, Michael E.; Thompson, Pamela J.; Matsuno, Rayna K.; Kjær, Susanne Krüger; Jensen, Allan; Høgdall, Claus; Kalli, Kimberly R.; Fridley, Brooke L.; Keeney, Gary L.; Vierkant, Robert A.; Cunningham, Julie M.; Brinton, Louise A.; Yang, Hannah P.; Sherman, Mark E.; Garcia-Closas, Montserrat; Lissowska, Jolanta; Odunsi, Kunle; Morrison, Carl; Lele, Shashikant; Bshara, Wiam; Sucheston, Lara; Jimenez-Linan, Mercedes; Blows, Fiona M.; Alsop, Jennifer; Mack, Marie; McGuire, Valerie; Rothstein, Joseph H.; Rosen, Barry P.; Bernardini, Marcus Q.; Mackay, Helen; Oza, Amit; Wozniak, Eva L.; Benjamin, Elizabeth; Gentry-Maharaj, Aleksandra; Gayther, Simon A.; Tinker, Anna V.; Prentice, Leah M.; Chow, Christine; Anglesio, Michael S.; Johnatty, Sharon E.; Chenevix-Trench, Georgia; Whittemore, Alice S.; Pharoah, Paul D. P.; Goode, Ellen L.; Huntsman, David G.; Ramus, Susan J.

    2014-01-01

    Background Ovarian cancer is a lethal disease comprised of distinct histopathological types. There are few established biomarkers of ovarian cancer prognosis, in part because subtype-specific associations may have been obscured in studies combining all subtypes. We examined whether progesterone receptor (PR) and estrogen receptor (ER) protein expression were associated with subtype-specific survival in the international Ovarian Tumor Tissue Analysis (OTTA) consortium. Methods PR and ER were assessed by central immunohistochemical analysis of tissue microarrays for 2933 women with invasive epithelial ovarian cancer from 12 study sites. Negative, weak, and strong expression were defined as positive staining in <1%, 1–50%, and ≥50% of tumor cell nuclei, respectively. Hazard ratios (HRs) for ovarian cancer death were estimated using Cox regression stratified by site and adjusted for age, stage, and grade. Results PR expression was associated with improved survival for endometrioid (EC; p<0·0001) and high-grade serous carcinoma (HGSC; p=0·0006), and ER expression was associated with improved EC survival (p<0·0001); no significant associations were found for mucinous, clear cell, or low-grade serous carcinoma. EC patients with hormone receptor (PR and/or ER) positive (weak or strong) versus negative tumors had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·33; 95% CI, 0·21–0·51; p<0·0001). HGSC patients with strong versus weak or negative tumor PR expression had significantly reduced risk of dying from their disease, independent of clinical factors (HR, 0·71; 95% CI, 0·55–0·91; p=0·0061). Interpretation PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to determine whether hormone receptor status predicts response to endocrine therapy, and can guide personalized treatment for ovarian cancer

  1. Determinants of immunogenic response to protein therapeutics.

    PubMed

    Singh, Satish K; Cousens, Leslie P; Alvarez, David; Mahajan, Pramod B

    2012-09-01

    Protein therapeutics occupy a very significant position in the biopharmaceutical market. In addition to the preclinical, clinical and post marketing challenges common to other drugs, unwanted immunogenicity is known to affect efficacy and/or safety of most biotherapeutics. A standard set of immunogenicity risk factors are routinely used to inform monitoring strategies in clinical studies. A number of in-silico, in vivo and in vitro approaches have also been employed to predict immunogenicity of biotherapeutics, but with limited success. Emerging data also indicates the role of immune tolerance mechanisms and impact of several product-related factors on modulating host immune responses. Thus, a comprehensive discussion of the impact of innate and adaptive mechanisms and molecules involved in induction of host immune responses on immunogenicity of protein therapeutics is needed. A detailed understanding of these issues is essential in order to fully exploit the therapeutic potential of this class of drugs. This Roundtable Session was designed to provide a common platform for discussing basic immunobiological and pharmacological issues related to the role of biotherapeutic-associated risk factors, as well as host immune system in immunogenicity against protein therapeutics. The session included overview presentations from three speakers, followed by a panel discussion with audience participation.

  2. Ovarian Autoantibodies Predict Ovarian Cancer

    DTIC Science & Technology

    2010-11-01

    ovarian adenocarcinomas from laying hens. Gynecol Oncol, 2007; 104: 192-198. 506 25. Hales DB, Zhuge Y, Lagman JA, Ansenberger K, Mahon C, Barua A...Ultrasound Med 2010, 29:173-182. 479 (19) Hales DB, Zhuge Y, Lagman JA, Ansenberger K, Mahon C, Barua A et al: 480 Cyclooxygenases expression and...adenocarcinomas from laying hens. Gynecol Oncol 2007, 507 104:192-198. 508 (30) Ansenberger K, Zhuge Y, Lagman JA, Richards C, Barua A, Bahr JM

  3. MRI reveals the in vivo cellular and vascular response to BEZ235 in ovarian cancer xenografts with different PI3-kinase pathway activity

    PubMed Central

    Cebulla, J; Huuse, E M; Pettersen, K; van der Veen, A; Kim, E; Andersen, S; Prestvik, W S; Bofin, A M; Pathak, A P; Bjørkøy, G; Bathen, T F; Moestue, S A

    2015-01-01

    Background: The phosphoinositide-3 kinase (PI3K) pathway is an attractive therapeutic target. However, difficulty in predicting therapeutic response limits the clinical implementation of PI3K inhibitors. This study evaluates the utility of clinically relevant magnetic resonance imaging (MRI) biomarkers for noninvasively assessing the in vivo response to the dual PI3K/mTOR inhibitor BEZ235 in two ovarian cancer models with differential PI3K pathway activity. Methods: The PI3K signalling activity of TOV-21G and TOV-112D human ovarian cancer cells was investigated in vitro. Cellular and vascular response of the xenografts to BEZ235 treatment (65 mg kg−1, 3 days) was assessed in vivo using diffusion-weighted (DW) and dynamic contrast-enhanced (DCE)-MRI. Micro-computed tomography was performed to investigate changes in vascular morphology. Results: The TOV-21G cells showed higher PI3K signalling activity than TOV-112D cells in vitro and in vivo. Treated TOV-21G xenografts decreased in volume and DW-MRI revealed an increased water diffusivity that was not found in TOV-112D xenografts. Treatment-induced improvement in vascular functionality was detected with DCE-MRI in both models. Changes in vascular morphology were not found. Conclusions: Our results suggest that DW- and DCE-MRI can detect cellular and vascular response to PI3K/mTOR inhibition in vivo. However, only DW-MRI could discriminate between a strong and weak response to BEZ235. PMID:25535727

  4. Tobacco Mosaic Virus-Delivered Cisplatin Restores Efficacy in Platinum-Resistant Ovarian Cancer Cells.

    PubMed

    Franke, Christina E; Czapar, Anna E; Patel, Ravi B; Steinmetz, Nicole F

    2017-09-19

    Platinum resistance in ovarian cancer is the major determinant of disease prognosis. Resistance can first appear at the onset of disease or develop in response to platinum-based chemotherapy. Due to poor response to alternate chemotherapies and lack of targeted therapies, there is an urgent clinical need for a new avenue toward treatment of platinum-resistant (PR) ovarian cancer. Nanoscale delivery systems hold potential to overcome resistance mechanisms. In this work, we present tobacco mosaic virus (TMV) as a nanocarrier for cisplatin for treatment of PR ovarian cancer cells. The TMV-cisplatin conjugate (TMV-cisPt) was synthesized using a charge-driven reaction that, like a classic click reaction, is simple and reliable for large-scale production. Up to ∼1900 cisPt were loaded per TMV-cisPt with biphasic release profiles characterized by a fast half-life (t1) of ∼1 h and slow half-life (t2) of ∼12 h independent of pH. Efficient cell uptake of TMV was observed when incubated with ovarian cancer cells, and TMV-cisPt demonstrated superior cytotoxicity and DNA double strand breakage (DSB) in platinum-sensitive (PS) and PR cancer cells when compared to free cisplatin. The cytotoxicity in PR ovarian cancer cells and overall lower effective dosage requirement makes TMV-cisPt a powerful candidate for improved ovarian cancer treatment strategies.

  5. Aromatase expression in ovarian epithelial cancers.

    PubMed

    Cunat, S; Rabenoelina, F; Daurès, J-P; Katsaros, D; Sasano, H; Miller, W R; Maudelonde, T; Pujol, P

    2005-01-01

    Our study focused on aromatase cytochrome P450 (CYP19) expression in ovarian epithelial normal and cancer cells and tissues. Aromatase mRNA expression was analyzed by real-time PCR in ovarian epithelial cancer cell lines, in human ovarian surface epithelial (HOSE) cell primary cultures, and in ovarian tissue specimens (n=94), including normal ovaries, ovarian cysts and cancers. Aromatase mRNA was found to be expressed in HOSE cells, in BG1, PEO4 and PEO14, but not in SKOV3 and NIH:OVCAR-3 ovarian cancer cell lines. Correlation analysis of aromatase expression was performed according to clinical, histological and biological parameters. Aromatase expression in ovarian tissue specimens was higher in normal ovaries and cysts than in cancers (P<0.0001). Using laser capture microdissection in normal postmenopausal ovaries, aromatase was found to be predominantly expressed in epithelial cells as compared to stromal component. Using immunohistochemistry (IHC), aromatase was also detected in the epithelium component. There was an inverse correlation between aromatase and ERalpha expression in ovarian tissues (P<0.001, r=-0.34). In the cancer group, no significant differences in aromatase expression were observed according to tumor histotype, grade, stage and survival. Aromatase activity was evaluated in ovarian epithelial cancer (OEC) cell lines by the tritiated water assay and the effects of third-generation aromatase inhibitors (AIs) on aromatase activity and growth were studied. Letrozole and exemestane were able to completely inhibit aromatase activity in BG1 and PEO14 cell lines. Interestingly, both AI showed an antiproliferative effect on the estrogen responsive BG1 cell line co-expressing aromatase and ERalpha. Aromatase expression was found in ovarian epithelial normal tissues and in some ovarian epithelial cancer cells and tissues. This finding raises the possibility that some tumors may respond to estrogen and provides a basis for ascertaining an antimitogenic

  6. Paraneoplastic syndromes in patients with ovarian neoplasia.

    PubMed

    Hudson, C N; Curling, M; Potsides, P; Lowe, D G

    1993-04-01

    The prevalence of several paraneoplastic syndromes associated with ovarian cancer was determined from a clinicopathological study of 908 patients with primary ovarian malignancy in the North East Thames Region. The diversity and rarity of these manifestations are great and the explanation for them is difficult. Circumstantial evidence suggests that in some cases an autoimmune phenomenon is the most plausible cause.

  7. Catechins are not major components responsible for the beneficial effect of Camellia sinensis on the ovarian δ-ALA-D activity inhibited by cadmium.

    PubMed

    Soares, Melina Bucco; Izaguirry, Aryele Pinto; Vargas, Laura Musacchio; Mendez, Andreas Sebastian Loureiro; Spiazzi, Cristiano Chiapinotto; Santos, Francielli Weber

    2013-05-01

    Cadmium has been associated with a wide spectrum of deleterious effects on the reproductive tissues, including ovary. This investigation evaluated the protective role of Camellia sinensis (green, white and red teas) in the cadmium-induced inhibition of ovarian δ-aminolevulinate dehydratase (δ-ALA-D) activity in vitro and ex vivo. This study demonstrated that green and white teas restored the cow ovary δ-ALA-D activity inhibited by cadmium whereas red tea had no effect in vitro. In addition, green tea was able to restore enzyme activity inhibited after acute cadmium exposure in mice ovary. Teas infusions composition was assessed by HPLC in a quantitative assay for catechins, purine alkaloids and gallic acid as well as total polyphenol content. The greatest effect of green tea observed in vitro as well as the protective role presented in the ex vivo study could be attributed to the major content of phenols, but not catechins. In fact, catechins were not able to restore enzyme activity inhibited by cadmium, demonstrating that these compounds are not major components responsible for the beneficial effect of green tea observed in this study. This study demonstrated the helpful effect of green tea infusion in ameliorating a marker protein of cadmium intoxication in ovarian tissue. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling

    PubMed Central

    Abedini, Atefeh; Zamberlam, Gustavo; Lapointe, Evelyne; Tourigny, Catherine; Boyer, Alexandre; Paquet, Marilène; Hayashi, Kanako; Honda, Hiroaki; Kikuchi, Akira; Price, Christopher; Boerboom, Derek

    2015-01-01

    Whereas the roles of the canonical wingless-type MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation of Wnt5a (but not Wnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genes in vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signaling via the WNT/Ca2+ or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both β-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decrease via a glycogen synthase kinase-3β-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.—Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling. PMID:26667040

  9. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.

    PubMed

    Abedini, Atefeh; Zamberlam, Gustavo; Lapointe, Evelyne; Tourigny, Catherine; Boyer, Alexandre; Paquet, Marilène; Hayashi, Kanako; Honda, Hiroaki; Kikuchi, Akira; Price, Christopher; Boerboom, Derek

    2016-04-01

    Whereas the roles of the canonical wingless-type MMTV (mouse mammary tumor virus) integration site family (WNT) signaling pathway in the regulation of ovarian follicle growth and steroidogenesis are now established, noncanonical WNT signaling in the ovary has been largely overlooked. Noncanonical WNTs, including WNT5a and WNT11, are expressed in granulosa cells (GCs) and are differentially regulated throughout follicle development, but their physiologic roles remain unknown. Using conditional gene targeting, we found that GC-specific inactivation ofWnt5a(but notWnt11) results in the female subfertility associated with increased follicular atresia and decreased rates of ovulation. Microarray analyses have revealed that WNT5a acts to down-regulate the expression of FSH-responsive genesin vitro, and corresponding increases in the expression of these genes have been found in the GCs of conditional knockout mice. Unexpectedly, we found that WNT5a regulates its target genes not by signalingviathe WNT/Ca(2+)or planar cell polarity pathways, but rather by inhibiting the canonical pathway, causing both β-catenin (CTNNB1) and cAMP responsive element binding (CREB) protein levels to decreaseviaa glycogen synthase kinase-3β-dependent mechanism. We further found that WNT5a prevents follicle-stimulating hormone and luteinizing protein from up-regulating the CTNNB1 and CREB proteins and their target genes, indicating that WNT5a functions as a physiologic inhibitor of gonadotropin signaling. Together, these findings identify WNT5a as a key regulator of follicle development and gonadotropin responsiveness.-Abedini, A., Zamberlam, G., Lapointe, E., Tourigny, C., Boyer, A., Paquet, M., Hayashi, K., Honda, H., Kikuchi, A., Price, C., Boerboom, D. WNT5a is required for normal ovarian follicle development and antagonizes gonadotropin responsiveness in granulosa cells by suppressing canonical WNT signaling.

  10. Increased levels of oxidative and carbonyl stress markers in normal ovarian cortex surrounding endometriotic cysts.

    PubMed

    Di Emidio, Giovanna; D'Alfonso, Angela; Leocata, Pietro; Parisse, Valentina; Di Fonso, Adina; Artini, Paolo Giovanni; Patacchiola, Felice; Tatone, Carla; Carta, Gaspare

    2014-11-01

    Many evidence support the view that endometriotic cyst may exert detrimental effect on the surrounding ovarian microenvironment so representing a risk to functionality of adjacent follicles. Patients with benign ovarian cyst (endometriotic, follicular and dermoid cysts) subjected to laparoscopic cystectomy were enrolled in the present retrospective study in order to analyze whether endometriotic tissue could negatively affect the surrounding normal ovarian cortex more severely than other ovarian cysts. To this end we carried out immunohistochemistry analysis and comparative determination of the transcription factor FOXO3A, oxidized DNA adduct 8-OHdG (8-hydroxy-2'-deoxyguanosine) and damaged proteins known as AGEs (Advanced Glycation End products) as markers of ovarian stress response and molecular damage. Our results show that all the markers analyzed were present in normal ovarian tissue surrounding benign cysts. We observed higher levels of FOXO3A (15.90 ± 0.28), 8-OHdG (13.33 ± 2.07) and AGEs (12.58 ± 4.34) staining in normal ovarian cortex surrounding endometriotic cysts in comparison with follicular cysts (9.04 ± 0.29, 2.67 ± 2.67, 11.31 ± 2.95, respectively) and dermoid cysts (2.02 ± 0.18, 4.33 ± 2.58 and 10.56 ± 4.03, respectively). These results provide evidence that ovarian endometrioma is responsible for more severe alterations to cellular biomolecules than follicular and dermoid cysts.

  11. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer

    PubMed Central

    Bowtell, David D.; Böhm, Steffen; Ahmed, Ahmed A.; Aspuria, Paul-Joseph; Bast, Robert C.; Beral, Valerie; Berek, Jonathan S.; Birrer, Michael J.; Blagden, Sarah; Bookman, Michael A.; Brenton, James; Chiappinelli, Katherine B.; Martins, Filipe Correia; Coukos, George; Drapkin, Ronny; Edmondson, Richard; Fotopoulou, Christina; Gabra, Hani; Galon, Jérôme; Gourley, Charlie; Heong, Valerie; Huntsman, David G.; Iwanicki, Marcin; Karlan, Beth Y.; Kaye, Allyson; Lengyel, Ernst; Levine, Douglas A.; Lu, Karen H.; McNeish, Iain A.; Menon, Usha; Narod, Steve A.; Nelson, Brad H.; Nephew, Kenneth P.; Pharoah, Paul; Powell, Daniel J.; Ramos, Pilar; Romero, Iris L.; Scott, Clare L.; Sood, Anil K.; Stronach, Euan A.; Balkwill, Frances R.

    2016-01-01

    High-grade serous ovarian cancer (HGSOC) accounts for 70-80% of ovarian cancer deaths, and overall survival has not changed significantly for several decades. In this Opinion article, we outline a set of research priorities that we believe will reduce incidence and improve outcomes for women with this disease. This ‘roadmap’ for HGSOC was determined after extensive discussions at an Ovarian Cancer Action meeting in January 2015. PMID:26493647

  12. Study on the proportion and determinants of polycystic ovarian syndrome among health sciences students in South India

    PubMed Central

    Joseph, Nitin; Reddy, Aditya G. R.; Joy, Divya; Patel, Vishakha; Santhosh, Pooja; Das, Shatarupa; Reddy, Siddharth K.

    2016-01-01

    Introduction: Polycystic ovarian syndrome (PCOS) constitutes most cases of endocrine disorder among females. Objectives: This study was done to assess the proportion of university students with PCOS and to study its risk factors. Materials and Methods: Data were collected from students of a private medical, dental, and nursing college using a self-administered questionnaire. Height and weight of all participants were recorded by standard procedures. Results: The mean age of students was 20.4 ΁ 1.5 years. Of the 480 participants, 39 (8.1%) were already diagnosed with PCOS. Out of the remaining 441 participants, 40 (9.1%) were at high risk, and 401 (90.9%) were at low risk for PCOS. Greater proportion of PCOS cases was seen in the age group 23-25 years (P = 0.026), among those with family history of PCOS (P = 0.002), among those who were permanent residents of urban areas (P = 0.048), and among those who were overweight or obese (P = 0.004). About 90% of PCOS cases and those at high risk for PCOS, each had difficulty in controlling excess weight or were experiencing difficulty in maintaining ideal weight. About 36 (92.3%) of PCOS cases and all those at high risk had emotional problems such as feeling moody or experiencing fatigability over the previous 2 weeks. Conclusion: PCOS is a common disorder among young women in this settings and this warrants periodic screening activities. A multidisciplinary approach is required to bring about lifestyle modification and help those with emotional problems due to this endocrine disorder. PMID:27433068

  13. The rate of high ovarian response in women identified at risk by a high serum AMH level is influenced by the type of gonadotropin.

    PubMed

    Arce, Joan-Carles; Klein, Bjarke M; La Marca, Antonio

    2014-06-01

    The aim was to compare ovarian response and clinical outcome of potential high-responders after stimulation with highly purified menotropin (HP-hMG) or recombinant follicle-stimulating hormone (rFSH) for in vitro fertilisation/intracytoplasmic sperm injection. Retrospective analysis was performed on data collected in two randomized controlled trials, one conducted following a long GnRH agonist protocol and the other with an antagonist protocol. Potential high-responders (n = 155 and n = 188 in the agonist and antagonist protocol, respectively) were defined as having an initial anti-Müllerian hormone (AMH) value >75th percentile (5.2 ng/ml). In both protocols, HP-hMG stimulation in women in the high AMH category was associated with a significantly lower occurrence of high response (≥15 oocytes retrieved) than rFSH stimulation; 33% versus 51% (p = 0.025) and 31% versus 49% (p = 0.015) in the long agonist and antagonist protocol, respectively. In the potential high-responder women, trends for improved live birth rate were observed with HP-hMG compared with rFSH (long agonist protocol: 33% versus 20%, p = 0.074; antagonist protocol: 34% versus 23%, p = 0.075; overall population: 34% versus 22%, p = 0.012). In conclusion, the type of gonadotropin used for ovarian stimulation influences high-response rates and potentially clinical outcome in women identified as potential high-responders.

  14. Individualization of controlled ovarian stimulation in vitro fertilization using ovarian reserve markers.

    PubMed

    Grisendi, Valentina; La Marca, Antonio

    2017-06-01

    In assisted reproduction technologies (ART) the controlled ovarian stimulation (COS) therapy is the starting point from which a good oocytes retrieval depends. Treatment individualization is based on ovarian response prediction, which largely depends on a woman's ovarian reserve. Anti-Müllerian hormone (AMH) and antral follicle count (AFC) are considered the most accurate and reliable markers of ovarian reserve. A literature search was carried out for studies that addressed the ability of AMH and AFC to predict poor and/or excessive ovarian response in IVF cycles. According to the predicted response to ovarian stimulation (poor- normal- or high-response) is today possible not only to personalize pre-treatment counseling with the couple, but also to individualize the ovarian stimulation protocol, choosing among GnRH-agonists or antagonists for endogenous follicle-stimulating hormone (FSH) suppression and formulating the FSH starting dose most adequate for the single patients. In this review we discuss how to choose the best COS therapy for the single patient, on the basis of the markers-guided ovarian response prediction.

  15. A novel serum microRNA panel to discriminate benign from malignant ovarian disease.

    PubMed

    Langhe, Ream; Norris, Lucy; Saadeh, Feras Abu; Blackshields, Gordon; Varley, Rachel; Harrison, Ashling; Gleeson, Noreen; Spillane, Cathy; Martin, Cara; O'Donnell, Dearbhaile M; D'Arcy, Tom; O'Leary, John; O'Toole, Sharon

    2015-01-28

    Ovarian cancer is the seventh most common cancer in women and the most frequent cause of gynaecological malignancy-related mortality in women. Currently, no standardized reliable screening test exists. MicroRNA profiling has allowed the identification of signatures associated with diagnosis, prognosis and response to treatment of human tumours. The aim of this study was to determine if a microRNA signature could distinguish between malignant and benign ovarian disease. A training set of 5 serous ovarian carcinomas and 5 benign serous cystadenomas were selected for the initial experiments. The validation set included 20 serous ovarian carcinomas and 20 benign serous cystadenomas. The serum/plasma focus microRNA Exiqon panel was used for the training set. For the validation set a pick and mix Exiqon panel, which focuses on microRNAs of interest was used. A panel of 4 microRNAs (let-7i-5p, miR-122, miR-152-5p and miR-25-3p) was significantly down regulated in cancer patients. These microRNAs target WNT signalling, AKT/mTOR and TLR-4/MyD88, which have previously been found to play a role in ovarian carcinogenesis and chemoresistance. let-7i-5p, miR-122, miR-152-5p and miR-25-3p could act as diagnostic biomarkers in ovarian cancer.

  16. Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O2 and Plasma Supply

    PubMed Central

    Koizume, Shiro; Miyagi, Yohei

    2017-01-01

    Tissue factor (TF) is a cell surface receptor for coagulation factor VII (fVII). The TF-activated fVII (fVIIa) complex is an essential initiator of the extrinsic blood coagulation process. Interactions between cancer cells and immune cells via coagulation factors and adhesion molecules can promote progression of cancer, including epithelial ovarian cancer (EOC). This process is not necessarily advantageous, as tumor tissues generally undergo hypoxia due to aberrant vasculature, followed by reduced access to plasma components such as coagulation factors. However, hypoxia can activate TF expression. Expression of fVII, intercellular adhesion molecule-1 (ICAM-1), and multiple pro-inflammatory cytokines can be synergistically induced in EOC cells in response to hypoxia along with serum deprivation. Thus, pro-inflammatory responses associated with the TF-fVIIa–ICAM-1 interaction are expected within hypoxic tissues. Tumor tissue consists of multiple components such as stromal cells, interstitial fluid, albumin, and other micro-factors such as proton and metal ions. These factors, together with metabolism reprogramming in response to hypoxia and followed by functional modification of TF, may contribute to coagulation factor-driven inflammatory responses in EOC tissues. The aim of this review was to describe potential coagulation factor-driven inflammatory responses in hypoxic EOC tissues. Arguments were extended to clinical issues targeting this characteristic tumor environment. PMID:28417928

  17. Comparative ovarian microarray analysis of juvenile hormone-responsive genes in water flea Daphnia magna: potential targets for toxicity.

    PubMed

    Toyota, Kenji; Williams, Timothy D; Sato, Tomomi; Tatarazako, Norihisa; Iguchi, Taisen

    2017-03-01

    The freshwater zooplankton Daphnia magna has been extensively employed in chemical toxicity tests such as OECD Test Guidelines 202 and 211. Previously, it has been demonstrated that the treatment of juvenile hormones (JHs) or their analogues to female daphnids can induce male offspring production. Based on this finding, a rapid screening method for detection of chemicals with JH-activity was recently developed using adult D. magna. This screening system determines whether a chemical has JH-activity by investigating the male offspring inducibility. Although this is an efficient high-throughput short-term screening system, much remains to be discovered about JH-responsive pathways in the ovary, and whether different JH-activators act via the same mechanism. JH-responsive genes in the ovary including developing oocytes are still largely undescribed. Here, we conducted comparative microarray analyses using ovaries from Daphnia magna treated with fenoxycarb (Fx; artificial JH agonist) or methyl farnesoate (MF; a putative innate JH in daphnids) to elucidate responses to JH agonists in the ovary, including developing oocytes, at a JH-sensitive period for male sex determination. We demonstrate that induction of hemoglobin genes is a well-conserved response to JH even in the ovary, and a potential adverse effect of JH agonist is suppression of vitellogenin gene expression, that might cause reduction of offspring number. This is the first report demonstrating different transcriptomics profiles from MF and an artificial JH agonist in D. magna ovary, improving understanding the tissue-specific mode-of-action of JH. Copyright © 2016 John Wiley & Sons, Ltd.

  18. Targeted Therapy in Ovarian Cancer

    PubMed Central

    Lim, Hui Jun; Ledger, William

    2016-01-01

    Among female-specific cancers worldwide, ovarian cancer is the leading cause of death from gynecologic malignancy in the western world. Despite radical surgery and initial high response rates to first-line chemotherapy, up to 70% of patients experience relapses with a median progression-free survival of 12–18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. This review aims to assess current understanding of targeted therapy in ovarian cancer and evaluate the evidence for targeting growth-dependent mechanisms involved in its pathogenesis. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and PARP inhibitors. PMID:27215391

  19. Mixed lineage kinase 3 is required for matrix metalloproteinase expression and invasion in ovarian cancer cells

    SciTech Connect

    Zhan, Yu; Abi Saab, Widian F.; Modi, Nidhi; Stewart, Amanda M.; Liu, Jinsong; Chadee, Deborah N.

    2012-08-15

    Mixed lineage kinase 3 (MLK3) is a mitogen-activated protein kinase kinase kinase (MAP3K) that activates MAPK signaling pathways and regulates cellular responses such as proliferation, migration and apoptosis. Here we report high levels of total and phospho-MLK3 in ovarian cancer cell lines in comparison to immortalized nontumorigenic ovarian epithelial cell lines. Using small interfering RNA (siRNA)-mediated gene silencing, we determined that MLK3 is required for the invasion of SKOV3 and HEY1B ovarian cancer cells. Furthermore, mlk3 silencing substantially reduced matrix metalloproteinase (MMP)-1, -2, -9 and -12 gene expression and MMP-2 and -9 activities in SKOV3 and HEY1B ovarian cancer cells. MMP-1, -2, -9 and-12 expression, and MLK3-induced activation of MMP-2 and MMP-9 requires both extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activities. In addition, inhibition of activator protein-1 (AP-1) reduced MMP-1, MMP-9 and MMP-12 gene expression. Collectively, these findings establish MLK3 as an important regulator of MMP expression and invasion in ovarian cancer cells. -- Highlights: Black-Right-Pointing-Pointer Ovarian cancer cell lines have high levels of total and phosphorylated MLK3. Black-Right-Pointing-Pointer MLK3 is required for MMP expression and activity in ovarian cancer cells. Black-Right-Pointing-Pointer MLK3 is required for invasion of SKOV3 and HEY1B ovarian cancer cells. Black-Right-Pointing-Pointer MLK3-dependent regulation of MMP-2 and MMP-9 activities requires ERK and JNK.

  20. Ovarian arteries with bilateral unusual courses.

    PubMed

    Sulak, Osman; Albay, Soner; Tagil, Suleyman M; Malas, Mehmet A

    2005-09-01

    Bilateral unusual coursed ovarian arteries were found in a 45-year-old female cadaver. The ovarian arteries arose from the abdominal aorta at a level inferior to the corpus of L1 vertebra bilaterally. The right ovarian artery was coursing behind the inferior vena cava. The left one was coursing between the left renal artery and vein upward to the level of the inferior part of the body of Th12 vertebra. At the level of Th12 vertebra, it turned caudally and proceeded downward between the anterior-inferior and posterior segmental renal veins. On both sides, ovarian arteries were on their normal routes below the L2 vertebra accompanying the ovarian veins. The variation determined by this study would reduce possible complications of nephrectomy operations that urologists, gynecologists and other related surgeons may encounter.

  1. HOX genes in ovarian cancer.

    PubMed

    Kelly, Zoë L; Michael, Agnieszka; Butler-Manuel, Simon; Pandha, Hardev S; Morgan, Richard Gl

    2011-09-09

    The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.

  2. Sex-determining region Y-box3 (SOX3) functions as an oncogene in promoting epithelial ovarian cancer by targeting Src kinase.

    PubMed

    Yan, Qin; Wang, Fangyuan; Miao, Yi; Wu, Xiaomei; Bai, Mingzhu; Xi, Xiaowei; Feng, Youji

    2016-09-01

    Ovarian cancer is one of the most common cancers which cause female mortality. The knowledge of ovarian cancer initiation and progression is critical to develop new therapeutic strategies to treat and prevent it. Recently, SOX3 has been reported to play a pivotal role in tumor progression. However, the clinical significance of SOX3 in human ovarian cancer remains elusive, and the identity of SOX3 in ovarian cancer initiation, progression, and the related underlying mechanism is unknown. In this study, we showed that SOX3 expression increased from benign and borderline to malignant ovarian tumors. Subsequently, we found that overexpression of SOX3 in EOC cells promoted proliferation, migration, and invasion, while restrained apoptosis and adhesion of ovarian cancer cells. In contrast, silencing of SOX3 gained the opposite results. Finally, we discovered SOX3 targeted Src kinase in EOC cells. These data imply that SOX3, acting as an oncogene in EOC, is not only a crucial factor in the carcinogenesis but also a promising therapeutic target for EOC.

  3. How to personalize ovarian stimulation in clinical practice.

    PubMed

    Sighinolfi, Giovanna; Grisendi, Valentina; La Marca, Antonio

    2017-09-01

    Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple's prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Müllerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF.

  4. How to personalize ovarian stimulation in clinical practice

    PubMed Central

    Sighinolfi, Giovanna; Grisendi, Valentina; La Marca, Antonio

    2017-01-01

    Controlled ovarian stimulation (COS) in in vitro fertilization (IVF) cycles is the starting point from which couple’s prognosis depends. Individualization in follicle-stimulating hormone (FSH) starting dose and protocol used is based on ovarian response prediction, which depends on ovarian reserve. Anti-Müllerian hormone levels and the antral follicle count are considered the most accurate and reliable markers of ovarian reserve. A literature search was performed for studies that addressed the ability of ovarian reserve markers to predict poor and high ovarian response in assisted reproductive technology cycles. According to the predicted response to ovarian stimulation (poor- normal- or high- response), it is possible to counsel couples before treatment about the prognosis, and also to individualize ovarian stimulation protocols, choosing among GnRH-agonists or antagonists for endogenous FSH suppression, and the FSH starting dose in order to decrease the risk of cycle cancellation and ovarian hyperstimulation syndrome. In this review we discuss how to choose the best COS therapy, based on ovarian reserve markers, in order to enhance chances in IVF. PMID:28890430

  5. Assessment of ovarian reserve: is there still a role for ovarian biopsy in the light of new data?

    PubMed

    Lass, Amir

    2004-03-01

    Ovarian reserve depends on the number of primordial follicles in the ovarian cortex. It was suggested that determining the follicular density directly by obtaining ovarian biopsy might be more accurate than current indirect biochemical and ultrasonic tests, especially for women in the later stage of their reproductive life. It might also be important and beneficial for young patients having chemotherapy for malignant disease in whom the ovarian tissue should be considered for reimplantation after recovery. The advantages and pitfalls of obtaining ovarian biopsy in these cases are discussed in light of new emerging data on the natural distribution of primordial follicles in the human ovary and its implications.

  6. 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

  7. Quantity and clinical relevance of circulating endothelial progenitor cells in human ovarian cancer

    PubMed Central

    2010-01-01

    Background Circulating bone marrow-derived endothelial progenitor cells (EPCs) have been reported to participate in tumor angiogenesis and growth; however, the role of circulating EPCs in tumor progression is controversial. The role of circulating EPCs in ovarian cancer progression and angiogenesis has not yet been investigated. Methods The number of circulating EPCs in the peripheral blood in 25 healthy volunteers and 42 patients with ovarian cancer was determined by flow cytometry. EPCs were defined by co-expression of CD34 and vascular endothelial growth factor receptor 2 (VEGFR2). In addition, we determined CD34 and VEGFR2 mRNA levels by real-time reverse transcription-polymerase chain reaction. Plasma levels of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) were determined by enzyme-linked immunosorbent assay. Results Circulating levels of EPCs were significantly increased in ovarian cancer patients, correlating with tumor stage and residual tumor size. Higher levels of EPCs were detected in patients with stage III and IV ovarian cancer than in patients with stage I and II disease. After excision of the tumor, EPCs levels rapidly declined. Residual tumor size greater than 2 cm was associated with significantly higher levels of EPCs. In addition, high circulating EPCs correlated with poor overall survival. Pretreatment CD34 mRNA levels were not significantly increased in ovarian cancer patients compared with healthy controls; however, VEGFR2 expression was increased, and plasma levels of VEGF and MMP-9 were also elevated. Conclusions Our results demonstrate the clinical relevance of circulating EPCs in ovarian cancer. EPCs may be a potential biomarker to monitor ovarian cancer progression and angiogenesis and treatment response. PMID:20334653

  8. Cytokeratin 5 positive cells represent a therapy resistant subpopulation in epithelial ovarian cancer

    PubMed Central

    Corr, Bradley R.; Finlay-Schultz, Jessica; Rosen, Rachel B.; Qamar, Lubna; Post, Miriam D.; Behbakht, Kian; Spillman, Monique A.; Sartorius, Carol A.

    2015-01-01

    Objective Cytokeratin 5 (CK5) is an epithelial cell marker implicated in stem and progenitor cell activity in glandular reproductive tissues and endocrine and chemotherapy resistance in estrogen receptor (ER)+ breast cancer. The goal of this study was to determine the prevalence of CK5 expression in ovarian cancer and the response of CK5+ cell populations to cisplatin therapy. Materials and Methods CK5 expression was evaluated in two ovarian tissue microarrays, representing 137 neoplasms, and six ovarian cancer cell lines. Cell lines were treated with IC50 cisplatin and the prevalence of CK5+ cells pre- and post-treatment determined. Proliferation of CK5+ vs. CK5− cell populations was determined using bromodeoxyuridine (BrdU) incorporation. Chemotherapy induced apoptosis in CK5+ vs. CK5− cells was measured using immunohistochemical staining for cleaved caspase-3. Results CK5 was expressed in 39.3% (42/107) of epithelial ovarian cancers with a range of 1-80% positive cells. Serous and endometrioid histologic subtypes had the highest percentage of CK5+ specimens. CK5 expression correlated with ER positivity (38/42 CK5+ tumors were also ER+). CK5 was expressed in 5/6 overall and 4/4 ER+ epithelial ovarian cancer cell lines ranging from 2.4-52.7% positive cells. CK5+ compared to CK5− cells were slower proliferating. The prevalence of CK5+ cells increased following 48 hour cisplatin treatment in 4/5 cell lines tested. CK5+ compared to CK5− ovarian cancer cells were more resistant to cisplatin induced apoptosis. Conclusions CK5 is expressed in a significant proportion of epithelial ovarian cancers and represents a slower proliferating, chemoresistant subpopulation that may warrant co-targeting in combination therapy. PMID:26495758

  9. 40 CFR 1065.845 - Response factor determination.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 40 Protection of Environment 32 2010-07-01 2010-07-01 false Response factor determination. 1065.845 Section 1065.845 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR POLLUTION CONTROLS ENGINE-TESTING PROCEDURES Testing With Oxygenated Fuels § 1065.845 Response...

  10. Ovarian vein thrombosis after debulking surgery for ovarian cancer: epidemiology and clinical significance.

    PubMed

    Mantha, Simon; Sarasohn, Debra; Ma, Weining; Devlin, Sean M; Chi, Dennis S; Roche, Kara Long; Suidan, Rudy S; Woo, Kaitlin; Soff, Gerald A

    2015-08-01

    Ovarian vein thrombosis is associated with pregnancy and pelvic surgery. Postpartum ovarian vein thrombosis is associated with infection and a high morbidity rate and is treated with anticoagulant and intravenous antibiotic therapy. The natural history of such thrombotic events after debulking surgery for ovarian cancer has not been well described. Our objective was to characterize the presentation and outcomes for patients with this condition at our institution. We conducted a retrospective study of patients who underwent surgical debulking for ovarian cancer at Memorial Sloan Kettering Cancer Center between the years 2001 and 2010. Patients were included if contrast computed tomography scans of both the abdomen and pelvis were performed within 12 weeks before and 12 weeks after the surgery. The images were reviewed to assess for the presence and extent of a new postoperative ovarian vein thrombosis. When available, subsequent studies were assessed for thrombus progression. Medical records were reviewed to determine whether anticoagulation was used for treatment of the thrombotic episode and to record the occurrence of any new significant venous thromboembolic event in the next year. One hundred fifty-nine patients had satisfactory imaging. New ovarian vein thrombosis was a common complication of debulking surgery, as found in 41 of patients (25.8%). Only 5 women with ovarian vein thrombosis were started on anticoagulation, of which 2 individuals had an independent venous thromboembolic event as indication for treatment. Only 2 of the ovarian vein thromboses (4.9%) progressed to the inferior vena cava or left renal vein on subsequent scan. The estimated cumulative incidence of venous thromboembolism 1 year after the first postoperative scan was 17.1% for patients in the new ovarian vein thrombosis group vs 15.3% of individuals for the group without a postoperative ovarian vein thrombosis (P = .78). Ovarian vein thrombosis is commonly encountered after debulking

  11. What Is Ovarian Cancer?

    MedlinePlus

    ... to be similar to widespread ovarian cancer. Fallopian tube cancer This is another rare cancer that is ... to epithelial ovarian cancer. It begins in the tube that carries an egg from the ovary to ...

  12. Evaluation of unilateral versus bilateral ovarian drilling in clomiphene citrate resistant cases of polycystic ovarian syndrome.

    PubMed

    Roy, K K; Baruah, Jinee; Moda, Nidhi; Kumar, Sunesh

    2009-10-01

    Laparoscopic ovarian drilling (LOD) has been put forward as the treatment of choice in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS), with tubo-ovarian adhesion formation as the major disadvantage. Our study proposed to compare the efficacy of laparoscopic unilateral ovarian drilling with bilateral ovarian drilling in terms of ovulation and pregnancy rate with the expected advantage of decreasing postoperative adhesion rate and change in fimbiro ovarian relationship with unilateral drilling. This prospective randomized study included 44 patients with anovulatory infertility due to PCOS. Twenty-two patients underwent unilateral ovarian drilling in group-I and 22 patients underwent bilateral ovarian drilling in group-II between June 2005 and June 2007. The number of drilling site in each ovary was limited to five. The clinical and biochemical response, ovulation and pregnancy rates over a follow-up period of 1 year were compared. Tubo-ovarian adhesion rate was compared during cesarean section or during repeat laparoscopy. There was no statistical difference between the two groups in terms of clinical and biochemical response, ovulation rate and pregnancy rate. Postoperatively, tubo-ovarian adhesions could be assessed in 36.3% of the patients and no adhesions were found in a single case in either group. Unilateral drilling cauterization of ovary is equally efficacious as bilateral drilling in inducing ovulation and achieving pregnancy. Unilateral ovarian drilling may be a suitable option in clomiphene citrate resistant infertility patient of PCOS which can replace bilateral ovarian drilling with the potential advantage of decreasing the chances of adhesion formation.

  13. Environmentally induced epigenetic transgenerational inheritance of ovarian disease.

    PubMed

    Nilsson, Eric; Larsen, Ginger; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Savenkova, Marina I; Skinner, Michael K

    2012-01-01

    The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology.

  14. Environmentally Induced Epigenetic Transgenerational Inheritance of Ovarian Disease

    PubMed Central

    Nilsson, Eric; Larsen, Ginger; Manikkam, Mohan; Guerrero-Bosagna, Carlos; Savenkova, Marina I.; Skinner, Michael K.

    2012-01-01

    The actions of environmental toxicants and relevant mixtures in promoting the epigenetic transgenerational inheritance of ovarian disease was investigated with the use of a fungicide, a pesticide mixture, a plastic mixture, dioxin and a hydrocarbon mixture. After transient exposure of an F0 gestating female rat during embryonic gonadal sex determination, the F1 and F3 generation progeny adult onset ovarian disease was assessed. Transgenerational disease phenotypes observed included an increase in cysts resembling human polycystic ovarian disease (PCO) and a decrease in the ovarian primordial follicle pool size resembling primary ovarian insufficiency (POI). The F3 generation granulosa cells were isolated and found to have a transgenerational effect on the transcriptome and epigenome (differential DNA methylation). Epigenetic biomarkers for environmental exposure and associated gene networks were identified. Epigenetic transgenerational inheritance of ovarian disease states was induced by all the different classes of environmental compounds, suggesting a role of environmental epigenetics in ovarian disease etiology. PMID:22570695

  15. [Update on current care guidelines: ovarian cancer].

    PubMed

    Leminen, Arto; Auranen, Annika; Bützow, Ralf; Hietanen, Sakari; Komulainen, Marja; Kuoppala, Tapio; Mäenpää, Johanna; Puistola, Ulla; Vuento, Maarit; Vuorela, Piia; Yliskoski, Merja

    2012-01-01

    Ovarian cancer is the most lethal gynaecological cancer. It appears that seemingly ovarian or primary peritoneal carcinomas, in fact, originate from fimbriae. BRCA1/2 mutation carriers are recommended for the removal of ovaries and fimbriae, to reduce the risk of cancer. Treatment of epithelial ovarian cancer is based on the combination of surgery and chemotherapy. The residual tumour volume at the primary operation is the most important predictive factor of survival. The best response at the primary treatment is observed with combination chemotherapy with taxane and platinum. Adding bevacitzumab to first line chemotherapy may improve survival.

  16. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial.

    PubMed

    Coleman, Robert L; Oza, Amit M; Lorusso, Domenica; Aghajanian, Carol; Oaknin, Ana; Dean, Andrew; Colombo, Nicoletta; Weberpals, Johanne I; Clamp, Andrew; Scambia, Giovanni; Leary, Alexandra; Holloway, Robert W; Gancedo, Margarita Amenedo; Fong, Peter C; Goh, Jeffrey C; O'Malley, David M; Armstrong, Deborah K; Garcia-Donas, Jesus; Swisher, Elizabeth M; Floquet, Anne; Konecny, Gottfried E; McNeish, Iain A; Scott, Clare L; Cameron, Terri; Maloney, Lara; Isaacson, Jeff; Goble, Sandra; Grace, Caroline; Harding, Thomas C; Raponi, Mitch; Sun, James; Lin, Kevin K; Giordano, Heidi; Ledermann, Jonathan A

    2017-09-12

    Rucaparib, a poly(ADP-ribose) polymerase inhibitor, has anticancer activity in recurrent ovarian carcinoma harbouring a BRCA mutation or high percentage of genome-wide loss of heterozygosity. In this trial we assessed rucaparib versus placebo after response to second-line or later platinum-based chemotherapy in patients with high-grade, recurrent, platinum-sensitive ovarian carcinoma. In this randomised, double-blind, placebo-controlled, phase 3 trial, we recruited patients from 87 hospitals and cancer centres across 11 countries. Eligible patients were aged 18 years or older, had a platinum-sensitive, high-grade serous or endometrioid ovarian, primary peritoneal, or fallopian tube carcinoma, had received at least two previous platinum-based chemotherapy regimens, had achieved complete or partial response to their last platinum-based regimen, had a cancer antigen 125 concentration of less than the upper limit of normal, had a performance status of 0-1, and had adequate organ function. Patients were ineligible if they had symptomatic or untreated central nervous system metastases, had received anticancer therapy 14 days or fewer before starting the study, or had received previous treatment with a poly(ADP-ribose) polymerase inhibitor. We randomly allocated patients 2:1 to receive oral rucaparib 600 mg twice daily or placebo in 28 day cycles using a computer-generated sequence (block size of six, stratified by homologous recombination repair gene mutation status, progression-free interval after the penultimate platinum-based regimen, and best response to the most recent platinum-based regimen). Patients, investigators, site staff, assessors, and the funder were masked to assignments. The primary outcome was investigator-assessed progression-free survival evaluated with use of an ordered step-down procedure for three nested cohorts: patients with BRCA mutations (carcinoma associated with deleterious germline or somatic BRCA mutations), patients with homologous

  17. Changes in Markers of Ovarian Reserve After Laparoscopic Ovarian Cystectomy.

    PubMed

    Ergun, Bulent; Ozsurmeli, Mehmet; Dundar, Ozgur; Comba, Cihan; Kuru, Oguzhan; Bodur, Serkan

    2015-01-01

    This study was conducted to determine the changes in ovarian reserve markers after laparoscopic ovarian cystectomy (LOC). Prospective cohort study (Canadian Task Force classification II-2). University teaching hospital. Fifty 50 patients who underwent LOC were prospectively examined to determine the changes in serum markers of ovarian reserve, starting from 1 month before and 3 months after consecutive operations. Changes in serum markers were compared between the following groups: endometrioma cysts (n = 26) versus nonendometrioma cysts (n = 24), unilateral cystectomy (n = 38) versus bilateral cystectomy (n = 12), and bilateral endometrioma extirpation (n = 10) versus other cystectomy operations (n = 40). A significant change was noticed between the preoperative and postoperative antimüllerian hormone (AMH) levels (2.67 ± 2.67 ng/mL vs 1.84 ± 1.72 ng/mL, p < .0001). Serum AMH levels were found to be significantly decreased in endometrioma (p = .002), nonendometrioma (p = .019), unilateral cystectomy (p = .001), bilateral cystectomy (p = .005), bilateral endometrioma (p = .011), and cysts other than bilateral endometrioma (p = .000) groups. The ovarian reserve was found to be diminished after LOC regardless of the presence of endometrioma that could be distinguishable by serum AMH levels. Copyright © 2015 AAGL. Published by Elsevier Inc. All rights reserved.

  18. Response to an abnormal ovarian cancer-screening test result: test of the social cognitive processing and cognitive social health information processing models.

    PubMed

    Andrykowski, Michael A; Pavlik, Edward J

    2011-04-01

    All cancer screening tests produce a proportion of abnormal results requiring follow up. Consequently, the cancer-screening setting is a natural laboratory for examining psychological and behavioural response to a threatening health-related event. This study tested hypotheses derived from the social cognitive processing and cognitive-social health information processing models in trying to understand response to an abnormal ovarian cancer (OC) screening test result. Women (n = 278) receiving an abnormal screening test result a mean of 7 weeks earlier were assessed prior to a repeat screening test intended to clarify their previous abnormal result. Measures of disposition (optimism, informational coping style), social environment (social support and constraint), emotional processing, distress, and benefit finding were obtained. Regression analyses indicated greater distress was associated with greater social constraint and emotional processing and a monitoring coping style in women with a family history of OC. Distress was unrelated to social support. Greater benefit finding was associated with both greater social constraint and support and greater distress. The primacy of social constraint in accounting for both benefit finding and distress was noteworthy and warrants further research on the role of social constraint in adaptation to stressful events.

  19. Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines

    PubMed Central

    Fleury, Hubert; Carmona, Euridice; Morin, Vincent G.; Meunier, Liliane; Masson, Jean-Yves; Tonin, Patricia N.; Provencher, Diane; Mes-Masson, Anne-Marie

    2017-01-01

    PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR. PMID:27374179

  20. Nuclear TBLR1 as an ER corepressor promotes cell proliferation, migration and invasion in breast and ovarian cancer.

    PubMed

    Wu, Xinyu; Zhan, Yang; Li, Xin; Wei, Jianjun; Santiago, Larion; Daniels, Garrett; Deng, Fangming; Zhong, Xuelin; Chiriboga, Luis; Basch, Ross; Xiong, Sheng; Dong, Yan; Zhang, Xinmin; Lee, Peng

    2016-01-01

    Estrogen receptors (ER) play important roles in the development and progression of breast and ovarian cancers. ERs mediate transcriptional regulation through interaction with cofactors and binding to response elements within the regulatory elements of target genes. Here, we examined the expression and function of TBLR1/TBL1XR1, a core component of NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid receptor) corepressor complexes, in breast and ovarian cancers. We found that although TBLR1 is present in both the nucleus and cytoplasm of normal and neoplastic breast and ovarian cells, it is expressed at significantly higher levels in the nucleus of malignant breast and ovarian cells compared to benign cells. TBLR1 functions as an ER corepressor to inhibit ER-mediated transcriptional activation in both breast and ovarian cell lines, but it has no effect on androgen receptor (AR) mediated transcriptional activation in these cells. Furthermore, ectopic expression of nuclear TBLR1 in breast and ovarian cancer cells stimulates cell proliferation. The increased cell proliferation by nuclear TBLR1 is through both ER-independent and ER-dependent mechanisms as evidenced by increased growth in hormone-free medium and estrogen medium, as well as reduced growth with ER knockdown by siRNA. Nuclear TBLR1 overexpression also increased migration and invasion in both breast and ovarian cancer cells. Determining the functional relationship between TBLR1 and ER may provide insights to develop novel treatment strategies and improve response to hormonal therapy in breast and ovarian cancers.

  1. Ovarian and PGF2α responses to stimulation of endogenous PRL pulses during the estrous cycle in mares.

    PubMed

    Pinaffi, F L V; Khan, F A; Silva, L A; Beg, M A; Ginther, O J

    2012-10-01

    The effects of a PRL-stimulating substance (sulpiride) on PRL and PGF2α secretion and on luteal and ovarian follicular dynamics were studied during the estrous cycle in mares. A control group (n = 9) and a sulpiride group (Sp; n = 10) were used. Sulpiride (25 mg) was given every 8 h from Day 13 postovulation to the next ovulation. Repeated sulpiride treatment did not appear to maintain PRL concentrations at 12-h intervals beyond Day 14. Therefore, the hypothesis that a long-term increase in PRL altered luteal and follicular end points was not testable. Hourly samples were collected from the hour of a treatment (Hour 0) to Hour 8 on Day 14. Concentrations of PRL increased to maximum at Hour 4 in the Sp group. The PRL pulses were more prominent (P < 0.008) in the sulpiride group (peak, 19.4 ± 1.9 ng/mL; mean ± SEM) than in the controls (11.5 ± 1.8 ng/mL). Concentrations of a metabolite of PGF2α (PGFM), number, and characteristics of PGFM pulses, and concentrations of progesterone during Hours 0 to 8 were not affected by the increased PRL. A novel observation was that the peak of a PRL pulse occurred at the same hour or 1 h later than the peak of a PGFM pulse in 8 of 8 PGFM pulses in the controls and in 6 of 10 pulses in the Sp group (P < 0.04), indicating that sulpiride interfered with the synchrony between PGFM and PRL pulses. The hypothesis that sulpiride treatment during the equine estrous cycle increases concentrations of PRL and the prominence of PRL pulses was supported.

  2. Chemotherapy drug response in ovarian cancer cells strictly depends on a cathepsin D-Bax activation loop

    PubMed Central

    Castino, Roberta; Peracchio, Claudia; Salini, Alessandra; Nicotra, Giuseppina; Trincheri, Nicol F; Démoz, Marina; Valente, Guido; Isidoro, Ciro

    2009-01-01

    The ovarian cancer cell lines A2780 (wild-type p53) and NIHOVCAR3 (mutated p53) showed, respectively, sensitivity and resistance towards several chemotherapy drugs. We hypothesized that the two cell lines differ in their ability to activate the intrinsic death pathway and have, therefore, dissected the lysosome-mitochondrion signalling pathway by pharmacological inhibition or genetic manipulation of key regulators and executioners. Biochemical and morphological confocal fluorescence studies showed that: (1) In A2780 cells bcl-2 is expressed at an undetectable level, whereas Bax is expressed at a rather high level; by contrast, bcl-2 is highly expressed and Bax is expressed at extremely low levels in NIHOVCAR3 cells; (2) Chemotherapy treatment reduced the expression of bcl-2 in NIHOVCAR3 cells, yet these cells resisted to drug toxicity; (3) Cathepsin D (CD), not cathepsin B or L, mediates the activation of the mitochondrial intrinsic death pathway in A2780 cells; (4) Lysosome leakage and cytosolic relocation of CD occurs in the chemosensitive A2780 cells, not in the chemoresistant NIHOVCAR3 cells; (5) Bax is essential for the permeabilization of both lysosomes and mitochondria in A2780 cells exposed to chemotherapy drugs; (6) CD activity is mandatory for the oligomerization of Bax on both mitochondrial and lysosomal membranes; (7) Bax activation did not occur in the resistant NIHOVCAR3 cells despite their high content in CD. The present data are consistent with a model in which on treatment with a cytotoxic drug the activation of a CD-Bax loop leads to the generalized permeabilization of lysosomes and eventually of mitochondria, thus reaching the point of no return, and culminates with the activation of the caspase cascade. Our data also imply that dysfunctional permeabilization of lysosomes contributes to the development of chemoresistance. PMID:18657225

  3. Effects of acute unilateral ovariectomy to pre-pubertal rats on steroid hormones secretion and compensatory ovarian responses

    PubMed Central

    2011-01-01

    In the present study we analyzed the existence of asymmetry in the secretion of steroid hormones in pre-pubertal female rats treated with unilateral ovariectomy (ULO) or unilateral perforation of the abdominal wall (sham-surgery). Treated rats were sacrificed at different times after surgery. Since sham-surgery had an apparent effect on the age of first vaginal estrous (FVE) and serum levels hormone, the results of the sham surgery groups were used to assess the effects of their respective surgery treatment groups. On the day of FVE, compensatory ovulation (CO) and compensatory ovarian hypertrophy (COH) were similar in animals with ULO, regardless of the ovary remaining in situ. In ULO treated animals, progesterone (P4) levels were higher than in animals with sham-surgery one hour after treatment but lower in rats sacrificed at FEV. Left-ULO resulted in lower testosterone (T) concentration 48 and 72 hours after surgery. In rats with Right-ULO lower T concentrations were observed in rats sacrificed one or 72 hours after surgery, and at FVE. ULO (left or right) resulted in lower estradiol (E2) concentrations one or 72 hours after treatment. In rats with Left-ULO, E2 levels were higher 48 hours after surgery and at FVE. Left-ULO resulted in higher levels of follicle stimulating hormone (FSH) five hours after surgery and at FVE. FSH levels were higher in rats with Right-ULO sacrificed on FVE. The present results suggest that in the pre-pubertal rat both ovaries have similar capacities to secrete P4, and that the right ovary has a higher capacity to secrete E2. Taken together, the present results support the idea that the effects of ULO result from the decrease in glandular tissue and changes in the neural information arising from the ovary. PMID:21450102

  4. Psychological adjustment among male partners in response to women's breast/ovarian cancer risk: a theoretical review of the literature.

    PubMed

    Sherman, Kerry A; Kasparian, Nadine A; Mireskandari, Shab

    2010-01-01

    For women at high risk of developing hereditary breast and/or ovarian cancer the process of undergoing genetic testing is anxiety provoking and stressful, entailing difficult and complex decisions. Partners of high-risk women are frequently perceived by the women as a source of support during this challenging time. Utilising Self Regulatory Theory, this paper provides a theoretically guided overview of existing data to delineate how partners respond emotionally and behaviourally to the woman's high-risk status. An extensive literature search was undertaken. Online searches of MEDLINE, CINAHL and PsycINFO databases were conducted, reference lists of all publications identified were examined; and the databases were searched for authors identified in these publications. The systematic search yielded 10 published studies on at-risk women and their male partners; one study did not investigate male partner distress as an outcome variable. Heterogeneity of methodology in this literature precluded quantitative meta-analyses of study outcomes. Review of the evidence suggests that the genetic testing process may be distressing for some partners, particularly for partners of women identified as mutation carriers. Associations were identified between partner distress and partner beliefs about the woman's perceived breast cancer risk; partner feelings of social separation and lack of couple communication; and partner perceptions of being alienated from the testing process. Lack of partner support was found to be associated with increased distress of the tested woman at the time of testing and following results disclosure. Data are lacking on the role of partner beliefs about breast cancer, partner perceived consequences of genetic testing, and personality factors such as information processing style, on partner distress. The high level of behavioural and psychological interdependence that exists between a tested woman and her partner means that future research seeking to

  5. The effect of germ-line BRCA mutations on response to chemotherapy and outcome of recurrent ovarian cancer.

    PubMed

    Safra, Tamar; Rogowski, Ori; Muggia, Franco M

    2014-03-01

    The treatment of recurrent epithelial ovarian cancer (rEOC) remains a major challenge because of the development of platinum resistance. To identify treatment regimens associated with better outcomes in BRCA mutation carriers compared with patients with nonhereditary (NH) disease, we summarized the experience after chemotherapy treatment of rEOC in 1 institution and compared the outcome in BRCA mutation carriers versus NH subsets. We retrospectively analyzed 256 patient records with rEOC who were treated with second-, third-, and fourth-line treatment with the usual sequential regimens consisting of either pegylated liposomal doxorubicin (PLD), taxanes, gemcitabine, or topotecan (alone or in combination with platinum) between 2002 and 2012 at our institution. The analysis of founder mutations in 8 hotspots was performed. The outcome in BRCA mutation carriers was compared with that of patients with NH disease. BRCA mutation carriers treated with PLD (with or without platinum) or with gemcitabine + platinum had improved progression-free survival (PFS) and a lower risk for disease progression (adjusted for age, line of treatment, and platinum sensitivity) compared with patients with NH disease. By contrast, treatment with taxanes (with or without platinum) or topotecan led to similar PFS in BRCA mutation carriers and in patients with NH disease. Under all treatment regimens, BRCA mutation carriers showed improved overall survival after adjusting for age, line of treatment, and platinum sensitivity. This single-institution experience provides indications of an enhanced benefit in PFS for BRCA mutation carriers compared with patients with NH disease across a number of drug regimens (PLD, platinum, or gemcitabine + platinum) regardless of platinum sensitivity and line of therapy.

  6. Evaluation of ovarian structures using computerized microtomography.

    PubMed

    Paulini, Fernanda; Chaves, Sacha B; Rôlo, José Luiz J P; Azevedo, Ricardo B DE; Lucci, Carolina M

    2017-06-29

    Visualization and clear understanding of the ovarian structures are important in determining the stage of oestrus, helping to diagnose several pathologies and supporting advances in reproductive technologies. In this research, computerized microtomography (microCT) was used to explore and characterize the ovarian structure of seven mammalian species. Ovaries of rats, female dog, queens, cows, mares, sows and a female donkey were used. After microCT scanning, the same samples were prepared for histologic evaluation, used here as a validation criterion. It was possible to distinguish regions of the cortex and medulla, visualize the morphology and distribution of blood vessels, clearly observe corpus luteum and antral follicles, and visualize oocytes inside some antral follicles. This is the first report using microCT to explore and compare ovarian structures in several domestic mammals. MicroCT revealed great potential for the evaluation of ovarian structures. This research open prospects for the use of computerized tomography (CT) as a non-invasive approach to studying ovarian structures in live animals, which may be especially attractive for scientific study of development of ovarian structures and/or ovarian pathologies in small animals' models.

  7. Ovarian Cancer Incidence Corrected for Oophorectomy

    PubMed Central

    Baldwin, Lauren A.; Chen, Quan; Tucker, Thomas C.; White, Connie G.; Ore, Robert N.; Huang, Bin

    2017-01-01

    Current reported incidence rates for ovarian cancer may significantly underestimate the true rate because of the inclusion of women in the calculations who are not at risk for ovarian cancer due to prior benign salpingo-oophorectomy (SO). We have considered prior SO to more realistically estimate risk for ovarian cancer. Kentucky Health Claims Data, International Classification of Disease 9 (ICD-9) codes, Current Procedure Terminology (CPT) codes, and Kentucky Behavioral Risk Factor Surveillance System (BRFSS) Data were used to identify women who have undergone SO in Kentucky, and these women were removed from the at-risk pool in order to re-assess incidence rates to more accurately represent ovarian cancer risk. The protective effect of SO on the population was determined on an annual basis for ages 5–80+ using data from the years 2009–2013. The corrected age-adjusted rates of ovarian cancer that considered SO ranged from 33% to 67% higher than age-adjusted rates from the standard population. Correction of incidence rates for ovarian cancer by accounting for women with prior SO gives a better understanding of risk for this disease faced by women. The rates of ovarian cancer were substantially higher when SO was taken into consideration than estimates from the standard population. PMID:28368298

  8. Selection of suitable reference genes for gene expression studies in normal human ovarian tissues, borderline ovarian tumours and ovarian cancer.

    PubMed

    Ofinran, Olumide; Bose, Ujjal; Hay, Daniel; Abdul, Summi; Tufatelli, Cristina; Khan, Raheela

    2016-12-01

    The use of reference genes is the most common method of controlling the variation in mRNA expression during quantitative polymerase chain reaction, although the use of traditional reference genes, such as β‑actin, glyceraldehyde‑3‑phosphate dehydrogenase or 18S ribosomal RNA, without validation occasionally leads to unreliable results. Therefore, the present study aimed to evaluate a set of five commonly used reference genes to determine the most suitable for gene expression studies in normal ovarian tissues, borderline ovarian and ovarian cancer tissues. The expression stabilities of these genes were ranked using two gene stability algorithms, geNorm and NormFinder. Using geNorm, the two best reference genes in ovarian cancer were β‑glucuronidase and β‑actin. Hypoxanthine phosphoribosyltransferase‑1 and β‑glucuronidase were the most stable in ovarian borderline tumours, and hypoxanthine phosphoribosyltransferase‑1 and glyceraldehyde‑3‑phosphate dehydrogenase were the most stable in normal ovarian tissues. NormFinder ranked β‑actin the most stable in ovarian cancer, and the best combination of two genes was β‑glucuronidase and β‑actin. In borderline tumours, hypoxanthine phosphoribosyltransferase‑1 was identified as the most stable, and the best combination was hypoxanthine phosphoribosyltransferase‑1 and β‑glucuronidase. In normal ovarian tissues, β‑glucuronidase was recommended as the optimum reference gene, and the most optimum pair of reference genes was hypoxanthine phosphoribosyltransferase‑1 and β‑actin. To the best of our knowledge, this is the first study to investigate the selection of a set of reference genes for normalisation in quantitative polymerase chain reactions in different ovarian tissues, and therefore it is recommended that β‑glucuronidase, β‑actin and hypoxanthine phosphoribosyltransferase‑1 are the most suitable reference genes for such analyses.

  9. Effects of ovarian steroids upon responses mediated by adrenoceptors in separated layers of the myometrium and in the costo-uterine muscle of the guinea-pig

    PubMed Central

    Hartley, Margaret L.; Pennefather, Jocelyn N.; Story, Margot E.

    1983-01-01

    1 This study describes the effects of ovarian steroid hormones upon the responses to adrenoceptor agonists of isolated myometrium, separated into its longitudinal and circular layers, and of costo-uterine muscle from guinea-pigs. The preparations were field-stimulated at 100 s intervals, and the adrenoceptor agonists phenylephrine and isoprenaline produced enhancement or inhibition of the evoked contractions. 2 Isoprenaline produced propranolol-sensitive inhibitory effects in longitudinal and circular myometrium and costo-uterine muscle preparations from animals from all experimental groups: i.e. from nonsteroid-treated animals (ovariectomized and intact); intact animals treated with either oestrogen or progesterone alone; ovariectomized animals treated with oestrogen; ovariectomized and intact animals treated with progesterone following oestrogen priming; and from animals 1-4 days post-partum. Longitudinal myometrial preparations from progesterone-treated oestrogen-primed and from post-partum animals were most sensitive to this agonist. 3 Phenylephrine produced phentolamine-sensitive excitatory effects in circular myometrial and costo-uterine muscle preparations from animals from all the experimental groups. In contrast, propranolol-sensitive inhibitory responses to phenylephrine occurred in longitudinal myometrial preparations taken from animals treated with progesterone following oestrogen priming, and from post-partum animals. Longitudinal myometrium from animals from the remaining experimental groups exhibited phentolamine-sensitive excitatory responses to phenylephrine. 4 The basis for the selective effect upon the longitudinal myometrium of exposure to progesterone following a period of oestrogen priming, is discussed. The results described are consistent with the possibility that in the longitudinal layer of guinea-pig uterus exposed to progesterone following oestrogen priming there is an increase in the proportion of β-adrenoceptors in this layer. This

  10. Recurrent ovarian cancer: is there a role for re-treatment with bevacizumab after an initial complete response to a bevacizumab-containing regimen?

    PubMed

    McCann, Georgia A; Smith, Blair; Backes, Floor J; Rath, Kellie; Chacko, Simi; Salani, Ritu; Eisenhauer, Eric; Fowler, Jeffrey M; Cohn, David E; O'Malley, David M

    2012-11-01

    To compare the progression free survival (PFS) and overall survival (OS) in patients with epithelial ovarian cancer (EOC) who received Bev after Bev (BAB) vs. those who were not re-treated with Bev (NOTBev) after initially experiencing a complete response (CR) to a Bev-containing regimen (BCR). We performed a retrospective chart review of patients with EOC that received Bev in either the front-line or recurrent setting. Patients who received additional therapy after achieving a CR to BCR were analyzed. 36 patients who had a CR to a BCR were included, 17 who received Bev at the time of their subsequent recurrence vs. 19 that did not. More patients in the NOTBev group received Bev as primary therapy (21% vs. 6%, p=0.2), but this was not statistically significant. Patients in the BAB group had significantly higher mean PFS compared to the NOTBev group (20 vs. 6 months, p=0.0019). On adjusting for covariates, there was a 78% improvement in their PFS (HR 0.22, p=0.0048). No difference in overall survival was noted between the groups (23 vs. 26 months, p=0.7244). Re-treatment with Bev after a prior Bev response is associated with a significantly improved PFS. This is the first of such reports in this patient population. The 14-month improvement in PFS strongly supports the re-use of Bev in patients who demonstrate an initial response to Bev. This strategy should be formally tested in future clinical trials and further investigation should include evaluation of predictors of response to Bev therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

  11. Borderline ovarian tumors: a review of treatment.

    PubMed Central

    Chambers, J. T.

    1989-01-01

    Borderline ovarian tumors have an excellent prognosis. In stage I disease, no therapy in addition to surgery is needed, and conservation of ovarian tissue for future childbearing may be appropriate. In advanced stages, the use of adjuvant therapy has not consistently led to cures, and complications have been reported. A randomized study of no adjuvant therapy versus adjuvant treatment with long-term follow-up will be necessary to determine the efficacy of additional treatment. PMID:2556863

  12. Functional Proteomics-Based Ovarian Cancer Biomarkers

    DTIC Science & Technology

    2010-11-01

    tissue , then incubating the samples at various time points to see the effect on RPPA –determined protein levels had already been done using breast tissue ...1985): 131. 27  Cao, Liyun, et al. " Tissue transglutaminase protects epithelial ovarian cancer cells from cisplatin-induced apoptosis by promoting...Dabholkar, Meenakshi, et al. "ERCC1 and ERCC2 expression in malignant tissues from ovarian cancer patients." Journal of the National Cancer Institute

  13. Antral follicle count (AFC) can be used in the prediction of ovarian response but cannot predict the oocyte/embryo quality or the in vitro fertilization outcome in an egg donation program.

    PubMed

    Melo, Marco Antonio Barreto; Garrido, Nicolás; Alvarez, Claudio; Bellver, José; Meseguer, Marcos; Pellicer, Antonio; Remohí, José

    2009-01-01

    To verify whether the antral follicle count (AFC) could predict ovarian response, oocyte/embryo quality, and IVF outcome. Prospective study. Instituto Universitario-Instituto Valenciano de Infertilidad, Valencia, Spain. One thousand seventy-four donors and 975 oocyte recipient cycles. Controlled ovarian hyperstimulation (COH), endometrial preparation, IVF/intracytoplasmic sperm injection, ET. COH and oocyte/embryo quality parameters and IVF outcome. We observed lower E(2) levels and fewer mature retrieved oocyte numbers among donors who showed an AFC that was <10. These donors also showed significantly higher cancellation and no-donation rates; poor and/or insufficient response was the principal cause (82%). However, there were no differences among the groups regarding embryo development parameters and IVF outcome. AFC is a noninvasive and simple tool that can improve the oocyte donor's selection of an egg donation program. This study suggests that AFC is a good predictor of ovarian response but cannot be used to predict oocyte/embryo quality or IVF outcome.

  14. BRCA1 Regulates Follistatin Function in Ovarian Cancer and Human Ovarian Surface Epithelial Cells

    PubMed Central

    Sneed, Rosie; Salamanca, Clara; Li, Xin; Xu, Jingwen; Kumar, Deepak; Rosen, Eliot M.; Saha, Tapas

    2012-01-01

    Follistatin (FST), a folliculogenesis regulating protein, is found in relatively high concentrations in female ovarian tissues. FST acts as an antagonist to Activin, which is often elevated in human ovarian carcinoma, and thus may serve as a potential target for therapeutic intervention against ovarian cancer. The breast cancer susceptibility gene 1 (BRCA1) is a known tumor suppressor gene in human breast cancer; however its role in ovarian cancer is not well understood. We performed microarray analysis on human ovarian carcinoma cell line SKOV3 that stably overexpress wild-type BRCA1 and compared with the corresponding empty vector-transfected clones. We found that stable expression of BRCA1 not only stimulates FST secretion but also simultaneously inhibits Activin expression. To determine the physiological importance of this phenomenon, we further investigated the effect of cellular BRCA1 on the FST secretion in immortalized ovarian surface epithelial (IOSE) cells derived from either normal human ovaries or ovaries of an ovarian cancer patient carrying a mutation in BRCA1 gene. Knock-down of BRCA1 in normal IOSE cells demonstrates down-regulation of FST secretion along with the simultaneous up-regulation of Activin expression. Furthermore, knock-down of FST in IOSE cell lines as well as SKOV3 cell line showed significantly reduced cell proliferation and decreased cell migration when compared with the respective controls. Thus, these findings suggest a novel function for BRCA1 as a regulator of FST expression and function in human ovarian cells. PMID:22685544

  15. 36 CFR 223.234 - Determination of responsibility.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... AGRICULTURE SALE AND DISPOSAL OF NATIONAL FOREST SYSTEM TIMBER Special Forest Products Award of Contracts, Permits, Or Other Authorizing Instruments § 223.234 Determination of responsibility. (a) A Contracting Officer shall not award a contract, permit, or other instrument authorizing the sale of special forest...

  16. Neurobiological determinism: human freedom of choice and criminal responsibility.

    PubMed

    Urbaniok, Frank; Laubacher, Arja; Hardegger, Judith; Rossegger, Astrid; Endrass, Jérôme; Moskvitin, Konstantin

    2012-04-01

    Several authors have argued that criminal behavior is generally caused by neurobiological deficits. This assumption not only questions the concept of free will and a person's responsibility for his or her own actions but also the principle of guilt in criminal law. When critically examining the current state of research, it becomes apparent that the results are not sufficient to support the existence of a universally valid neurobiological causality of criminal behavior. Moreover, the assumption of total neurobiological determination of human behavior and the impossibility of individual responsibility are characterized by both faulty empiricism and methodical misconceptions. The principle of relative determinism and the analysis of the offender's behavior at the time of the offense thus remain the central and cogent approach to the assessment of criminal responsibility.

  17. Familial ovarian cancer.

    PubMed Central

    Elit, L.

    2001-01-01

    OBJECTIVE: To assist family physicians in evaluating patients' risk for hereditary ovarian cancer and to review strategies for preventing ovarian cancer. QUALITY OF EVIDENCE: The MEDLINE, EMBASE, CANCERLIT, and CINAHL databases were searched from 1970 to 1999 using key words related to hereditary ovarian cancer, screening, oral contraceptives, prophylactic oophorectomy, cancer worriers, satisfaction, and perceived risk. Recommendations in this paper are based on evidence from case-control and cohort studies and, where appropriate, consensus conferences. MAIN MESSAGE: Of all women who present with ovarian cancer, 20% have a family history of ovarian cancer and 8% carry a BRCA 1 or BRCA 2 mutation. Women who carry a BRCA 1 mutation have a 63% lifetime risk of developing ovarian cancer, and women who carry a BRCA 2 mutation have a 27% lifetime risk of developing ovarian cancer. Preventive strategies include screening (level 3 evidence for postmenopausal women and level 5 evidence for women with a family history of ovarian cancer), use of oral contraceptives (level 3 evidence for the general population and for mutation carriers), and prophylactic oophorectomy (level 3 evidence in first-degree relatives of patients with breast or ovarian cancer). CONCLUSION: Women who have a family history of ovarian cancer should be offered genetic counseling and discussion of various preventive strategies for minimizing their risk. PMID:11340759

  18. Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

    DTIC Science & Technology

    2016-12-01

    to identify PARPi sensitivity. Large-scale disarray in chromosome structure is common in HRR-deficient cancers and may be quantitated by several...duplication of chromosomal regions, also known as genomic loss of heterozygosity (LOH).4−6 Half of all high-grade serous ovarian carcinomas are estimated...frequent in older ovarian cancer patients. Genes Chromosomes Cancer 2013; 52: 794−801. 6 Marquard AM, Eklund AC, Joshi T, et al. Pan-cancer analysis of

  19. Evaluation of DNA Repair Function as a Predictor of Response in a Clinical Trial of PARP Inhibitor Monotherapy for Recurrent Ovarian Carcinoma

    DTIC Science & Technology

    2014-10-01

    NCT01891344). 15. SUBJECT TERMS ovarian cancer, drug resistance, rucaparib, phase 2, DNA repair, homologous recombination , nonhomologous end- joining...words: ovarian cancer, drug resistance, rucaparib, phase 2, DNA repair, homologous recombination , nonhomologous end-joining (NHEJ), poly(ADP-ribose...REPORT DATE October2014 2. REPORT TYPE Annual Report 3. DATES COVERED 4. TITLE AND SUBTITLE Evaluation of DNA Repair Function as a Predictor

  20. Ovarian Granulosa Cell Survival and Proliferation Requires the Gonad-Selective TFIID Subunit TAF4b

    PubMed Central

    Voronina, Ekaterina; Lovasco, Lindsay A.; Gyuris, Aron; Baumgartner, Robert A.; Parlow, Albert F.; Freiman, Richard N.

    2007-01-01

    Oocyte development in the mammalian ovary requires productive interactions with somatic granulosa cells of the ovarian follicle. Proliferating granulosa cells support the progression of follicular growth and maturation, multiplying dramatically as it unfolds. The cell cycle recruitment of granulosa cells is regulated at least in part by hormones such as follicle-stimulating hormone (FSH) and estrogen. Follicles recruited into the growth phase following formation of multiple layers of granulosa cells have two major fates: either to continue proliferation followed by differentiation, or to die by programmed cell death, or atresia. While many of the signaling pathways orchestrating ovarian follicle development are known, the downstream transcriptional regulators that integrate such signals in the mammalian ovary remain to be defined. Recent experiments in diverse organisms have revealed multiple instances of gonad-selective components of the basal transcriptional machinery. One such protein, TAF4b, is a gonadal-enriched coactivator subunit of the TFIID complex required for normal female fertility in the mouse. To determine the etiology of female infertility of the TAF4b-deficient mice, we have determined multiple functions of TAF4b during postnatal ovarian follicle development. Here we demonstrate that the TAF4b protein is expressed in the granulosa cell compartment of the mammalian ovarian follicle. Furthermore, TAF4b-deficient mouse ovaries contain reduced numbers of primordial as well as growing follicles and a concomitant increased proportion of apoptotic follicles in comparison to wild type counterparts. Importantly, TAF4b-null follicles are largely resistant to induction of proliferation in response to multiple hormonal stimuli including estrogen and FSH and demonstrate compromised granulosa cell survival. Together, these data suggest that TAF4b integrates a program of granulosa cell gene expression required for normal ovarian follicle survival and proliferation

  1. Alopecia as surrogate marker for chemotherapy response in patients with primary epithelial ovarian cancer: a metaanalysis of four prospective randomised phase III trials with 5114 patients.

    PubMed

    Sehouli, Jalid; Fotopoulou, Christina; Erol, Edibe; Richter, Rolf; Reuss, Alexander; Mahner, Sven; Lauraine, Eric Pujade; Kristensen, Gunnar; Herrstedt, Jörn; du Bois, Andreas; Pfisterer, Jacobus

    2015-05-01

    Alopecia is a common side-effect of chemotherapy and affects quality of life of cancer patients. Some patients and physicians believe that alopecia could be a surrogate marker for response to chemotherapy and impact on prognosis. However, this was never been tested in a sufficiently large cohort of ovarian cancer patients. We analysed retrospectively the meta-databank of four prospective randomised phase-III-trials with platinum- and taxane-based 1st-line-chemotherapy in patients with advanced epithelial ovarian cancer (EOC) regarding the impact of alopecia overall outcome. For 4705 (92.0%) of a total of 5114 EOC-patients alopecia was documented. They had received on median six cycle platinum-taxane chemotherapy (range 0-11) with 4186 (89.0%) having completed ⩾ 6 cycles. Worst alopecia grade was 0 in 2.4%, 1 in 2.9% and 2 in 94.7% of the patients. In a univariate analysis, including all patients, grade-0/1 alopecia was associated with significantly lower progression free survival (PFS) and overall survival (OS) compared to grade-2 alopecia. However when assessing only those patients who completed ⩾ 6 chemotherapy-cycles and hence eliminating the bias of lower total dose of treatment, alopecia failed to retain any significant impact on survival in the multivariate analysis. Merely the time point of alopecia onset was an independent prognostic factor of survival: patients who developed grade-2 alopecia up to cycle 3 had a significantly longer OS compared to patients who experienced alopecia later during therapy (hazard ratio (HR): 1.25; 95% confidence interval (CI): 1.04-1.50). Within a large EOC-patient cohort with 1st-line platinum- and taxane-based chemotherapy early onset alopecia appears to be significantly associated with a more favourable outcome in those patients who completed ⩾ 6 chemotherapy cycles. It remains to be elucidated if early onset alopecia is just a surrogate marker for higher sensitivity to chemotherapy or if other biological effects are

  2. 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.

  3. Novel IEF Peptide Fractionation Method Reveals a Detailed Profile of N-Terminal Acetylation in Chemotherapy-Responsive and -Resistant Ovarian Cancer Cells.

    PubMed

    Weiland, Florian; Arentz, Georgia; Klingler-Hoffmann, Manuela; McCarthy, Peter; Lokman, Noor A; Kaur, Gurjeet; Oehler, Martin K; Hoffmann, Peter

    2016-11-04

    Although acetylation is regarded as a common protein modification, a detailed proteome-wide profile of this post-translational modification may reveal important biological insight regarding differential acetylation of individual proteins. Here we optimized a novel peptide IEF fractionation method for use prior to LC-MS/MS analysis to obtain a more in depth coverage of N-terminally acetylated proteins from complex samples. Application of the method to the analysis of the serous ovarian cancer cell line OVCAR-5 identified 344 N-terminally acetylated proteins, 12 of which are previously unreported. The protein peptidyl-prolyl cis-trans isomerase A (PPIA) was detected in both the N-terminally acetylated and unmodified forms and was further analyzed by data-independent acquisition in carboplatin-responsive parental OVCAR-5 cells and carboplatin-resistant OVCAR-5 cells. This revealed a higher ratio of unacetylated to acetylated N-terminal PPIA in the parental compared with the carboplatin-resistant OVCAR-5 cells and a 4.1-fold increase in PPIA abundance overall in the parental cells relative to carboplatin-resistant OVCAR-5 cells (P = 0.015). In summary, the novel IEF peptide fractionation method presented here is robust, reproducible, and can be applied to the profiling of N-terminally acetylated proteins. All mass spectrometry data is available as a ProteomeXchange repository (PXD003547).

  4. Natural Killer Cells Response to IL-2 Stimulation Is Distinct between Ascites with the Presence or Absence of Malignant Cells in Ovarian Cancer Patients

    PubMed Central

    da Silva, Rodrigo Fernandes; Yoshida, Adriana; Cardozo, Daniela Maira; Jales, Rodrigo Menezes; Paust, Silke; Derchain, Sophie; Guimarães, Fernando

    2017-01-01

    Peritoneal ascites are a distinguishable feature of patients with advanced epithelial ovarian cancer (EOC). The presence of different lymphocyte subsets has been reported in EOC-associated ascites, which also can or not contain malignant cells. The goal of this study was to analyze the functional characteristics of natural killer (NK) cells from EOC-associated ascites in terms of their expression of activating receptors and ascites’ contents of lymphocyte subtypes, cytokine profile and presence of EOC cells. NK cell function was evaluated by the expression of the degranulation marker CD107a in resting and interleukin (IL)-2 stimulated NK cells from ascites and blood. Degranulation of NK cells from EOC cell-free ascites was significantly (p < 0.05) higher than all the other groups, either in their resting state or after IL-2 stimulation, suggesting a previous local stimulation. In contrast, treatment with IL-2 had no effect on NK cells from ascites with EOC cells. The amount of regulatory T cells was significantly higher in ascites with EOC cells compared to EOC cell-free ascites. Ascites with EOC cells also had higher levels of tumor necrosis factor (TNF)-α, suggesting inflammation related to the malignancy. In conclusion, the functional performance of NK cells was distinct between EOC cell-free ascites and ascites with EOC cells. The impairment of NK cell response to IL-2 in ascites with EOC cells was consistent with an immunosuppressive tumor microenvironment. PMID:28513532

  5. Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium.

    PubMed

    Dimitrova, Desislava; Ruscito, Ilary; Olek, Sven; Richter, Rolf; Hellwag, Alexander; Türbachova, Ivana; Woopen, Hannah; Baron, Udo; Braicu, Elena Ioana; Sehouli, Jalid

    2016-09-01

    Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network ( www.toc-network.de ). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

  6. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio are predictive of chemotherapeutic response and prognosis in epithelial ovarian cancer patients treated with platinum-based chemotherapy.

    PubMed

    Miao, Yi; Yan, Qin; Li, Shuangdi; Li, Bilan; Feng, Youji

    2016-06-07

    The aim of present study was to investigate the role of preoperative neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) used as prognostic markers for predicting chemotherapeutic response and survival outcomes in patients with epithelial ovarian cancer (EOC) who are receiving platinum-based chemotherapy. A total of 344 patients diagnosed with EOC who are receiving platinum-based chemotherapy from 2005 to 2010 in the hospital were enrolled. NLR and PLR were calculated from complete blood cell count taken before operation. The patients were divided into platinum-resistant (P-R) group and platinum-sensitive (P-S) group according to chemotherapeutic response. Clinicopathologic variables and outcomes were retrospectively collected and compared among groups. We used receiver operating characteristic (ROC) curves to calculate optimal cut-off values for NLR and PLR to predict chemotherapeutic response and prognosis. The AUC, sensitivity, specificity of NLR > 3.02 to predict platinum resistance were 0.819, 75.0% and 81.45%, respectively. The corresponding values of PLR > 207 were 0.727, 60.42% and 85.48%, respectively. Patients with lower value of NLR (NLR < 3.02) or PLR (PLR < 207) had a longer progression-free survival (PFS) and overall survival (OS). In multivariate analysis, NLR and PLR showed a significant association with PFS (hazard ratio [HR], 1.733; 95%CI, 1.225-2.453, P = 0.002 and HR, 1.952; 95%CI, 1.430-2.662, P < 0.001) and OS (HR, 1.616; 95%CI, 1.138-2.297, P = 0.007, and HR, 2.167; 95%CI, 1.565-3.000, P < 0.001). These results suggest that the assessment of NLR and PLR could assist the identification of patients with poor prognosis and had potential clinical value in predicting platinum resistance in patients with EOC.

  7. Social support, psychological distress, and natural killer cell activity in ovarian cancer.

    PubMed

    Lutgendorf, Susan K; Sood, Anil K; Anderson, Barrie; McGinn, Stephanie; Maiseri, Heena; Dao, Minh; Sorosky, Joel I; De Geest, Koen; Ritchie, Justine; Lubaroff, David M

    2005-10-01

    Psychosocial stress has been related to impaired immunity in cancer patients. However, the extent to which these relationships exist in immune cells in the tumor microenvironment in humans has not been explored. We examined relationships among distress, social support, and natural killer (NK) cell activity in ovarian cancer patients in peripheral-blood mononuclear cells (PBMC), ascitic fluid, and tumor-infiltrating lymphocytes (TIL). Patients awaiting surgery for a pelvic mass suspected of being ovarian cancer completed psychological questionnaires and gave a presurgical sample of peripheral blood. Samples of tumor and ascites were taken during surgery, lymphocytes were then isolated, and NK cytotoxicity and percentage were determined. The final sample, which was confirmed by surgical diagnosis, included 42 patients with epithelial ovarian cancer and 23 patients with benign masses. Peripheral NK cell activity was significantly lower among ovarian cancer patients than in patients with benign masses. Among ovarian cancer patients, NK cytotoxicity in TIL was significantly lower than in PBMC or ascitic fluid. Social support was related to higher NK cytotoxicity in PBMC and TIL, adjusting for stage. Distress was related to lower NK cytotoxicity in TIL. A multivariate model indicated independent associations of both distress and social support with NK cell activity in TIL. Psychosocial factors, such as social support and distress, are associated with changes in the cellular immune response, not only in peripheral blood, but also at the tumor level. These relationships were more robust in TIL. These findings support the presence of stress influences in the tumor microenvironment.

  8. The inherent cellular radiosensitivity of epithelial ovarian carcinoma

    SciTech Connect

    Rotmensch, J.; Schwartz, J.L.; Atcher, R.W.; Grdina, D.J.; Toohill, M.; Weichselbaum, R.W. )

    1989-12-01

    Ovarian carcinomas of similar histology have variable responses to radiation therapy. It has been suggested that inherent cellular resistance to radiation may in part underlie radiotherapy failure. To determine in vitro radiobiological parameters of papillary serous adenocarcinoma of the ovary, we investigated the cellular responses of 16 early-passage ovarian carcinoma cell lines to radiation. The radiosensitivity, as measured by D0, ranged from 1.05 to 2.40 Gy (mean 1.70 Gy), and, as measured by D, ranged from 1.65 to 3.54 Gy (mean 2.38 Gy). The extrapolation number -n ranged from 1.1 to 2.0 (mean 1.5). The cells had a 1.3- to 5.4-fold (mean 2.8) ability to recover from potential lethal damage (PLDR) 24 hr after irradiation and subculture from plateau-phase cultures. Their inherent radioresistance may be one factor in the failure of some ovarian cancers to be sterilized by radiation.

  9. Executive impairment determines ADHD medication response: implications for academic achievement.

    PubMed

    Hale, James B; Reddy, Linda A; Semrud-Clikeman, Margaret; Hain, Lisa A; Whitaker, James; Morley, Jessica; Lawrence, Kyle; Smith, Alex; Jones, Nicole

    2011-01-01

    Methylphenidate (MPH) often ameliorates attention-deficit/hyperactivity disorder (ADHD) behavioral dysfunction according to indirect informant reports and rating scales. The standard of care behavioral MPH titration approach seldom includes direct neuropsychological or academic assessment data to determine treatment efficacy. Documenting "cool" executive-working memory (EWM) and "hot" self-regulation (SR) neuropsychological impairments could aid in differential diagnosis of ADHD subtypes and determining cognitive and academic MPH response. In this study, children aged 6 to 16 with ADHD inattentive type (IT; n = 19) and combined type (n = 33)/hyperactive-impulsive type (n = 4) (CT) participated in double-blind placebo-controlled MPH trials with baseline and randomized placebo, low MPH dose, and high MPH dose conditions. EWM/ SR measures and behavior ratings/classroom observations were rank ordered separately across conditions, with nonparametric randomization tests conducted to determine individual MPH response. Participants were subsequently grouped according to their level of cool EWM and hot SR circuit dysfunction. Robust cognitive and behavioral MPH response was achieved for children with significant baseline EWM/SR impairment, yet response was poor for those with adequate EWM/ SR baseline performance. Even for strong MPH responders, the best dose for neuropsychological functioning was typically lower than the best dose for behavior. Findings offer one possible explanation for why long-term academic MPH treatment gains in ADHD have not been realized. Implications for academic achievement and medication titration practices for children with behaviorally diagnosed ADHD will be discussed.

  10. Evaluation and therapy of polycystic ovarian syndrome.

    PubMed

    Loy, R; Seibel, M M

    1988-12-01

    The amenorrhea associated with bilateral polycystic ovaries, described by Stein and Leventhal, actually represents a syndrome involving various organs and systems. Clinically, this symptom complex commonly presents as menstrual disturbances, infertility, excessive body weight, and hirsutism. An understanding of the pathophysiology that underlies these symptoms provides a logical basis for evaluation and treatment of the syndrome. The diagnostic approach may involve biochemical determinations (baseline, stimulated, and suppressed) and radiologic testing. Therapy is directed at chronic anovulation, the hyperandrogenism responsible for hirsutism and acne, and the prophylaxis against endometrial and breast carcinomas. Ovulation can be induced with various agents, many of which have a risk of ovarian hyperstimulation in the PCOD patient. The use of GnRH agonists with HMG or FSH for ovulation induction will probably increase in the future. Although classic wedge resection has little place in modern management of PCOD, the recent laparoscopic ovarian cautery remains largely unstudied with respect to long-term postoperative plasma androgen levels and pelvic adhesions. It is too premature to evaluate this new surgical therapy. Hirsutism is effectively treated with estrogen-progestin combinations, medroxyprogesterone acetate, androgen receptor blockers (spironolactone, cimetidine, cyproterone acetate, and cyproheptadine), and glucocorticoids. To date, the available GnRH agonists have not been found selective enough to be used in the treatment of hirsutism, owing to possible long-term complications. Most medical approaches should include electrolysis for permanent hair removal. At present, gynecologic surgery seems to have little place in the management of hirsutism.

  11. The Heat Shock Transcription Factor HSF1 Induces Ovarian Cancer Epithelial-Mesenchymal Transition in a 3D Spheroid Growth Model

    PubMed Central

    Aoisa, Candice; Menzie, Christopher J.; Ubaldini, Ashley

    2016-01-01

    Ovarian cancer is the most lethal gynecological cancer, with over 200,000 women diagnosed each year and over half of those cases leading to death. The proteotoxic stress-responsive transcription factor HSF1 is frequently overexpressed in a variety of cancers and is vital to cellular proliferation and invasion in some cancers. Upon analysis of various patient data sets, we find that HSF1 is frequently overexpressed in ovarian tumor samples. In order to determine the role of HSF1 in ovarian cancer, inducible HSF1 knockdown cell lines were created. Knockdown of HSF1 in SKOV3 and HEY ovarian cancer cell lines attenuates the epithelial-to-mesenchymal transition (EMT) in cells treated with TGFβ, as determined by western blot and quantitative RT-PCR analysis of multiple EMT markers. To further explore the role of HSF1 in ovarian cancer EMT, we cultured multicellular spheroids in a non-adherent environment to simulate early avascular tumors. In the spheroid model, cells more readily undergo EMT; however, EMT inhibition by HSF1 becomes more pronounced in the spheroid model. These findings suggest that HSF1 is important in the ovarian cancer TGFβ response and in EMT. PMID:27997575

  12. 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

  13. Divergent effects of the 677C>T mutation of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene on ovarian responsiveness and anti-Müllerian hormone concentrations.

    PubMed

    Pavlik, Roman; Hecht, Stephanie; Ochsenkühn, Robert; Noss, Ulrich; Lohse, Peter; Thaler, Christian J

    2011-06-01

    To investigate the influence of the 5,10-methylenetetrahydrofolate reductase (MTHFR) 677C>T mutation on serum anti-Müllerian hormone (AMH) concentrations and on the numbers of oocytes retrieved (NOR) following controlled ovarian hyperstimulation (COH). Prospective cohort study. University-based infertility clinic. Two hundred and seventy women undergoing COH for IVF with or without intracytoplasmic sperm injection. None. AMH levels were determined from blood samples collected after 10 days of GnRH superagonist treatment and before COH. The MTHFR 677C>T genotype was characterized by a TaqMan 5' nuclease assay. AMH serum concentrations correlated significantly with the NOR in all individuals studied. Average (±SD) AMH levels of TT carriers (2.85±2.23 ng/mL) were significantly higher than those of homozygous CC (1.91±1.59 ng/mL) or heterozygous CT individuals (2.23±1.74 ng/mL). When evaluated by multiple regression analysis, AMH had a significant positive effect on NOR, whereas age and MTHFR 677TT genotype had significant negative effects. The MTHFR 677TT genotype is associated with higher serum AMH concentrations and has a negative effect on NOR. This apparent paradox might be resolved in light of recent findings describing a negative feedback function of AMH in the coordination of follicle development. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  14. Overcoming Platinum Resistance in Ovarian Carcinoma

    PubMed Central

    Matsuo, Koji; Lin, Yvonne G.; Roman, Lynda D.; Sood, Anil K.

    2010-01-01

    Importance of the field Ovarian cancer remains a deadly malignancy because most patients develop recurrent disease that is resistant to chemotherapy, including platinum. Because response rates for current treatment regimens are relatively similar and unfortunately low, no standard chemotherapy for platinum-resistant ovarian cancer exists. Areas covered in this review A systematic literature review of clinical studies published between January 2005 and March 2010 was conducted using search engines, PubMed and MEDLINE with the entry keywords, ovarian cancer and platinum resistance. This search revealed 40 clinical trials (1793 patients). What the reader will gain Gemcitabine was the most common drug used in clinical trials reporting higher response rates, ≥+1 SD of overall response rate (5 out of 8). Gemcitabine-based combination therapy showed an average response rate of 27.2% (95%CI 22.4–32.0). Combination of gemcitabine and pegylated liposomal doxorubicin (PLD) was the most common regimen (n=3) and was associated with possible additive effects in platinum-resistant ovarian cancer patients: response rate, gemcitabine alone 6.1%, PLD alone 19.8%, and gemcitabine with PLD 28.7% (95%CI 20.4–37.0), respectively. Take home message Analysis of recent clinical trials showed that gemcitabine-based combination chemotherapy was associated with the highest anti-tumor effects in platinum-resistant ovarian cancer patients during the study period. PMID:20815774

  15. Antenatal Hypoxia Induces Programming of Reduced Arterial Blood Pressure Response in Female Rat Offspring: Role of Ovarian Function

    PubMed Central

    Xiao, DaLiao; Huang, Xiaohui; Xue, Qin; Zhang, Lubo

    2014-01-01

    In utero exposure to adverse environmental factors increases the risk of cardiovascular disease in adulthood. The present study tested the hypothesis that antenatal hypoxia causes a gender-dependent programming of altered arterial blood pressure response (BP) in adult offspring. Time-dated pregnant rats were divided into normoxic and hypoxic (10.5% O2 from days 15 to 21 of gestation) groups. The experiments were conducted in adult offspring. Antenatal hypoxia caused intrauterine growth restriction, and resulted in a gender-dependent increase Angiotensin II (Ang II)-induced BP response in male offspring, but significant decrease in BP response in female offspring. The baroreflex sensitivity was not significantly altered. Consistent with the reduced blood pressure response, antenatal hypoxia significantly decreased Ang II-induced arterial vasoconstriction in female offspring. Ovariectomy had no significant effect in control animals, but significantly increased Ang II-induced maximal BP response in prenatally hypoxic animals and eliminated the difference of BP response between the two groups. Estrogen replacement in ovariectomized animals significantly decreased the BP response to angiotensin II I only in control, but not in hypoxic animals. The result suggests complex programming mechanisms of antenatal hypoxia in regulation of ovary function. Hypoxia-mediated ovary dysfunction results in the phenotype of reduced vascular contractility and BP response in female adult offspring. PMID:24905716

  16. BRCA1 founder mutations compared to ovarian cancer in Belarus.

    PubMed

    Savanevich, Alena; Oszurek, Oleg; Lubiński, Jan; Cybulski, Cezary; Dębniak, Tadeusz; Narod, Steven A; Gronwald, Jacek

    2014-09-01

    In Belarus and other Slavic countries, founder mutations in the BRCA1 gene are responsible for a significant proportion of breast cancer cases, but the data on contribution of these mutations to ovarian cancers are limited. To estimate the proportion of ovarian cancers in Belarus, which are dependent on BRCA1 Slavic founder mutations, we sought the presence of three most frequent mutations (BRCA1: 5382insC, C61G and, 4153delA) in 158 consecutive unselected cases of ovarian cancer. One of the three founder mutations was present in 25 of 158 unselected cases of ovarian cancer (15.8 %). We recommend that all cases of ovarian cancer in Belarus be offered genetic testing for these founder mutations. Furthermore, genetic testing of the Belarusian population will provide the opportunity to prevent a significant proportion of ovarian cancer.

  17. Response conflict determines sequential effects in serial response time tasks with short response-stimulus intervals.

    PubMed

    Jentzsch, Ines; Leuthold, Hartmut

    2005-08-01

    In serial choice reaction time (RT) tasks, performance in each trial critically depends on the sequence of preceding events. In this study, the authors specifically examined the mechanism underlying RT sequence effects at short response-stimulus intervals (RSIs), in which performance is impaired in the current trial N if events alternate rather than repeat from trial N-2 to trial N-1. Different accounts of this RT pattern in terms of perceptual noise, response-selection monitoring, and response conflict were tested in 4 experiments. Second-order RT costs were caused by the response sequence rather than the stimulus sequence. Manipulation of stimulus contrast, stimulus classification difficulty, and set-level compatibility did not modulate the response-related second-order RT effect, whereas this effect increased when spatially incompatible responses were demanded. These findings support a response conflict account of higher order sequential effects in short-RSI situations.

  18. Immunology of Addison's disease and premature ovarian failure.

    PubMed

    Husebye, Eystein S; Løvås, Kristian

    2009-06-01

    Autoimmune Addison's disease and autoimmune ovarian insufficiency are caused by selective targeting by T and B lymphocytes to the steroidogenic apparatus in these organs. Autoantibodies toward 21-hydroxylase are a clinically useful marker for autoimmune Addison's disease. Autoantibodies to 21-hydroxylase are found in premature ovarian insufficiency, but others also can be present, notably antibodies against side-chain cleavage enzyme. The autoimmune response primarily targets the theca cells, yielding elevated concentrations of inhibin, which is emerging as a useful diagnostic marker for autoimmune etiology of ovarian insufficiency. Little is known about its immunogenetics, but in contrast to Addison's disease, several experimental models of autoimmune premature ovarian insufficiency are available for study.

  19. Molecular profiles and pathogen-induced transcriptional responses of prawn B cell lymphoma-2 related ovarian killer protein (BOK).

    PubMed

    Chaurasia, Mukesh Kumar; Palanisamy, Rajesh; Harikrishnan, Ramasamy; Arasu, Mariadhas Valan; Al-Dhabi, Naif Abdullah; Arockiaraj, Jesu

    2015-08-01

    In this study, we have reported a molecular characterization of the first B cell lymphoma-2 (BCL-2) related ovarian killer protein (BOK) from freshwater prawn Macrobrachium rosenbergii (Mr). BOK is a novel pro-apoptotic protein of the BCL-2 family that entails in mediating apoptosis to remove cancer cells. A cDNA sequence of MrBOK was identified from the prawn cDNA library and its full length was obtained by internal sequencing. The coding region of MrBOK yields a polypeptide of 291 amino acids. The analysis revealed that MrBOK contains a transmembrane helix at V(261)-L(283) and a putative BCL-2 family domain at V(144)-W(245). MrBOK also possessed four putative BCL-2 homology domains including BH1, BH2, BH3 and weak BH4. The BH3 contains 21 binding sites and among them five residues are highly conserved with the aligned BOK proteins. The homology analysis showed that MrBOK shared maximum similarity with the Caligus rogercresseyi BOK A. The topology of the phylogenetic tree was classified into nine sister groups which includes BOK, BAK, BAX, BAD, BCL-2, BCL-XL, NR13 and MCL members. The BOK protein group further sub-grouped into vertebrate and invertebrate BOK, wherein MrBOK located within insect monophyletic clad of invertebrate BOK. The secondary structural analysis showed that MrBOK contains 11 α-helices (52.2%) which are connected over random coils (47.7%). The 3D structure of MrBOK showed three central helices (α6, α7 and α8) which formed the core of the protein and are flanked on one side by α1, α2 and α3, and on the other side by α4, α5 and α11. MrBOK mRNA is expressed most abundantly (P < 0.05) in ovary compared to other tissues taken for analysis. Hence ovary was selected to study the possible roles of MrBOK mRNA regulation upon bacterial (Aeromonas hydrophila and Vibrio harveyi) and viral [white spot syndrome virus (WSSV) and M. rosenbergii nodovirus] infection. During bacterial and viral infection, the highest MrBOK mRNA transcription was varied

  20. Expression of SDF-1 and CXCR4 transcript variants and CXCR7 in epithelial ovarian cancer.

    PubMed

    Jaszczynska-Nowinka, Karolina; Rucinski, Marcin; Ziolkowska, Agnieszka; Markowska, Anna; Malendowicz, Ludwik K

    2014-05-01

    Chemokine stromal cell-derived factor-1 (SDF-1) and its receptors, CXCR4 and CXCR7, have been implicated in epithelial ovarian cancer progression and metastasis. However, limited data are available on the expression levels of SDF-1 and CXCR4 variants and CXCR7 in human epithelial ovarian cancer. The present study aimed to characterize the expression pattern and levels of SDF-1, CXCR4 and CXCR7 in normal human ovaries and epithelial ovarian cancer. The expression of SDF-1 and CXCR4 transcript variants and CXCR7 was determined by quantitative polymerase chain reaction (qPCR). Plasma SDF-1α levels were determined by commercially available EIA kits and cancer antigen 125 (CA 125) levels were quantified by automated microparticle enzyme immunosorbent assay. High expression levels of SDF-1 transcript variant 1 were identified in ovarian cancer and control ovaries. By contrast, in both groups the expression levels of SDF-1 transcript variants 3 and 4 were extremely low. Furthermore, SDF-1 variant 1 levels were notably higher in epithelial ovarian cancer than in control ovaries, while data for the remaining transcripts were similar in both groups. CXCR4 transcript variant 2 and CXCR7 expression levels in normal and neoplastic ovaries were similar. In both groups, CXCR4 transcript variant 2 was not detected. Plasma SDF-1α levels were notably higher in females with epithelial ovarian cancer than in the control ovaries. Elevated levels of blood SDF-1α were found prior to surgery, 6 days after surgery and following completion of the first chemotherapy course. These increases were independent of the type of epithelial ovarian cancer. Our results suggest that the expression of SDF-1 and the genes controlling alternative splicing are elevated in epithelial ovarian cancer, leading to an increased formation of SDF-1 variant 1. Elevated plasma SDF-1α levels in epithelial ovarian cancer patients are not associated with the presence of tumors and/or metastases, however reflect a

  1. Determination Method of Bridge Rotation Angle Response Using MEMS IMU.

    PubMed

    Sekiya, Hidehiko; Kinomoto, Takeshi; Miki, Chitoshi

    2016-11-09

    To implement steel bridge maintenance, especially that related to fatigue damage, it is important to monitor bridge deformations under traffic conditions. Bridges deform and rotate differently under traffic load conditions because their structures differ in terms of length and flexibility. Such monitoring enables the identification of the cause of stress concentrations that cause fatigue damage and the proposal of appropriate countermeasures. However, although bridge deformation monitoring requires observations of bridge angle response as well as the bridge displacement response, measuring the rotation angle response of a bridge subject to traffic loads is difficult. Theoretically, the rotation angle response can be calculated by integrating the angular velocity, but for field measurements of actual in-service bridges, estimating the necessary boundary conditions would be difficult due to traffic-induced vibration. To solve the problem, this paper proposes a method for determining the rotation angle response of an in-service bridge from its angular velocity, as measured by a inertial measurement unit (IMU). To verify our proposed method, field measurements were conducted using nine micro-electrical mechanical systems (MEMS) IMUs and two contact displacement gauges. The results showed that our proposed method provided high accuracy when compared to the reference responses calculated by the contact displacement gauges.

  2. Determination Method of Bridge Rotation Angle Response Using MEMS IMU

    PubMed Central

    Sekiya, Hidehiko; Kinomoto, Takeshi; Miki, Chitoshi

    2016-01-01

    To implement steel bridge maintenance, especially that related to fatigue damage, it is important to monitor bridge deformations under traffic conditions. Bridges deform and rotate differently under traffic load conditions because their structures differ in terms of length and flexibility. Such monitoring enables the identification of the cause of stress concentrations that cause fatigue damage and the proposal of appropriate countermeasures. However, although bridge deformation monitoring requires observations of bridge angle response as well as the bridge displacement response, measuring the rotation angle response of a bridge subject to traffic loads is difficult. Theoretically, the rotation angle response can be calculated by integrating the angular velocity, but for field measurements of actual in-service bridges, estimating the necessary boundary conditions would be difficult due to traffic-induced vibration. To solve the problem, this paper proposes a method for determining the rotation angle response of an in-service bridge from its angular velocity, as measured by a inertial measurement unit (IMU). To verify our proposed method, field measurements were conducted using nine micro-electrical mechanical systems (MEMS) IMUs and two contact displacement gauges. The results showed that our proposed method provided high accuracy when compared to the reference responses calculated by the contact displacement gauges. PMID:27834871

  3. Satellite Aerodynamics and Density Determination from Satellite Dynamic Response

    NASA Technical Reports Server (NTRS)

    Karr, G. R.

    1972-01-01

    The aerodynamic drag and lift properties of a satellite are first expressed as a function of two parameters associated with gas-surface interaction at the satellite surface. The dynamic response of the satellite as it passes through the atmosphere is then expressed as a function of the two gas-surface interaction parameters, the atmospheric density, the satellite velocity, and the satellite orientation to the high speed flow. By proper correlation of the observed dynamic response with the changing angle of attack of the satellite, it is found that the two unknown gas-surface interaction parameters can be determined. Once the gas-surface interaction parameters are known, the aerodynamic properties of the satellite at all angles of attack are also determined.

  4. Identification of anti-CA125 antibody responses in ovarian cancer patients by a novel deep sequence-coupled biopanning platform

    PubMed Central

    Frietze, Kathryn M.; Roden, Richard B.S.; Lee, Ji-Hyun; Shi, Yang; Peabody, David S.; Chackerian, Bryce

    2015-01-01

    High-grade epithelial ovarian cancer (OvCa) kills more women than any other gynecologic cancer and is rarely diagnosed at an early stage. We sought to identify tumor-associated antigens (TAA) as candidate diagnostic and/or immunotherapeutic targets by taking advantage of tumor autoantibody responses in individuals with OvCa. Plasma-derived IgG from a pool of five patients with advanced OvCa was subjected to iterative biopanning using a library of bacteriophage MS2 virus-like particles (MS2-VLPs) displaying diverse short random peptides. After two rounds of biopanning, we analyzed the selectant population of MS2-VLPs by Ion Torrent deep-sequencing. One of the top 25 most abundant peptides identified (DISGTNTSRA) had sequence similarity to cancer antigen 125 (CA125/MUC16), a well-known OvCa-associated antigen. Mice immunized with MS2-DISGTNTSRA generated antibodies that cross-reacted with purified soluble CA125 from OvCa cells but not membrane-bound CA125, indicating that the DISGTNTSRA peptide was a CA125/MUC16 peptide mimic of soluble CA125. Pre-operative OvCa patient plasma (n = 100) was assessed for anti-DISGTNTSRA, anti-CA125, and CA125. Patients with normal CA125 (< 35 IU/mL) at time of diagnosis had significantly more antibodies to DISGTNTSRA and to CA125 than those patients who had high CA125 (> 35 IU/mL). A statistically significant survival advantage was observed for patients who had either normal CA125 and/or higher concentrations of antibodies to CA125 at time of diagnosis. These data show the feasibility of using deep sequence-coupled biopanning to identify TAA autoantibody responses from cancer patient plasma and suggest a possible antibody-mediated mechanism for low CA125 plasma concentrations in some OvCa patients. PMID:26589767

  5. Response to Intervention for English Learners: Examining Models for Determining Response and Nonresponse

    ERIC Educational Resources Information Center

    Richards-Tutor, Catherine; Solari, Emily J.; Leafstedt, Jill M.; Gerber, Michael M.; Filippini, Alexis; Aceves, Terese C.

    2013-01-01

    Using extant data, the purpose of this study is to examine methods for determining response to intervention (RTI) in a sample of kindergarten English Learners (ELs). Three commonly used methods for determining RTI--(a) benchmark criteria, (b) slope discrepancy, and (c) dual discrepancy--are investigated. Participants included 117 ELs. Students…

  6. Response to Intervention for English Learners: Examining Models for Determining Response and Nonresponse

    ERIC Educational Resources Information Center

    Richards-Tutor, Catherine; Solari, Emily J.; Leafstedt, Jill M.; Gerber, Michael M.; Filippini, Alexis; Aceves, Terese C.

    2013-01-01

    Using extant data, the purpose of this study is to examine methods for determining response to intervention (RTI) in a sample of kindergarten English Learners (ELs). Three commonly used methods for determining RTI--(a) benchmark criteria, (b) slope discrepancy, and (c) dual discrepancy--are investigated. Participants included 117 ELs. Students…

  7. B lymphocyte immune response gene phenotype is genetically determined

    SciTech Connect

    Tse, H.Y.; Mond, J.J.; Longo, D.L.

    1982-04-01

    We examined the effects of the developmental milieu on the capacity of B cells to undergo immune response gene-controlled, T cell-dependent polyclonal proliferation. Although I-Aq poly(Glu60 Ala30 Tyr10)n (GAT)-nonresponder T cells developing in a responder environment become phenotypic GAT-responders, I-Aq B cells remain unresponsive to GAT, even after maturation in a GAT-responder animal. Conversely, (B10.A x B10.Q)F1 ((GAT responder x GAT nonresponder)F1) T cells developing in a B10.Q GAT nonresponder host fail to respond to GAT, but F1 B cells from the same F1 leads to parent chimeras make excellent proliferative responses in the presence of GAT and responder T cells. Thus, by this assay, B cell immune response gene function is genetically determined and is not affected by the developmental milieu.

  8. Determination of the full response function of personal neutron dosemeters.

    PubMed

    Reginatto, M; Luszik-Bhadra, M

    2007-01-01

    The response of neutron dosemeters may be determined directly from measurements, provided a sufficiently large number of measurements in monoenergetic neutron fields covering the entire energy range of interest is available. In practice this is not feasible due to the lack of monoenergetic neutron fields in the thermal and intermediate energy region (i.e. energies<24 keV). To deal with this difficulty, we have developed a method which can take into account additional information about the response of the dosemeter. Our analysis makes use of two types of data, measurements made using monoenergetic neutron beams and measurements made in neutron fields with broad energy distributions. The dosemeter responses are described using a parametrised model, based on a minimum of assumptions: that they should fit the data within experimental uncertainties, and that they should remain close to a simple interpolation of the monoenergetic and thermal neutron field data.

  9. 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

  10. Determining Effects of Genes, Environment, and Gene X Environment Interaction That Are Common to Breast and Ovarian Cancers Via Bivariate Logistic Regression

    DTIC Science & Technology

    2003-07-01

    genetic and/or common environmental effects. Data are summarized in the form of 2 x 2 tables (for monozygotic and dizygotic twins ) by combining...A new method for the simultaneous genetic analysis of two or more discrete traits such as the presence of breast and ovarian cancers in twins was...traits based upon explicit patterns of trait concordance and discordance within twin pairs; this shared trait is assessed for the influence of additive

  11. Pharmacogenetics of controlled ovarian hyperstimulation.

    PubMed

    de Castro, Francisco; Morón, Francisco J; Montoro, Luis; Real, Luis M; Ruiz, Agustín

    2005-09-01

    Controlled ovarian hyperstimulation (COH) is a routine treatment employed in most assisted reproductive techniques (ARTs). The existence of genetic factors involved in COH has been suspected. The main challenge for clinicians involved in ART is COH cycle cancellation, which usually occurs due to two opposing situations. On the one hand, there is the presence of a poor response during COH treatment, and on the other there is the presentation of a side effect related to gonadotropin hypersensitivity (ovarian hyperstimulation syndrome [OHSS]). Evidence for an association between single nucleotide polymorphisms and COH outcome has been obtained during the last decade. The genetic dissection of both extreme phenotypes of COH will be the main objective of this review. The development of predictive panels useful for the clinical management of COH is currently underway, and will improve the clinical management of patients undergoing ART.

  12. Ovarian cancer screening in menopausal females with a family history of breast or ovarian cancer.

    PubMed

    Lai, Tiffany; Kessel, Bruce; Ahn, Hyeong Jun; Terada, Keith Y

    2016-07-01

    To determine whether annual screening reduces ovarian cancer mortality in women with a family history of breast or ovarian cancer. Data was obtained from the Prostate, Lung, Colorectal, and Ovarian cancer trial, a randomized multi-center trial conducted to determine if screening could reduce mortality in these cancers. The trial enrolled 78,216 women, randomized into either a screening arm with annual serum cancer antigen 125 and pelvic ultrasounds, or usual care arm. This study identified a subgroup that reported a first degree relative with breast or ovarian cancer. Analysis was performed to compare overall mortality and disease specific mortality in the screening versus usual care arm. In patients diagnosed with ovarian cancer, stage distribution, and survival were analyzed as a secondary endpoint. There was no significant difference in overall mortality or disease specific mortality between the two arms. Ovarian cancer was diagnosed in 48 patients in the screening arm and 44 patients in the usual care arm. Screened patients were more likely to be diagnosed at an earlier stage than usual care patients. Patients in the screening arm diagnosed with ovarian cancer experienced a significantly improved survival compared to patients in the usual care arm; relative risk 0.66 (95% CI, 0.47 to 0.93). Screening did not appear to decrease ovarian cancer mortality in participants with a family history of breast or ovarian cancer. Secondary endpoints, however, showed notable differences. Significantly fewer patients were diagnosed with advanced stage disease in the screening arm; and survival was significantly improved. Further investigation is warranted to assess screening efficacy in women at increased risk.

  13. A preoperative low cancer antigen 125 level (≤25.8 mg/dl) is a useful criterion to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in epithelial ovarian cancer.

    PubMed

    Morimoto, Akemi; Nagao, Shoji; Kogiku, Ai; Yamamoto, Kasumi; Miwa, Maiko; Wakahashi, Senn; Ichida, Kotaro; Sudo, Tamotsu; Yamaguchi, Satoshi; Fujiwara, Kiyoshi

    2016-06-01

    The purpose of this study is to investigate the clinical characteristics to determine the optimal timing of interval debulking surgery following neoadjuvant chemotherapy in patients with advanced epithelial ovarian cancer. We reviewed the charts of women with advanced epithelial ovarian cancer, fallopian tube cancer or primary peritoneal cancer who underwent interval debulking surgery following neoadjuvant chemotherapy at our cancer center from April 2006 to April 2014. There were 139 patients, including 91 with ovarian cancer [International Federation of Gynecology and Obstetrics (FIGO) Stage IIIc in 56 and IV in 35], two with fallopian tube cancers (FIGO Stage IV, both) and 46 with primary peritoneal cancer (FIGO Stage IIIc in 27 and IV in 19). After 3-6 cycles (median, 4 cycles) of platinum-based chemotherapy, interval debulking surgery was performed. Sixty-seven patients (48.2%) achieved complete resection of all macroscopic disease, while 72 did not. More patients with cancer antigen 125 levels ≤25.8 mg/dl at pre-interval debulking surgery achieved complete resection than those with higher cancer antigen 125 levels (84.7 vs. 21.3%; P< 0.0001). Patients with no ascites at pre-interval debulking surgery also achieved a higher complete resection rate (63.5 vs. 34.1%; P< 0.0001). Moreover, most patients (86.7%) with cancer antigen 125 levels ≤25.8 mg/dl and no ascites at pre-interval debulking surgery achieved complete resection. A low cancer antigen 125 level of ≤25.8 mg/dl and the absence of ascites at pre-interval debulking surgery are major predictive factors for complete resection during interval debulking surgery and present useful criteria to determine the optimal timing of interval debulking surgery. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Response diversity determines the resilience of ecosystems to environmental change.

    PubMed

    Mori, Akira S; Furukawa, Takuya; Sasaki, Takehiro

    2013-05-01

    A growing body of evidence highlights the importance of biodiversity for ecosystem stability and the maintenance of optimal ecosystem functionality. Conservation measures are thus essential to safeguard the ecosystem services that biodiversity provides and human society needs. Current anthropogenic threats may lead to detrimental (and perhaps irreversible) ecosystem degradation, providing strong motivation to evaluate the response of ecological communities to various anthropogenic pressures. In particular, ecosystem functions that sustain key ecosystem services should be identified and prioritized for conservation action. Traditional diversity measures (e.g. 'species richness') may not adequately capture the aspects of biodiversity most relevant to ecosystem stability and functionality, but several new concepts may be more appropriate. These include 'response diversity', describing the variation of responses to environmental change among species of a particular community. Response diversity may also be a key determinant of ecosystem resilience in the face of anthropogenic pressures and environmental uncertainty. However, current understanding of response diversity is poor, and we see an urgent need to disentangle the conceptual strands that pervade studies of the relationship between biodiversity and ecosystem functioning. Our review clarifies the links between response diversity and the maintenance of ecosystem functionality by focusing on the insurance hypothesis of biodiversity and the concept of functional redundancy. We provide a conceptual model to describe how loss of response diversity may cause ecosystem degradation through decreased ecosystem resilience. We explicitly explain how response diversity contributes to functional compensation and to spatio-temporal complementarity among species, leading to long-term maintenance of ecosystem multifunctionality. Recent quantitative studies suggest that traditional diversity measures may often be uncoupled from

  15. Technique for Determining Bridge Displacement Response Using MEMS Accelerometers

    PubMed Central

    Sekiya, Hidehiko; Kimura, Kentaro; Miki, Chitoshi

    2016-01-01

    In bridge maintenance, particularly with regard to fatigue damage in steel bridges, it is important to determine the displacement response of the entire bridge under a live load as well as that of each member. Knowing the displacement response enables the identification of dynamic deformations that can cause stresses and ultimately lead to damage and thus also allows the undertaking of appropriate countermeasures. In theory, the displacement response can be calculated from the double integration of the measured acceleration. However, data measured by an accelerometer include measurement errors caused by the limitations of the analog-to-digital conversion process and sensor noise. These errors distort the double integration results. Furthermore, as bridges in service are constantly vibrating because of passing vehicles, estimating the boundary conditions for the numerical integration is difficult. To address these problems, this paper proposes a method for determining the displacement of a bridge in service from its acceleration based on its free vibration. To verify the effectiveness of the proposed method, field measurements were conducted using nine different accelerometers. Based on the results of these measurements, the proposed method was found to be highly accurate in comparison with the reference displacement obtained using a contact displacement gauge. PMID:26907287

  16. Technique for Determining Bridge Displacement Response Using MEMS Accelerometers.

    PubMed

    Sekiya, Hidehiko; Kimura, Kentaro; Miki, Chitoshi

    2016-02-19

    In bridge maintenance, particularly with regard to fatigue damage in steel bridges, it is important to determine the displacement response of the entire bridge under a live load as well as that of each member. Knowing the displacement response enables the identification of dynamic deformations that can cause stresses and ultimately lead to damage and thus also allows the undertaking of appropriate countermeasures. In theory, the displacement response can be calculated from the double integration of the measured acceleration. However, data measured by an accelerometer include measurement errors caused by the limitations of the analog-to-digital conversion process and sensor noise. These errors distort the double integration results. Furthermore, as bridges in service are constantly vibrating because of passing vehicles, estimating the boundary conditions for the numerical integration is difficult. To address these problems, this paper proposes a method for determining the displacement of a bridge in service from its acceleration based on its free vibration. To verify the effectiveness of the proposed method, field measurements were conducted using nine different accelerometers. Based on the results of these measurements, the proposed method was found to be highly accurate in comparison with the reference displacement obtained using a contact displacement gauge.

  17. 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 ...

  18. 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 ...

  19. 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 ...

  20. 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 ...

  1. Premature ovarian failure.

    PubMed

    Kalantaridou, S N; Davis, S R; Nelson, L M

    1998-12-01

    In 1% of women, premature ovarian failure develops by 40 years of age, a condition causing amenorrhea, infertility, sex steroid deficiency, and elevated gonadotropins. Early loss of ovarian function has significant psychosocial sequelae and major health implications. These young women have a nearly two-fold age-specific increase in mortality rate. Among women with spontaneous premature ovarian failure who have a normal karyotype, half have ovarian follicles remaining in the ovary that function intermittently. Indeed, pregnancies have occurred after the diagnosis of premature ovarian failure. Thus, premature ovarian failure should not be considered as a premature menopause. Young women with this disorder have a 5% to 10% chance for spontaneous pregnancy. Attempts at ovulation induction using various regimens fail to induce ovulation rates greater than those seen in untreated patients; however, oocyte donation for women desiring fertility is an option. Young women with premature ovarian failure need a thorough assessment, sex steroid replacement, and long-term surveillance to monitor therapy. Estrogen-progestin replacement therapy should be instituted as soon as the diagnosis is made. Androgen replacement should also be considered for women with low libido, persistent fatigue, and poor well-being despite taking adequate estrogen replacement. Women with premature ovarian failure should be followed up for the presence of associated autoimmune endocrine disorders such as hypothyroidism, adrenal insufficiency, and diabetes mellitus.

  2. 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

  3. Gene Bionetwork Analysis of Ovarian Primordial Follicle Development

    PubMed Central

    Nilsson, Eric E.; Savenkova, Marina I.; Schindler, Ryan; Zhang, Bin; Schadt, Eric E.; Skinner, Michael K.

    2010-01-01

    Ovarian primordial follicles are critical for female reproduction and comprise a finite pool of gametes arrested in development. A systems biology approach was used to identify regulatory gene networks essential for primordial follicle development. Transcriptional responses to eight different growth factors known to influence primordial follicles were used to construct a bionetwork of regulatory genes involved in rat primordial follicle development. Over 1,500 genes were found to be regulated by the various growth factors and a network analysis identified critical gene modules involved in a number of signaling pathways and cellular processes. A set of 55 genes was identified as potential critical regulators of these gene modules, and a sub-network associated with development was determined. Within the network two previously identified regulatory genes were confirmed (i.e., Pdgfa and Fgfr2) and a new factor was identified, connective tissue growth factor (CTGF). CTGF was tested in ovarian organ cultures and found to stimulate primordial follicle development. Therefore, the relevant gene network associated with primordial follicle development was validated and the critical genes and pathways involved in this process were identified. This is one of the first applications of network analysis to a normal developmental process. These observations provide insights into potential therapeutic targets for preventing ovarian disease and promoting female reproduction. PMID:20661288

  4. Rapidly-progressive catatonia responsive to zolpidem in a patient with ovarian teratoma-associated paraneoplastic encephalitis.

    PubMed

    Amorim, Edilberto; McDade, Eric M

    2016-08-01

    Psychiatric symptoms and catatonia are key components of the clinical presentation of paraneoplastic encephalitis; additionally symptoms can be long-lasting and often difficult to treat. We report a 73-year-old patient with rapidly progressive catatonia not responsive to immunotherapy, tumor resection, electroconvulsive therapy, or benzodiazepines who had significant improvement after zolpidem administration. This report suggests that zolpidem is an option in the treatment of patients with refractory catatonia and paraneoplastic encephalitis.

  5. Ovarian function in Duarte galactosemia.

    PubMed

    Badik, Jennifer R; Castañeda, Uriel; Gleason, Tyler J; Spencer, Jessica B; Epstein, Michael P; Ficicioglu, Can; Fitzgerald, Kristi; Fridovich-Keil, Judith L

    2011-08-01

    To determine if girls with Duarte variant galactosemia (DG) have an increased risk of developing premature ovarian insufficiency based on prepubertal anti-Müllerian hormone (AMH) levels. Cross-sectional study. University research laboratory. Study volunteers included 57 girls with DG, 89 girls with classic galactosemia (GG), and 64 control girls between the ages of <1 month and 10.5 years. Blood sampling. We determined AMH and FSH levels in study volunteers with and without Duarte variant or GG. FSH levels were significantly higher and AMH levels significantly lower in girls with GG than in age-stratified control girls, but there was no significant difference between FSH and AMH levels in girls with DG and control girls. Although >80% of girls with GG in this study demonstrated low to undetectable AMH levels consistent with diminished ovarian reserve, 100% of girls with DG in our study demonstrated no apparent decrease in AMH levels or increase in FSH levels, suggesting that these girls are not at increased risk for premature ovarian insufficiency. Copyright © 2011. Published by Elsevier Inc.

  6. Genetics of the ovarian reserve

    PubMed Central

    Pelosi, Emanuele; Forabosco, Antonino; Schlessinger, David

    2015-01-01

    Primordial follicles or non-growing follicles (NGFs) are the functional unit of reproduction, each comprising a single germ cell surrounded by supporting somatic cells. NGFs constitute the ovarian reserve (OR), prerequisite for germ cell ovulation and the continuation of the species. The dynamics of the reserve is determined by the number of NGFs formed and their complex subsequent fates. During the reproductive lifespan, the OR progressively diminishes due to follicle atresia as well as recruitment, maturation, and ovulation. The depletion of the OR is the major determining driver of menopause, which ensues when the number of primordial follicles falls below a threshold of ∼1,000. Therefore, genes and processes involved in follicle dynamics are particularly important to understand the process of menopause, both in the typical reproductive lifespan and in conditions like primary ovarian insufficiency, defined as menopause before age 40. Genes and their variants that affect the timing of menopause thereby provide candidates for diagnosis of and intervention in problems of reproductive lifespan. We review the current knowledge of processes and genes involved in the development of the OR and in the dynamics of ovarian follicles. PMID:26528328

  7. Autoimmune premature ovarian failure

    PubMed Central

    2017-01-01

    Premature ovarian failure (POF), also termed as primary ovarian insufficiency (POI), is a highly heterogenous condition affecting 0.5-3.0% of women in childbearing age. These young women comprise quite a formidable group with unique physical and psychological needs that require special attention. Premature ovarian senescence (POS) in all of its forms evolves insidiously as a basically asymptomatic process, leading to complete loss of ovarian function, and POI/POF diagnoses are currently made at relatively late stages. Well-known and well-documented risk factors exist, and the presence or suspicion of autoimmune disorder should be regarded as an important one. Premature ovarian failure is to some degree predictable in its occurrence and should be considered while encountering young women with loss of menstrual regularity, especially when there is a concomitant dysfunction in the immune system. PMID:28250725

  8. A high response to controlled ovarian stimulation induces premature luteinization with a negative impact on pregnancy outcomes in a gonadotropin-releasing hormone antagonist cycle

    PubMed Central

    Koo, Hwa Seon; Cha, Sun Hwa; Kim, Hye Ok; Song, In Ok; Min, Eung Gi; Yang, Kwang Moon

    2015-01-01

    Objective The goal of this study was to investigate the relationship between serum progesterone (P4) levels on the day of human chorionic gonadotropin (hCG) administration and the pregnancy rate among women undergoing controlled ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) using a flexible antagonist protocol. Methods This prospective study included 200 IVF and ICSI-ET cycles in which a flexible antagonist protocol was used. The patients were divided into five distinct groups according to their serum P4 levels at the time of hCG administration (0.80, 0.85, 0.90, 0.95, and 1.00 ng/mL). The clinical pregnancy rate (CPR) was calculated for each P4 interval. Statistically significant differences were observed at a serum P4 level of 0.9 ng/mL. These data suggest that a serum P4 concentration of 0.9 ng/mL may represent the optimal threshold level for defining premature luteinization (PL) based on the presence of a significant negative impact on the CPR. Results The CPR for each round of ET was significantly lower in the PL group defined using this threshold (25.8% vs. 41.8%; p=0.019), and the number of oocytes retrieved was significantly higher than in the non-PL group (17.3±7.2 vs. 11.0±7.2; p=0.001). Elevated serum P4 levels on the day of hCG administration were associated with a reduced CPR, despite the retrieval of many oocytes. Conclusion Measuring serum P4 values at the time of hCG administration is necessary in order to determine the optimal strategy for embryo transfer. PMID:26816874

  9. A high response to controlled ovarian stimulation induces premature luteinization with a negative impact on pregnancy outcomes in a gonadotropin-releasing hormone antagonist cycle.

    PubMed

    Koo, Hwa Seon; Cha, Sun Hwa; Kim, Hye Ok; Song, In Ok; Min, Eung Gi; Yang, Kwang Moon; Park, Chan Woo

    2015-12-01

    The goal of this study was to investigate the relationship between serum progesterone (P4) levels on the day of human chorionic gonadotropin (hCG) administration and the pregnancy rate among women undergoing controlled ovarian stimulation for in vitro fertilization (IVF) or intracytoplasmic sperm injection-embryo transfer (ICSI-ET) using a flexible antagonist protocol. This prospective study included 200 IVF and ICSI-ET cycles in which a flexible antagonist protocol was used. The patients were divided into five distinct groups according to their serum P4 levels at the time of hCG administration (0.80, 0.85, 0.90, 0.95, and 1.00 ng/mL). The clinical pregnancy rate (CPR) was calculated for each P4 interval. Statistically significant differences were observed at a serum P4 level of 0.9 ng/mL. These data suggest that a serum P4 concentration of 0.9 ng/mL may represent the optimal threshold level for defining premature luteinization (PL) based on the presence of a significant negative impact on the CPR. The CPR for each round of ET was significantly lower in the PL group defined using this threshold (25.8% vs. 41.8%; p=0.019), and the number of oocytes retrieved was significantly higher than in the non-PL group (17.3±7.2 vs. 11.0±7.2; p=0.001). Elevated serum P4 levels on the day of hCG administration were associated with a reduced CPR, despite the retrieval of many oocytes. Measuring serum P4 values at the time of hCG administration is necessary in order to determine the optimal strategy for embryo transfer.

  10. Determination of sheep learning responses to a directional audio cue.

    PubMed

    Morris, Jessica E; Fisher, Andrew D; Doyle, Rebecca E; Bush, Russell D

    2010-01-01

    There are scientific opinions that a nonhuman animal cannot feel emotions, and, hence, positive experiences, without being cognitive. Therefore, determining an animal's cognitive capacity can be useful in supporting the existence of emotions. Research shows that sheep can perform tasks based on olfactory and visual stimuli; however, little research exists on determining the ability of sheep to perform such tasks based on auditory cues. This study demonstrates that sheep can perform a discriminant, operant task based on a visual cue (p < .001); however, sheep could not exhibit the desired response to a directional audio cue in 2 subsequent studies (p = .346; p = .031). Nonetheless, the study provides further evidence on the complex cognitive abilities of sheep and indicates the potential for sheep to use audio cues in their learning.

  11. Response Conflict Determines Sequential Effects in Serial Response Time Tasks with Short Response-Stimulus Intervals

    ERIC Educational Resources Information Center

    Jentzsch, Ines; Leuthold, Hartmut

    2005-01-01

    In serial choice reaction time (RT) tasks, performance in each trial critically depends on the sequence of preceding events. In this study, the authors specifically examined the mechanism underlying RT sequence effects at short response-stimulus intervals (RSIs), in which performance is impaired in the current trial N if events alternate rather…

  12. Clinical significance of serum follistatin levels in the diagnosis of ovarian endometrioma and benign ovarian cysts.

    PubMed

    Ant, Ömer; Özakşit, Gülnur; Güzel, Ali İrfan; Cavkaytar, Sabri; Kaba, Metin; Topçu, Hasan Onur

    2015-06-01

    To determine the clinical significance of serum follistatin levels in women with an ovarian endometrioma. This is a prospective study of 89 women, 56 with an ovarian endometrioma (endometrioma group) and 33 with a benign ovarian cyst (control group) who underwent laparoscopic excision. Age, parity, body mass index, serum CA-125, serum CA 19-9, and serum follistatin levels were determined for all participants and evaluated as potential prognostic factors prior to laparoscopic cystectomy. There were no significant differences in demographic factors between the endometrioma group and the control group. However, serum follistatin levels were significantly higher in the endometrioma group (9350 ± 895 pg/mL vs. control group 725 ± 72 pg/mL, p < 0.05). The optimal diagnostic cut-off values (sensitivity and specificity) of CA-125, CA 19-9, and follistatin for ovarian endometrioma were 23.2 IU/mL (82.14% and 72.73%), 30.14 IU/mL (45.28% and 87.50%), and 2350 pg/mL (53.7% and 60.61%), respectively. Despite the increased serum follistatin levels in patients with ovarian endometrioma, CA-125 was determined to be a more sensitive and specific marker than follistatin for the diagnosis of ovarian endometrioma and endometriosis. Copyright © 2015. Published by Elsevier B.V.

  13. Gene bionetworks that regulate ovarian primordial follicle assembly.

    PubMed

    Nilsson, Eric; Zhang, Bin; Skinner, Michael K

    2013-07-23

    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. 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. 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.

  14. 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

  15. DIFFERENTIAL REGULATION OF THE BUMETANIDE-SENSITIVE COTRANSPORTER (NKCC2) BY OVARIAN HORMONES

    PubMed Central

    Musselman, Teddy M; Zhang, Zheng; Masilamani, Shyama ME

    2010-01-01

    The Na-K-2Cl cotransporter (NKCC2) regulates sodium transport along the thick ascending limb of Henle’s loop and is important in control of sodium balance, renal concentrating ability and renin release. To determine if there are sex differences in NKCC2 abundance and/or distribution, and to evaluate the contribution of ovarian hormones to any such differences, we performed semiquantitative immunoblotting and immunoperoxidase immunohistochemistry for NKCC2 in the kidney of Sprague Dawley male, female and ovariectomized (OVX) rats with and without 17-β estradiol or progesterone supplementation. Intact females demonstrated greater NKCC2 protein in homogenates of whole kidney (334%±29), cortex (219%±20) and outer medulla (133%±9) compared to males. Ovarian hormone supplementation to OVX rats regulated NKCC2 in the outer medulla only, with NKCC2 protein abundance decreasing slightly in response to progesterone but increasing in response to 17-β estradiol. Immunohistochemistry demonstrated prominent NKCC2 labeling in the apical membrane of thick ascending limb cells. Kidney section NKCC2 labeling confirmed regionalized regulation of NKCC2 by ovarian hormones. Localized regulation of NKCC2 by ovarian hormones may have importance in controlling sodium and water balance over the lifetime of women as the milieu of sex hormones varies. PMID:20580730

  16. Bleaching response of Symbiodinium (zooxanthellae): determination by flow cytometry.

    PubMed

    Lee, Co Sin; Yeo, Yin Sheng Wilson; Sin, Tsai Min

    2012-10-01

    Coral bleaching is of increasing concern to reef management and stakeholders. Thus far, quantification of coral bleaching tends to be heavily reliant on the enumeration of zooxanthellae, with less emphasis on assessment of photosynthetic or physiological condition, these being often assessed separately by techniques such as liquid chromatography. Traditional methods of enumeration using microscopy are time consuming, subjected to low precision and great observer error. In this study, we presented a method for the distinction of physoiological condition and rapid enumeration of zooxanthellae using flow cytometry (FCM). Microscopy verified that healthy looking/live versus damaged/dead zooxanthellae could be reliably and objectively distinguished and counted by FCM on the basis of red and green fluorescence and light scatter. Excellent correlations were also determined between FCM and microscopy estimates of cell concentrations of fresh zooxanthellae isolates from Pocillopora damicornis. The relative intensities of chlorophyll and β-carotene fluorescences were shown to be important in understanding the results of increased cell counts in freshly isolated zooxanthellae experimentally exposed to high temperatures (34, 36, and 38°C) over 24 h, with ambient temperature (29°C) used as controls. The ability to simultaneously identify and enumerate subpopulations of different physiological states in the same sample provides an enormous advantage in not just determining bleaching responses, but elucidating adaptive response and mechanisms for tolerance. Therefore, this approach might provide a rapid, convenient, and reproducible methodology for climate change studies and reef management programs. Copyright © 2012 International Society for Advancement of Cytometry.

  17. Exploratory Analysis of TP53 Mutations in Circulating Tumour DNA as Biomarkers of Treatment Response for Patients with Relapsed High-Grade Serous Ovarian Carcinoma: A Retrospective Study

    PubMed Central

    Piskorz, Anna M.; Biggs, Heather; Addley, Helen; Freeman, Sue; Moyle, Penelope; Sala, Evis; Sayal, Karen; Hosking, Karen; Gounaris, Ioannis; Earl, Helena M.; Rosenfeld, Nitzan; Brenton, James D.

    2016-01-01

    Background Circulating tumour DNA (ctDNA) carrying tumour-specific sequence alterations may provide a minimally invasive means to dynamically assess tumour burden and response to treatment in cancer patients. Somatic TP53 mutations are a defining feature of high-grade serous ovarian carcinoma (HGSOC). We tested whether these mutations could be used as personalised markers to monitor tumour burden and early changes as a predictor of response and time to progression (TTP). Methods and Findings We performed a retrospective analysis of serial plasma samples collected during routine clinical visits from 40 patients with HGSOC undergoing heterogeneous standard of care treatment. Patient-specific TP53 assays were developed for 31 unique mutations identified in formalin-fixed paraffin-embedded tumour DNA from these patients. These assays were used to quantify ctDNA in 318 plasma samples using microfluidic digital PCR. The TP53 mutant allele fraction (TP53MAF) was compared to serum CA-125, the current gold-standard response marker for HGSOC in blood, as well as to disease volume on computed tomography scans by volumetric analysis. Changes after one cycle of treatment were compared with TTP. The median TP53MAF prior to treatment in 51 relapsed treatment courses was 8% (interquartile range [IQR] 1.2%–22%) compared to 0.7% (IQR 0.3%–2.0%) for seven untreated newly diagnosed stage IIIC/IV patients. TP53MAF correlated with volumetric measurements (Pearson r = 0.59, p < 0.001), and this correlation improved when patients with ascites were excluded (r = 0.82). The ratio of TP53MAF to volume of disease was higher in relapsed patients (0.04% per cm3) than in untreated patients (0.0008% per cm3, p = 0.004). In nearly all relapsed patients with disease volume > 32 cm3, ctDNA was detected at ≥20 amplifiable copies per millilitre of plasma. In 49 treatment courses for relapsed disease, pre-treatment TP53MAF concentration, but not CA-125, was associated with TTP. Response to

  18. Mechanistic Study on Triptorelin Action in Protecting From 5-FU-Induced Ovarian Damage in Rats.

    PubMed

    Wang, Ying; Tian, Xiaoyu; Liang, Lingxia; Wang, Yan; Wang, Ruifang; Cheng, Xiaolin; Yan, Zhen; Chen, Yawei; Qi, Pengwei

    2014-01-01

    Triptorelin, a kind of GnRH agonist, is widely used in the treatment of hormone-responsive cancers in the clinic. This study aimed to discover the underlying mechanism of triptorelin in protection from 5-fluorouracil (5-FU)-induced ovarian damage in Sprague-Dawley rats. In the present study, after using 5-FU to induce ovarian damage in rats, body weight and wet ovaries were weighed, the levels of estradiol (E2), follicle-stimulating hormone (FSH), and anti-Müllerian hormone (AMH) in blood were detected, and the expression of Bcl-2, Bax, and NF-κB was determined. It suggested that, compared to the control, body weight gain, the ratio of ovarian wet weight to body weight, primary follicle numbers, and the levels of AMH were significantly decreased, while the concentration of E2 and FSH was heavily increased following 5-FU administration. In contrast, after coadministration of triptorelin with 5-FU, the ratio of ovarian wet weight to body weight and the levels of AMH were significantly increased, whereas the level of E2 and FSH was decreased significantly when compared with the 5-FU group. Furthermore, at indicated times, 5-FU led to the reduced Bcl-2 and NF-κB expression and increased Bax expression while triptorelin plus 5-FU increased Bcl-2 and NF-κB expression and decreased Bax expression. It was indicated that triptorelin could protect rats from 5-FU-induced ovarian damage by modulation of hormones, Bcl-2, Bax, and NF-κB. These results might highlight the mechanism of triptorelin as a protective agent in clinical chemotherapy for ovarian damage.

  19. Lysophosphatidic acid expression in theca cells depends on the type of bovine ovarian follicle.

    PubMed

    Sinderewicz, E; Grycmacher, K; Boruszewska, D; Kowalczyk-Zięba, I; Woclawek-Potocka, I

    2017-02-01

    Lysophosphatidic acid (LPA) exerts various actions on the mammalian reproductive system. In cows, LPA stimulates the synthesis and secretion of luteotropic factors in the ovary, which affects the growth and development of ovarian follicles. The role of LPA in granulosa cells, oocyte and oocyte-cumulus complex (COC) has previously been investigated; but its role in the theca layer, which is an important structural and functional component of the ovarian follicle, is still unclear. The goal of this study was to investigate the expression of LPA in theca cells originating from different bovine ovarian follicle types. Theca cells were separated from healthy, transitional and atretic ovarian follicles, based on intrafollicular estradiol: progesterone ratios. LPA concentration in the follicular fluid (FF) in different follicle types was measured, and expression of the enzymes responsible for LPA synthesis (autotaxin [AX], phospholipase A2 [PLA2]) and receptors for LPA (LPAR1-4) were determined. The obtained results confirmed the follicle-type dependent presence of LPA in the FF of the bovine ovarian follicles. The highest concentration of LPA was detected in follicles classified as healthy and dominant. LPAR1-4, PLA2 and AX expression in theca cells in all of the types of follicles examined were detected at mRNA and protein level. These results suggest that theca cells can be a source of LPA synthesis other than granulosa cells and COCs, as well as the target for its action in the bovine ovarian follicle, with PLA2 and LPAR4 playing major roles in LPA synthesis and action. © 2016 Blackwell Verlag GmbH.

  20. Insulin-Like Growth Factor 2 Silencing Restores Taxol Sensitivity in Drug Resistant Ovarian Cancer

    PubMed Central

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J.; Wang, Yanhua; Huang, Gloria S.

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone. PMID:24932685

  1. Meeting Report: Structural Determination of Environmentally Responsive Proteins

    PubMed Central

    Reinlib, Leslie

    2005-01-01

    The three-dimensional structure of gene products continues to be a missing lynchpin between linear genome sequences and our understanding of the normal and abnormal function of proteins and pathways. Enhanced activity in this area is likely to lead to better understanding of how discrete changes in molecular patterns and conformation underlie functional changes in protein complexes and, with it, sensitivity of an individual to an exposure. The National Institute of Environmental Health Sciences convened a workshop of experts in structural determination and environmental health to solicit advice for future research in structural resolution relative to environmentally responsive proteins and pathways. The highest priorities recommended by the workshop were to support studies of structure, analysis, control, and design of conformational and functional states at molecular resolution for environmentally responsive molecules and complexes; promote understanding of dynamics, kinetics, and ligand responses; investigate the mechanisms and steps in posttranslational modifications, protein partnering, impact of genetic polymorphisms on structure/function, and ligand interactions; and encourage integrated experimental and computational approaches. The workshop participants also saw value in improving the throughput and purity of protein samples and macromolecular assemblies; developing optimal processes for design, production, and assembly of macromolecular complexes; encouraging studies on protein–protein and macromolecular interactions; and examining assemblies of individual proteins and their functions in pathways of interest for environmental health. PMID:16263521

  2. Experimental determination of storage ring optics using orbit response measurements

    NASA Astrophysics Data System (ADS)

    Safranek, J.

    1997-02-01

    The measured response matrix giving the change in orbit at beam position monitors (BPMs) with changes in steering magnet excitation can be used to accurately calibrate the linear optics in an electron storage ring [1-8]. A computer code called LOCO (Linear Optics from Closed Orbits) was developed to analyze the NSLS X-Ray Ring measured response matrix to determine: the gradients in all 56 quadrupole magnets; the calibration of the steering magnets and BPMs; the roll of the quadrupoles, steering magnets, and BPMs about the electron beam direction; the longitudinal magnetic centers of the orbit steering magnets; the horizontal dispersion at the orbit steering magnets; and the transverse mis-alignment of the electron orbit in each of the sextupoles. Random orbit measurement error from the BPMs propagated to give only 0.04% rms error in the determination of individual quadrupole gradients and 0.4 mrad rms error in the determination of individual quadrupole rolls. Small variations of a few parts in a thousand in the quadrupole gradients within an individual family were resolved. The optics derived by LOCO gave accurate predictions of the horizontal dispersion, the beta functions, and the horizontal and vertical emittances, and it gave good qualitative agreement with the measured vertical dispersion. The improved understanding of the X-Ray Ring has enabled us to increase the synchrotron radiation brightness. The LOCO code can also be used to find the quadrupole family gradients that best correct for gradient errors in quadrupoles, in sextupoles, and from synchrotron radiation insertion devices. In this way the design periodicity of a storage ring's optics can be restored. An example of periodicity restoration will be presented for the NSLS VUV Ring. LOCO has also produced useful results when applied to the ALS storage ring [8].

  3. Nintedanib in ovarian cancer.

    PubMed

    Khalique, Saira; Banerjee, Susana

    2017-09-01

    Advanced ovarian cancer remains an unmet clinical need. Angiogenesis is considered a therapeutic target in ovarian cancer, with bevacizumab, a monoclonal antibody against VEGF, being the first drug to show a progression-free survival benefit. Nintedanib is an oral tyrosine kinase inhibitor targeting VEGF receptor 1-3, FGFR 1-3 and PDGFR α and β, which has entered phase III trial development in ovarian cancer. Areas covered: This article reviews the preclinical and clinical efficacy of nintedanib in ovarian cancer, its pharmacokinetic and pharmacodynamics profile, safety issues, together with an overview of clinical trials carried out so far. A literature search was made in PubMed for nintedanib, ovarian cancer, angiogenesis, and on ClinicalTrials.gov site for clinical trials with nintedanib. Expert opinion: An ongoing phase III trial investigating nintedanib combined with first-line chemotherapy in ovarian cancer has shown a statistically significant progression free survival benefit, although there were toxicity issues. The true clinical benefit of nintedanib in ovarian cancer including its optimal treatment setting and dosage still need to be addressed.

  4. Ovarian cortex cryopreservation in pediatric and adolescent medicine

    PubMed

    Revel; Davis; Casper

    2000-05-01

    Background: Increased pediatric/adolescent cancer survivor rates have enhanced awareness of long-term effects of therapy, specifically gonadal failure. Ovarian cortex cryopreservation may hold the promise of fertility for those at risk for ovarian failure due to medical therapy. The object of this study was to determine if an ovarian cryopreservation program is feasible and to define suitable candidates.Method: A MEDLINE search supplemented by bibliographies. The review was limited to English articles on ovarian failure rates following radiation and/or chemotherapy and on ovarian cryopreservation. Investigators in the field were consulted to identify other sources.Results: Approximately one third of postpubertal females exposed to chemotherapy or radiotherapy develop ovarian failure. The risk is mostly significant for patients exposed to pelvic radiotherapy (up to 32% decrease in fertility) and alkylating agent based chemotherapy (infertility in 22%). A ninefold increase in premature ovarian failure results from exposure to combined pelvic radiotherapy and alkylator based chemotherapy. Practically all patients exposed to multiple agent chemotherapy combined with pelvic radiotherapy at doses used in preparation for bone marrow transplant will undergo irreversible loss of ovarian function. Currently human ovarian cortex can be cryopreserved, thawed and stimulated with gonadotrophins to produce follicles when transplanted into immunosuppressed mice, however there has yet to be any human pregnancies. The immunosupressed mouse model could also serve as a test to determine whether the tissue carries metastatic risk prior to reimplantation into the donor.Conclusion: Based on the literature we propose ovarian cortex cryopreservation and banking for postpubertal females prior to chemotherapy and/or radiation therapy that holds a high risk of ovarian failure. In the future this may provide oocytes for reproductive purposes. A protocol is currently under approval by the

  5. Cardiovascular response to noise in type A and type B female subjects: Effect of the ovarian cycle

    NASA Astrophysics Data System (ADS)

    Di Nisi, J.; Muzet, A.

    1989-10-01

    The aim of the investigation was to study the heart rate and finger pulse responses during the menstrual cycle in type A and type B female subjects. Nine type A's and nine type B's were selected by using the French version of Bortner's short rating scale questionnaire. They were exposed to noise in three different periods of the menstrual cycle; menses (day 0-2), pre-ovulation (8-10) and post-ovulation (22-24). No significant difference in tonic heart rate level between type A's and type B's was found. The percentages of HRR and FPR were not significantly different for the two types of subjects. However, the amplitude of HRR and FPR were significantly higher in type A's than in type B's. significant differences related to the periods of the menstrual cycle were also found. In type B's, the amplitude of HRR was larger during menses than during the two other periods. In type A's, the amplitude of the FPR was higher during the menses than during the pre-ovulation. The percentage of noise stimuli eliciting HRR and FPR did not vary as a function of the menstrual cycle. These results are discussed in terms of excitability and balance of the autonomic nervous system.

  6. Determinants of cortisol awakening responses to naps and nighttime sleep.

    PubMed

    Devine, Jaime K; Wolf, Jutta M

    2016-01-01

    The cortisol awakening response (CAR) is a phenomenon describing the sharp increase in basal cortisol levels shortly after waking from sleep. While extensively studied, little is known about the role of sleep architecture contributing to CAR. Furthermore, the potential for CAR after a shorter bout of sleep--a nap--has not been directly investigated. The current studies thus aimed at assessed sleep duration, time of day, and sleep architecture as potential determinants of the cortisol awakening response. Saliva samples were collected during the first hour (0, 30, 45, 60 min) following several EEG-monitored laboratory sleep conditions. Those included afternoon naps wherein 17 participants (4 men; ages 18-26) napped for 50 min and 24 participants (11 men; ages 18-24) napped for 90 min. Furthermore, 20 participants (10 men; ages 18-35) visited the lab twice and in addition to staying overnight, napped 90 min in the morning either under placebo conditions or pharmacologically-manipulated sleep conditions (5mg Zolpidem). Cortisol increases were observed in response to each sleep condition except to 50-min afternoon naps. Furthermore, CARs were predicted by Stage 2 sleep when following nighttime sleep (r=.46, p=.04) and by Stage 1 sleep when following placebo morning naps (r=.54, p=.01). The current study established cortisol awakening responses to naps and implicates sleep duration and architecture in the generation of CAR to both napping and nighttime sleep. Assessing CAR in conjunction with the specific type of sleep may thus contribute to our understanding of mechanisms underlying positive and negative health effects of napping. Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. MV-NIS Infected Mesenchymal Stem Cells in Treating Patients With Recurrent Ovarian Cancer

    ClinicalTrials.gov

    2017-03-14

    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

  8. 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

  9. Inhibition of ovarian cancer cell proliferation by a cell cycle inhibitory peptide fused to a thermally responsive polypeptide carrier

    PubMed Central

    Massodi, Iqbal; Moktan, Shama; Rawat, Aruna; Bidwell, Gene L.; Raucher, Drazen

    2009-01-01

    Current treatment of solid tumors is limited by normal tissue tolerance, resulting in a narrow therapeutic index. To increase drug specificity and efficacy and to reduce toxicity in normal tissues, we have developed a polypeptide carrier for a cell cycle inhibitory peptide, which has the potential to be thermally targeted to the tumor site. The design of this polypeptide is based on elastin-like polypeptide (ELP). The coding sequence of ELP was modified by the addition of the cell penetrating peptide Bac-7 at the N-terminus and a 23 amino acid peptide derived from p21 at the C-terminus (Bac-ELP1-p21). Bac-ELP1-p21 is soluble in aqueous solutions below physiological temperature (37°C) but aggregates when the temperature is raised above 39°C, making it a promising thermally responsive therapeutic carrier that may be actively targeted to solid tumors by application of focused hyperthermia. While Bac-ELP1-p21 at 37°C did not have any effect on SKOV-3 cell proliferation, the use of hyperthermia increased the antiproliferative effect of Bac-ELP1-p21 compared with a thermally unresponsive control polypeptide. Bac-ELP1-p21 displayed both a cytoplasmic and nuclear distribution in the SKOV-3 cells, with nuclear-localized polypeptide enriched in the heated cells, as revealed by confocal microscopy. Using Western blotting, we show that Bac-ELP1-p21 caused a decrease in Rb phosphorylation levels in cells treated at 42°C. The polypeptide also induced caspase activation, PARP cleavage, and cell cycle arrest in S-phase and G2/M-phase. These studies indicate that ELP is a promising macromolecular carrier for the delivery of cell cycle inhibitory peptides to solid tumors. PMID:19588502

  10. Characterization of bovine early growth response factor-1 and its gonadotropin-dependent regulation in ovarian follicles prior to ovulation.

    PubMed

    Sayasith, Khampoune; Brown, Kristy A; Lussier, Jacques G; Doré, Monique; Sirois, Jean

    2006-10-01

    Early growth response factor-1 (EGR-1) is a transcription factor that is involved in the transactivation of several genes. The objective of this study was to characterize gonadotropin-dependent regulation of bovine EGR-1 in preovulatory follicles prior to ovulation. Bovine EGR-1 cDNA was obtained by RT-PCR, 5'- and 3'-RACE, its open reading frame composed of 1623 bp, and its coding region encodes a 540-amino acid protein that displays 62-93% identity to known mammalian homologs. The regulation of EGR-1 mRNA was studied in bovine preovulatory follicles which were isolated 0-24 h post-hCG using semiquantitative RT-PCR/Southern blot. Results revealed that the levels of EGR-1 mRNA were very low in follicles at 0 h, markedly increased at 6 h (P < 0.05) when compared to 0 h, and decreased between 12 and 24 h post-hCG. High levels of the EGR-1 mRNA were also observed in corpus luteum, uterus, kidney, pituitary, and spleen, moderate and low in other bovine tissues tested. Analyses performed on isolated preparations of granulosa and theca cells indicated that EGR-1 mRNA was regulated in both cell types, with a predominant expression in granulosa cells. Immunohistochemistry on sections of preovulatory follicles isolated before and after hCG confirmed its protein expression in granulosa cells, 24 h post-hCG. Studies of EGR-1 regulation in primary granulosa cells cultured with forskolin showed that levels of EGR-1 mRNA were low at 0 h, highly increased at 6 h post-forskolin (P < 0.05), and declined to steady state thereafter. Immunoblotting confirmed forskolin-induced EGR-1 protein in cultures. Interestingly, overexpression of EGR-1 increased the levels of mRNA for prostaglandin (PG) G/H synthase-2 (PGHS-2), PG E synthase (PGES), PG E2 receptor (EP2), LH receptor (LH-R), but not for cytochrome P450-side chain cleavage (P450scc), and cytochrome P450 aromatase (P450arom) in granulosa cultures. Thus, this study reports for the first time, a gonadotropin-dependent induction of

  11. Algorithms for Determining Physical Responses of Structures Under Load

    NASA Technical Reports Server (NTRS)

    Richards, W. Lance; Ko, William L.

    2012-01-01

    Ultra-efficient real-time structural monitoring algorithms have been developed to provide extensive information about the physical response of structures under load. These algorithms are driven by actual strain data to measure accurately local strains at multiple locations on the surface of a structure. Through a single point load calibration test, these structural strains are then used to calculate key physical properties of the structure at each measurement location. Such properties include the structure s flexural rigidity (the product of the structure's modulus of elasticity, and its moment of inertia) and the section modulus (the moment of inertia divided by the structure s half-depth). The resulting structural properties at each location can be used to determine the structure s bending moment, shear, and structural loads in real time while the structure is in service. The amount of structural information can be maximized through the use of highly multiplexed fiber Bragg grating technology using optical time domain reflectometry and optical frequency domain reflectometry, which can provide a local strain measurement every 10 mm on a single hair-sized optical fiber. Since local strain is used as input to the algorithms, this system serves multiple purposes of measuring strains and displacements, as well as determining structural bending moment, shear, and loads for assessing real-time structural health. The first step is to install a series of strain sensors on the structure s surface in such a way as to measure bending strains at desired locations. The next step is to perform a simple ground test calibration. For a beam of length l (see example), discretized into n sections and subjected to a tip load of P that places the beam in bending, the flexural rigidity of the beam can be experimentally determined at each measurement location x. The bending moment at each station can then be determined for any general set of loads applied during operation.

  12. A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF: a multicenter randomized non-inferiority trial.

    PubMed

    Youssef, M A; van Wely, M; Al-Inany, H; Madani, T; Jahangiri, N; Khodabakhshi, S; Alhalabi, M; Akhondi, M; Ansaripour, S; Tokhmechy, R; Zarandi, L; Rizk, A; El-Mohamedy, M; Shaeer, E; Khattab, M; Mochtar, M H; van der Veen, F

    2017-01-01

    In subfertile women with poor ovarian reserve undergoing IVF does a mild ovarian stimulation strategy lead to comparable ongoing pregnancy rates in comparison to a conventional ovarian stimulation strategy? A mild ovarian stimulation strategy in women with poor ovarian reserve undergoing IVF leads to similar ongoing pregnancy rates as a conventional ovarian stimulation strategy. Women diagnosed with poor ovarian reserve are treated with a conventional ovarian stimulation strategy consisting of high-dose gonadotropins and pituitary downregulation with a long mid-luteal start GnRH-agonist protocol. Previous studies comparing a conventional strategy with a mild ovarian stimulation strategy consisting of low-dose gonadotropins and pituitary downregulation with a GnRH-antagonist have been under powered and their effectiveness is inconclusive. This open label multicenter randomized trial was designed to compare one cycle of a mild ovarian stimulation strategy consisting of low-dose gonadotropins (150 IU FSH) and pituitary downregulation with a GnRH-antagonist to one cycle of a conventional ovarian stimulation strategy consisting of high-dose gonadotropins (450 IU HMG) and pituitary downregulation with a long mid-luteal GnRH-agonist in women of advanced maternal age and/or women with poor ovarian reserve undergoing IVF between May 2011 and April 2014. Couples seeking infertility treatment were eligible if they fulfilled the following inclusion criteria: female age ≥35 years, a raised basal FSH level >10 IU/ml irrespective of age, a low antral follicular count of ≤5 follicles or poor ovarian response or cycle cancellation during a previous IVF cycle irrespective of age. The primary outcome was ongoing pregnancy rate per woman randomized. Analyses were on an intention-to-treat basis. We randomly assigned 195 women to the mild ovarian stimulation strategy and 199 women to the conventional ovarian stimulation strategy. Ongoing pregnancy rate was 12.8% (25/195) for mild

  13. The Role and Application of Sirtuins and mTOR Signaling in the Control of Ovarian Functions

    PubMed Central

    Sirotkin, Alexander V.

    2016-01-01

    The present short review demonstrates the involvement of sirtuins (SIRTs) in the control of ovarian functions at various regulatory levels. External and endocrine factors can affect female reproduction via SIRTs-mammalian target of rapamycin (mTOR) system, which, via hormones and growth factors, can in turn regulate basic ovarian functions (proliferation, apoptosis, secretory activity of ovarian cells, their response to upstream hormonal regulators, ovarian folliculo- and oogenesis, and fecundity). SIRTs and SIRTs-related signaling molecules and drugs regulating mTOR can be used for characterization, prediction, and regulation of ovarian functions, as well as for diagnostics and treatment of ovarian disorders. PMID:27886120

  14. Reflex modulation of ovarian estradiol secretion by noxious mechanical stimulation of a hindpaw in anesthetized rats.

    PubMed

    Uchida, Sae; Kagitani, Fusako; Hotta, Harumi

    2012-11-02

    Previously, we demonstrated that electrical stimulation of the superior ovarian nerve in rats reduces the ovarian estradiol secretion rate. In the present study, we examined the effect of noxious mechanical afferent stimulation (pinching) of a hindpaw on the ovarian estradiol secretion rate in rats. The rats were anesthetized on the day of estrus, and the ovarian venous blood was collected intermittently. The secretion rate of estradiol from the ovary was calculated from differences in the estradiol concentration between ovarian venous plasma and systemic arterial blood plasma, and from the flow rate of ovarian venous plasma. Pinching stimulation of a hindpaw for 5 min decreased the estradiol secretion rate from the ovary. A significant reduction of the estradiol secretion rate began at 5 min after the end of the stimulation and lasted for 20 min. The minimum decrease in estradiol secretion rate was 71.1 ± 14.0% of the prestimulus basal values at 15 min after the stimulation ended. The decrease responses of the ovarian estradiol secretion rate were abolished by bilateral severance of the superior ovarian nerves. The efferent activity of the superior ovarian nerves was increased following hindpaw pinching. After spinal transection at the second cervical level, the increased response of the superior ovarian nerve activity by hindpaw pinching was abolished. These results indicate that noxious mechanical stimulation of a hindpaw decreases the estradiol secretion rate from the ovary, and that the response is due to reflex activation of ovarian sympathetic nerves, mediated by supraspinal structures.

  15. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice.

    PubMed

    La Marca, Antonio; Sunkara, Sesh Kamal

    2014-01-01

    The main objective of individualization of treatment in IVF is to offer every single woman the best treatment tailored to her own unique characteristics, thus maximizing the chances of pregnancy and eliminating the iatrogenic and avoidable risks resulting from ovarian stimulation. Personalization of treatment in IVF should be based on the prediction of ovarian response for every individual. The starting point is to identify if a woman is likely to have a normal, poor or a hyper response and choose the ideal treatment protocol tailored to this prediction. The objective of this review is to summarize the predictive ability of ovarian reserve markers, such as antral follicle count (AFC) and anti-Mullerian hormone (AMH), and the therapeutic strategies that have been proposed in IVF after this prediction. A systematic review of the existing literature was performed by searching Medline, EMBASE, Cochrane library and Web of Science for publications in the English language related to AFC, AMH and their incorporation into controlled ovarian stimulation (COS) protocols in IVF. Literature available to May 2013 was included. The search generated 305 citations of which 41 and 25 studies, respectively, reporting the ability of AMH and AFC to predict response to COS were included in this review. The literature review demonstrated that AFC and AMH, the most sensitive markers of ovarian reserve identified to date, are ideal in planning personalized COS protocols. These sensitive markers permit prediction of the whole spectrum of ovarian response with reliable accuracy and clinicians may use either of the two markers as they can be considered interchangeable. Following the categorization of expected ovarian response to stimulation clinicians can adopt tailored therapeutic strategies for each patient. Current scientific trend suggests the elective use of the GnRH antagonist based regimen for hyper-responders, and probably also poor responders, as likely to be beneficial. The

  16. Determinants of ambulance response time: A study in Sabah, Malaysia

    NASA Astrophysics Data System (ADS)

    Chin, Su Na; Cheah, Phee Kheng; Arifin, Muhamad Yaakub; Wong, Boh Leng; Omar, Zaturrawiah; Yassin, Fouziah Md; Gabda, Darmesah

    2017-04-01

    Ambulance response time (ART) is one of the standard key performance indicators (KPI) in measuring the emergency medical services (EMS) delivery performances. When the mean time of ART of EMS system reaches the KPI target, it shows that the EMS system performs well. This paper considers the determinants of ART, using data sampled from 967 ambulance runs in a government hospital in Sabah. Multiple regression analysis with backward elimination was proposed for the identification of significant factors. Amongst the underlying factors, travel distance, age of patients, type of treatment and peak hours were identified to be significantly affecting ART. Identifying factors that influence ART helps the development of strategic improvement planning for reducing the ART.

  17. Determination of bacterial chemotaxis response functions by optical trapping

    NASA Astrophysics Data System (ADS)

    Altindal, Tuba

    A two-lobe response function is considered as a manifestation of temporal signal comparison in bacterial chemosensing. The second lobe in the response function appears as a result of adaptive behavior of the underlying signaling network, which allows bacteria to stay sensitive over a wide range of background signal levels. It has been argued that this two-lobe response reflects the dual requirements of the bacteria to taxis along a chemical gradient and to localize once the top of the gradient is reached. Calculations based on the run-tumble motility pattern of Escherichia coli showed that the second lobe improved the bacterium's localization capability. Intrigued by a recently observed run-reverse-flick motility cycle of a marine bacterium Vibrio alginolyticus, we investigate the motility-response relationship in this bacterium. Using a novel optical trapping technique, we measure the response of V. alginolyticus to an impulsive stimulus of chemoattractant serine. By exploiting an asymmetry in the rotation of the polar flagellum, we are able to determine for the first time how the bacterium responds to chemical stimuli while swimming forward or backward. Our measurements suggest that this marine bacterium regulates its forward and backward swimming intervals differently, exhibiting behaviors that is consistent with an exploration-exploitation strategy. In our measurements, we also find that the cell-body O( t) and the flagellar o(t) rotational angular frequencies oscillate in time and are in synchrony with the forward and backward swimming intervals. Unexpectedly, O(t) and o( t) are found to be anticorrelated in that the cell body rotates slower in the forward direction than in the backward direction, Of < Ob, but the flagellum rotates faster in the the forward direction than in the backward direction. The change in the rotational load (~ 25%) is significantly greater than that predicted by flagellum deformation but can be accounted for by the precession of the

  18. Surface responses and desirability functions to determine optimal granulation domains.

    PubMed

    Giry, K; Viana, M; Genty, M; Wüthrich, P; Chulia, D

    2010-09-01

    Single pot mixer-granulator-dryer (high-shear granulator with in situ double jacket vacuum drying) and multiphase equipment (high-shear granulator associated with fluid bed dryer) are classically used for wet granulation. At present time, industrial production imperatives may require to switch one formulation from one equipment to another. To compare the two processes and to define, for each of them, the optimal formulation domain, experiments were organized according to Doehlert experimental designs. Response surfaces were used to identify the levels of each factor (binder and filler ratios) inducing the more satisfying responses. The contribution of binder and filler ratios to granule properties was highlighted according to the process. Then the desirability function was used to determine and compare the optimal formulation domain for each process. In the studied formulation domain and for the considered equipment, the transposition from a single pot to a multiphase high-shear granulation process did not seem to raise difficulties; the same formulations were out of specification for both processes and other trials, the technological properties were maintained or improved in the Fielder/Niro equipment.

  19. Biomagnetic activity in ovarian lesions.

    PubMed

    Anastasiadis, P; Anninos, P; Kotini, A; Limberis, B; Galazios, G

    1998-01-01

    BACKGROUND-MATERIALS: This study aimed to investigate biomagnetic activity in benign and malignant ovarian diseases using the biomagnetometer SQUID. Magnetic recordings were obtained from 40 patients with palpable ovarian lesions. 19 of these were invasive carcinomas, and 21 were benign ovarian lesions. We used a one channel biomagnetometer SQUID (superconducting quantum interference device), in order to measure the magnetic field from benign and malignant ovarian diseases. Interestingly, the ovarian lesion waveforms and the corresponding spectral densities were of high amplitude in most (96%) malignant ovarian lesions, and of low amplitude in most (95%) benign ovarian diseases. These findings were of statistical significance (students t-test p < 0.005). It is suggested that biomagnetic measurement of benign and malignant ovarian diseases, which is an entirely new application of SQUID technology, is a promising procedure for assessing ovarian tumors.

  20. Determinants of Paramedic Response Readiness for CBRNE Threats

    PubMed Central

    Jones, Alison; Smith, George; Nelson, Jenny; Agho, Kingsley; Taylor, Melanie; Raphael, Beverley

    2010-01-01

    Paramedics play a pivotal role in the response to major emergencies. Recent evidence indicates that their confidence and willingness to respond to chemical, biological, radiological, nuclear, and explosives-related (CBRNE) incidents differs from that relating to their “routine” emergency work. To further investigate the factors underpinning their readiness to respond to CBRNE incidents, paramedics in New South Wales (NSW), Australia, were asked to complete a validated online survey instrument. Univariate and multivariate analyses were performed to examine associated factors determining readiness. The sample of 663 respondents was weighted to reflect the NSW paramedic population as a whole. The univariate analysis indicated that gender, length of service, deployment concern, perceived personal resilience, CBRNE training, and incident experience were significantly associated with perceived CBRNE response readiness. In the initial multivariate analysis, significantly higher response readiness was associated with male gender, university education, and greater length of service (10-15 years). In the final multivariate model, the combined effect of training/incident experience negated the significant effects observed in the initial model and, importantly, showed that those with recent training reported higher readiness, irrespective of incident experience. Those with lower concern regarding CBRNE deployment and those with higher personal resilience were significantly more likely to report higher readiness (Adjusted Relative Risk [ARR] = 0.91, 95% CI: 0.84-0.99; ARR = 1.40, 95% CI: 1.11-1.72, respectively). These findings will assist emergency medical planners in recognizing occupational and dispositional factors associated with enhanced CBRNE readiness and highlight the important role of training in redressing potential readiness differences associated with these factors. PMID:20569060

  1. Determinants of paramedic response readiness for CBRNE threats.

    PubMed

    Stevens, Garry; Jones, Alison; Smith, George; Nelson, Jenny; Agho, Kingsley; Taylor, Melanie; Raphael, Beverley

    2010-06-01

    Paramedics play a pivotal role in the response to major emergencies. Recent evidence indicates that their confidence and willingness to respond to chemical, biological, radiological, nuclear, and explosives-related (CBRNE) incidents differs from that relating to their "routine" emergency work. To further investigate the factors underpinning their readiness to respond to CBRNE incidents, paramedics in New South Wales (NSW), Australia, were asked to complete a validated online survey instrument. Univariate and multivariate analyses were performed to examine associated factors determining readiness. The sample of 663 respondents was weighted to reflect the NSW paramedic population as a whole. The univariate analysis indicated that gender, length of service, deployment concern, perceived personal resilience, CBRNE training, and incident experience were significantly associated with perceived CBRNE response readiness. In the initial multivariate analysis, significantly higher response readiness was associated with male gender, university education, and greater length of service (10-15 years). In the final multivariate model, the combined effect of training/incident experience negated the significant effects observed in the initial model and, importantly, showed that those with recent training reported higher readiness, irrespective of incident experience. Those with lower concern regarding CBRNE deployment and those with higher personal resilience were significantly more likely to report higher readiness (Adjusted Relative Risk [ARR] = 0.91, 95% CI: 0.84-0.99; ARR = 1.40, 95% CI: 1.11-1.72, respectively). These findings will assist emergency medical planners in recognizing occupational and dispositional factors associated with enhanced CBRNE readiness and highlight the important role of training in redressing potential readiness differences associated with these factors.

  2. Reversing Platinum Resistance in High-Grade Serous Ovarian Carcinoma: Targeting BRCA and the Homologous Recombination System.

    PubMed

    Wiedemeyer, W Ruprecht; Beach, Jessica A; Karlan, Beth Y

    2014-01-01

    Resistance to platinum chemotherapy is one of the main factors driving ovarian cancer mortality, and overcoming platinum resistance is considered one of the greatest challenges in ovarian cancer research. Genetic and functional evidence points to the homologous recombination (HR) DNA repair system, and BRCA1 and BRCA2 in particular, as main determinants of response to platinum therapy. BRCA-mutant ovarian cancers are especially sensitive to platinum, associated with better survival, and amenable to poly ADP ribose polymerase inhibitor treatment. Here, we discuss a therapeutic concept that seeks to disrupt HR capacity via targeting of BRCA1 and BRCA2 functionality in order to reverse platinum resistance in BRCA-proficient high-grade serous ovarian cancers (HGSOC). We review the molecular signaling pathways that converge on BRCA1 and BRCA2, their activation status in ovarian cancer, and therapeutic options to modulate BRCA function. Several recent publications demonstrate efficient chemosensitization of BRCA-proficient cancers by combining targeted therapy with standard platinum-based agents. Due to its inherent genomic heterogeneity, molecularly defined subgroups of HGSOC may require different approaches. We seek to provide an overview of available agents and their potential use to reverse platinum resistance by inhibiting the HR system, either directly or indirectly, by targeting oncogenic activators of HR.

  3. Salinomycin reduces stemness and induces apoptosis on human ovarian cancer stem cell

    PubMed Central

    Lee, Hyun-Gyo; Shin, So-Jin; Cha, Soon-Do

    2017-01-01

    Objective Cancer stem cells (CSCs) represent a subpopulation of undifferentiated tumorigenic cells thought to be responsible for tumor initiation, maintenance, drug resistance, and metastasis. The role of CSCs in drug resistance and relapse of cancers could significantly affect outcomes of ovarian cancer patient. Therefore, therapies that target CSCs could be a promising approach for ovarian cancer treatment. The antibiotic salinomycin has recently been shown to deplete CSCs. In this study, we evaluated the effect of salinomycin on ovarian cancer stem cells (OCSCs), both alone and in combination with paclitaxel (PTX). Methods The CD44+CD117+CSCs were obtained from the ascitic fluid of patients with epithelial ovarian cancer by using an immune magnetic-activated cell sorting system. OCSCs were treated with PTX and salinomycin either singly or in combination. Cell viability and apoptosis assays were performed and spheroid-forming ability was measured. The expression of sex determining region Y-box 2 (SOX2) and octamer-binding transcription factor 3/4 (OCT3/4) mRNA was determined using reverse transcription polymerase chain reaction, and protein expression was observed using western blot analysis. Results Treatment with salinomycin alone reduced the stemness marker expression and spheroid-forming ability of OCSCs. Treatment with PTX alone did not decrease the viability of OCSCs. Treatment with a combination of salinomycin decreased the viability of OCSCs and promoted cell apoptosis. The enhancement of combination treatment was achieved through the apoptosis as determined by annexin V/propidium iodide (PI) staining, caspase-3 activity, and DNA fragmentation assay. Conclusion Based on our findings, combining salinomycin with other anti-cancer therapeutic agents holds promise as an ovarian cancer treatment approach that can target OCSCs. PMID:27894167

  4. Ovarian Cancer: Nutrition

    MedlinePlus

    ... and phytochemicals. High fiber intakes may have a positive benefit by altering hormonal actions of ovarian and other hormonal-dependent cancers. Daily fiber intake should be 25-35 grams of insoluble and soluble fiber. Important Plant Sources ...

  5. Primary Ovarian Insufficiency (POI)

    MedlinePlus

    ... Overview Condition Information What are common symptoms? How many people are affected/at risk? ... Ovarian Insufficiency (POI): Condition Information Skip sharing on social media links Share this: Page Content What is POI? ...

  6. Dietary factors and epithelial ovarian cancer.

    PubMed Central

    Shu, X. O.; Gao, Y. T.; Yuan, J. M.; Ziegler, R. G.; Brinton, L. A.

    1989-01-01

    Dietary data from a population-based case-control study of 172 epithelial ovarian cancer cases and 172 controls were analysed. A significant (P less than 0.01) dose-response relationship was found between intake of fat from animal sources and risk of ovarian cancer, but plant fat was not associated. Although the effect of animal fat was confounded by education, an adjusted odds ratio of 1.8 persisted for those in the upper quartile compared to the lower quartile of consumption (P for trend = 0.03). After adjustment for animal fat intake, calorific and protein intake had minimal effects on risk. Total vegetables were found to be somewhat protective, but the mechanism of action was unclear. Weight, height and relative weight (weight/height2) were not related to risk of ovarian cancer. PMID:2757927

  7. Trastuzumab Sensitizes Ovarian Cancer Cells to EGFR-targeted Therapeutics.

    PubMed

    Wilken, Jason A; Webster, Kristy T; Maihle, Nita J

    2010-03-27

    Early studies have demonstrated comparable levels of HER2/ErbB2 expression in both breast and ovarian cancer. Trastuzumab (Herceptin), a therapeutic monoclonal antibody directed against HER2, is FDA-approved for the treatment of both early and late stage breast cancer. However, clinical studies of trastuzumab in epithelial ovarian cancer (EOC) patients have not met the same level of success. Surprisingly, however, no reports have examined either the basis for primary trastuzumab resistance in ovarian cancer or potential ways of salvaging trastuzumab as a potential ovarian cancer therapeutic. An in vitro model of primary trastuzumab-resistant ovarian cancer was created by long-term culture of HER2-positive ovarian carcinoma-derived cell lines with trastuzumab. Trastuzumab treated vs. untreated parental cells were compared for HER receptor expression, trastuzumab sensitivity, and sensitivity to other HER-targeted therapeutics. In contrast to widely held assumptions, here we show that ovarian cancer cells that are not growth inhibited by trastuzumab are still responsive to trastuzumab. Specifically, we show that responsiveness to alternative HER-targeted inhibitors, such as gefitinib and cetuximab, is dramatically potentiated by long-term trastuzumab treatment of ovarian cancer cells. HER2-positive ovarian carcinoma-derived cells are, therefore, not "unresponsive" to trastuzumab as previously assumed, even when they not growth inhibited by this drug. Given the recent success of EGFR-targeted therapeutics for the treatment of other solid tumors, and the well-established safety profile of trastuzumab, results presented here provide a rationale for re-evaluation of trastuzumab as an experimental ovarian cancer therapeutic, either in concert with, or perhaps as a "primer" for EGFR-targeted therapeutics.

  8. Hereditary ovarian cancer.

    PubMed

    Russo, Antonio; Calò, Valentina; Bruno, Loredana; Rizzo, Sergio; Bazan, Viviana; Di Fede, Gaetana

    2009-01-01

    At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong family history or BRCA mutation carriers include transvaginal pelvic ultrasound with color Doppler and serum CA125 every 6 months. Bilateral salpingo-oophorectomy appears to be effective to reduce the risk of ovarian cancer in BRCA mutation carriers. Hysterosalpingo-oophorectomy should be considered in HNPCC women who undergo surgery for colorectal carcinoma.

  9. S1P differentially regulates migration of human ovarian cancer and human ovarian surface epithelial cells

    PubMed Central

    Wang, Dongmei; Zhao, Zhenwen; Caperell-Grant, Andrea; Yang, Gong; Mok, Samuel C.; Liu, Jinsong; Bigsby, Robert M.; Xu, Yan

    2009-01-01

    Epithelial ovarian cancer (EOC) arises from the epithelial layer covering the surface of ovaries and intra-peritoneal metastasis is commonly observed at diagnosis. Sphingosine-1-phosphate (S1P), a bioactive lipid signaling molecule, is potentially involved in EOC tumorigenesis. We have found that S1P is elevated in human EOC ascites. We show that physiologically relevant concentrations of S1P stimulate migration and invasion of EOC cells, but inhibit migration of human ovarian surface epithelial (HOSE) cells. In addition, S1P inhibits lysophosphatidic acid (LPA)-induced cell migration in HOSE, but not in EOC cells. We have provided the first line of evidence that the expression levels of S1P receptor subtypes are not the only determinants for how cells respond to S1P. Even though S1P1 is expressed and functional in HOSE cells, the inhibitory effect mediated by S1P2 is dominant in those cells. The cellular pre-existing stress fibers are also important determinants for the migratory response to S1P. Differential S1P-induced morphology changes are noted in EOC and HOSE cells. Pre-existing stress fibers in HOSE cells are further enhanced by S1P treatment, resulting in the negative migratory response to S1P. By contrast, EOC cells lost stress fibers and S1P treatment induces filopodium-like structures at cell edges, which correlates with increased cell motility. In addition, inhibition of the protein kinase C pathway is likely to be involved in the inhibitory effect of S1P on LPA-induced cell migration in HOSE cells. These findings are important for the development of new therapeutics targeting S1P and LPA in EOC. PMID:18645009

  10. [Actinomycotic tubo-ovarian abscess. Contribution of pelvic angioscanner].

    PubMed

    Bazot, M; Davenne, C; Benzakine, Y; Boudghène, F; Bigot, J M

    1997-07-01

    Pelvic actinomycosis is uncommon and usually responsible for tubo-ovarian abscesses which are similar in aspect with nonactinomycotic abscesses. They are usually a complication of an intra-uterine device (IUD) that can be absent as in this case. The differential diagnosis is ovarian cancer. The role of the dynamic CT scan for differential diagnosis in this case is presented. Preoperative diagnosis in this affection is important because of the excellent response to Penicillin.

  11. Ovarian follicle diameter at timed insemination and estrous response influence likelihood of ovulation and pregnancy after estrous synchronization with progesterone or progestin-based protocols in suckled Bos indicus cows.

    PubMed

    Sá Filho, M F; Crespilho, A M; Santos, J E P; Perry, G A; Baruselli, P S

    2010-07-01

    The objectives of the present study were to evaluate factors associated with estrous synchronization responses and pregnancy per insemination (P/AI) in Bos indicus beef cows submitted to progesterone-based fixed-time artificial insemination (FTAI) protocols. A total of 2388 cows (1869 Nellore and 519 crossbred NellorexAngus) from 10 commercial farms were evaluated to determine the relationships among breed, body condition score (BCS) on the first day of the FTAI protocol, the occurrence of estrus between progesterone device removal and FTAI, and diameter of largest ovarian follicle (LF) at FTAI on estrous synchronization responses and P/AI. Cows (n=412 primiparous; 1976 multiparous) received an intravaginal device containing progesterone or an ear implant containing norgestomet (a progestin), and an injection of estradiol at the beginning of the estrous synchronization protocol. Body condition was scored using a 1-5 scale on the first day of the FTAI protocol and at 30-60 days postpartum. Females received 300IU of equine chorionic gonadotropin (eCG) and PGF(2alpha) on the day the progesterone device/implant was removed and were inseminated 48-60h later. At insemination, cows (n=2388) were submitted to an ultrasonographic exam to determine the diameter of the LF. Follicles were classified into four categories based on mean and standard deviation (SD) of the LF (LF1=two SD below the mean; LF2=mean minus one SD; LF3=mean plus one SD; LF4=two SD above the mean). Ovulation rate was determined in a subset of cows (n=813) by three consecutive ultrasonographic exams: (1) at time of progesterone device/implant removal, (2) at time of FTAI and (3) 48h after FTAI. Ovulation was defined as the disappearance of a large follicle (>or=8.0mm) that was previously recorded. Estrus was determined in a subset of the cows (n=445) by the activation of a detection of estrous patch placed on the tail head on the day of progesterone device/implant removal. Pregnancy was diagnosed 30 days

  12. Is immune system-related hypertension associated with ovarian hormone deficiency?

    PubMed

    Sandberg, Kathryn; Ji, Hong; Einstein, Gillian; Au, April; Hay, Meredith

    2016-03-01

    What is the topic of this review? This review summarizes recent data on the role of ovarian hormones and sex in inflammation-related hypertension. What advances does it highlight? The adaptive immune system has recently been implicated in the development of hypertension in males but not in females. The role of the immune system in the development of hypertension in women and its relationship to ovarian hormone production are highlighted. The immune system is known to contribute to the development of high blood pressure in males. However, the role of the immune system in the development of high blood pressure in females and the role of ovarian hormones has only recently begun to be studied. In animal studies, both the sex of the host and the T cell are critical biological determinants of susceptibility and resistance to hypertension induced by angiotensin II. In women, natural menopause is known to result in significant changes in the expression of genes regulating the immune system. Likewise, in animal models, ovariectomy results in hypertension and an upregulation in T-cell tumour necrosis factor-α-related genes. Oestrogen replacement results in decreases in inflammatory genes in the brain regions involved in blood pressure regulation. Together, these studies suggest that the response of the adaptive immune system to ovarian hormone deficiency is a significant contributor to hypertension in women. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

  13. High dose intensity combination chemotherapy for advanced epithelial ovarian carcinoma: results of a pilot study.

    PubMed Central

    Sweetenham, J. W.; McKendrick, J. J.; Jones, D. H.; Whitehouse, J. M.; Williams, C. J.

    1990-01-01

    Retrospective studies have recently demonstrated a significant correlation between dose intensity of chemotherapy and response rates and survival in various diseases including epithelial ovarian carcinoma. As part of a proposed randomised trial to assess the effect of dose intensity on outcome in ovarian carcinoma, a pilot study has been undertaken to determine the toxicity and efficacy of the high intensity therapy. Nineteen patients with advanced ovarian carcinoma received initial treatment with cisplatin 120 mg m-2 i.v. day 1, and cyclophosphamide 1,000 mg-2 i.v. day 1, given at 21-day intervals for six cycles. The average relative dose intensity of this therapy is 1.14 when compared with the CHAP regimen. Severe toxicity was experienced by most patients. The median received average relative dose intensity was 0.90, with only one patient receiving treatment to the proposed intensity. Randomised studies of the effect of dose intensity in ovarian carcinoma are essential, but an initial step must be to assess whether the proposed high dose treatment can be delivered. PMID:2155645

  14. CMKLR1 deficiency maintains ovarian steroid production in mice treated chronically with dihydrotestosterone

    PubMed Central

    Tang, Mi; Huang, Chen; Wang, Yu-Fei; Ren, Pei-Gen; Chen, Li; Xiao, Tian-Xia; Wang, Bao-Bei; Pan, Yan-Fei; Tsang, Benjamin K.; Zabel, Brian A; Ma, Bao-Hua; Zhao, Hui-Ying; Zhang, Jian V.

    2016-01-01

    Elevated serum chemerin levels correlate with increased severity of polycystic ovary syndrome (PCOS). However, the role of CMKLR1 signaling in ovarian biology under conditions of excess DHT remains unclear. In this study we compared the effects of continuous 90-day high dose DHT exposure (83.3 □g/day) on wild type and CMKLR1-deficient mice. DHT induced PCOS-like clinical signs in wild type mice as well as significant changes in the expression of hormone receptors, steroid synthesis enzymes, and BMPs and their receptors. In contrast, CMKLR1-deficient mice significantly attenuated DHT-induced clinical signs of PCOS and alterations in ovarian gene expression. To determine whether the BMP4 signaling pathway was involved in the pathogenic effects of CMKLR1 signaling in DHT-induced ovarian steroidogenesis, antral follicles were isolated from wild type and CMKLR1 knockout (KO) mice and treated in vitro with combinations of hCG, DHT, and BMP4 inhibitors. BMP4 inhibition attenuated the induction effects of hCG and DHT on estrogen and progesterone secretion in CMKLR1 KO mice, but not in WT mice, implicating the BMP4 signaling pathway in the CMKLR1-dependent response to DHT. In conclusion, CMKLR1 gene deletion attenuates the effects of chronic DHT treatment on ovarian function in experimental PCOS, likely via BMP4 signaling. PMID:26893072

  15. [Ovarian pregnancy: about 3 cases and review of the literature].

    PubMed

    Ranaivoson, Haingo Voahangy Rabetafika; Ranaivomanana, Volahasina Françine; Nomenjanahary, Lalaina; Andriamampionona, Tsitohery Francine; Randrianjafisamindrakotroka, Nantenaina Soa

    2016-01-01

    Ovarian pregnancy is a rare event among women with ectopic pregnancy in whom the ovary is the site of implantation. Its diagnosis requires a well codified approach. The peculiarities of the determining factors, of the histopathological and evolutionary features typical of ovarian pregnancies led us to focus on this form of ectopic pregnancy. We report 3 cases of ovarian pregnancy diagnosed in our Department. The three women were between 30 and 42 years, at 13 to 37 weeks of amenorrhea. All women had abdominal pain of varying intensity associated with shock. Anatomopathological examination of the right annex, normal site of implantation of ovarian pregnancies, confirmed the diagnosis. All women had juxtaposition ovarian cortical pregnancy. Ovarian pregnancy is a rare event among women with ectopic pregnancy, having specific peculiarities. Its diagnosis is difficult and is based on preoperative findings. The identification of the ovarian implantation on histopathological examination is ideal for confirming the diagnosis. Currently, it is assumed that ovarian pregnancy is the form of ectopic pregnancy which can develop to term or even result in a live birth.

  16. Histogenesis of ovarian malignant mixed mesodermal tumours.

    PubMed Central

    Clarke, T J

    1990-01-01

    The histogenesis of ovarian malignant mixed mesodermal tumours, which includes the concept of metaplastic carcinoma, is controversial. Four such tumours were examined for evidence of metaplastic transition from carcinoma to sarcoma using morphology and reticulin stains. Consecutive sections were stained immunohistochemically using cytokeratin and vimentin to determine whether cells at the interface between carcinoma and sarcoma expressed both cytokeratin and vimentin. There was no evidence of morphological, architectural, or immunohistochemical transitions from carcinoma to sarcoma in the four tumours studied. This suggests that ovarian malignant mixed mesodermal tumours are not metaplastic carcinomas but are composed of histogenetically different elements. Images PMID:2160478

  17. Burn size determines the inflammatory and hypermetabolic response

    PubMed Central

    Jeschke, Marc G; Mlcak, Ronald P; Finnerty, Celeste C; Norbury, William B; Gauglitz, Gerd G; Kulp, Gabriela A; Herndon, David N

    2007-01-01

    Background Increased burn size leads to increased mortality of burned patients. Whether mortality is due to inflammation, hypermetabolism or other pathophysiologic contributing factors is not entirely determined. The purpose of the present study was to determine in a large prospective clinical trial whether different burn sizes are associated with differences in inflammation, body composition, protein synthesis, or organ function. Methods Pediatric burned patients were divided into four burn size groups: <40% total body surface area (TBSA) burn, 40–59% TBSA burn, 60–79% TBSA burn, and >80% TBSA burn. Demographic and clinical data, hypermetabolism, the inflammatory response, body composition, the muscle protein net balance, serum and urine hormones and proteins, and cardiac function and changes in liver size were determined. Results One hundred and eighty-nine pediatric patients of similar age and gender distribution were included in the study (<40% TBSA burn, n = 43; 40–59% TBSA burn, n = 79; 60–79% TBSA burn, n = 46; >80% TBSA burn, n = 21). Patients with larger burns had more operations, a greater incidence of infections and sepsis, and higher mortality rates compared with the other groups (P < 0.05). The percentage predicted resting energy expenditure was highest in the >80% TBSA group, followed by the 60–79% TBSA burn group (P < 0.05). Children with >80% burns lost the most body weight, lean body mass, muscle protein and bone mineral content (P < 0.05). The urine cortisol concentration was highest in the 80–99% and 60–79% TBSA burn groups, associated with significant myocardial depression and increased change in liver size (P < 0.05). The cytokine profile showed distinct differences in expression of IL-8, TNF, IL-6, IL-12p70, monocyte chemoattractant protein-1 and granulocyte–macrophage colony-stimulating factor (P < 0.05). Conclusion Morbidity and mortality in burned patients is burn size dependent, starts at a 60% TBSA burn and is due to an

  18. Determining blood and plasma volumes using bioelectrical response spectroscopy

    NASA Technical Reports Server (NTRS)

    Siconolfi, S. F.; Nusynowitz, M. L.; Suire, S. S.; Moore, A. D. Jr; Leig, J.

    1996-01-01

    We hypothesized that an electric field (inductance) produced by charged blood components passing through the many branches of arteries and veins could assess total blood volume (TBV) or plasma volume (PV). Individual (N = 29) electrical circuits (inductors, two resistors, and a capacitor) were determined from bioelectrical response spectroscopy (BERS) using a Hewlett Packard 4284A Precision LCR Meter. Inductance, capacitance, and resistance from the circuits of 19 subjects modeled TBV (sum of PV and computed red cell volume) and PV (based on 125I-albumin). Each model (N = 10, cross validation group) had good validity based on 1) mean differences (-2.3 to 1.5%) between the methods that were not significant and less than the propagated errors (+/- 5.2% for TBV and PV), 2) high correlations (r > 0.92) with low SEE (< 7.7%) between dilution and BERS assessments, and 3) Bland-Altman pairwise comparisons that indicated "clinical equivalency" between the methods. Given the limitation of this study (10 validity subjects), we concluded that BERS models accurately assessed TBV and PV. Further evaluations of the models' validities are needed before they are used in clinical or research settings.

  19. Determining blood and plasma volumes using bioelectrical response spectroscopy

    NASA Technical Reports Server (NTRS)

    Siconolfi, S. F.; Nusynowitz, M. L.; Suire, S. S.; Moore, A. D. Jr; Leig, J.

    1996-01-01

    We hypothesized that an electric field (inductance) produced by charged blood components passing through the many branches of arteries and veins could assess total blood volume (TBV) or plasma volume (PV). Individual (N = 29) electrical circuits (inductors, two resistors, and a capacitor) were determined from bioelectrical response spectroscopy (BERS) using a Hewlett Packard 4284A Precision LCR Meter. Inductance, capacitance, and resistance from the circuits of 19 subjects modeled TBV (sum of PV and computed red cell volume) and PV (based on 125I-albumin). Each model (N = 10, cross validation group) had good validity based on 1) mean differences (-2.3 to 1.5%) between the methods that were not significant and less than the propagated errors (+/- 5.2% for TBV and PV), 2) high correlations (r > 0.92) with low SEE (< 7.7%) between dilution and BERS assessments, and 3) Bland-Altman pairwise comparisons that indicated "clinical equivalency" between the methods. Given the limitation of this study (10 validity subjects), we concluded that BERS models accurately assessed TBV and PV. Further evaluations of the models' validities are needed before they are used in clinical or research settings.

  20. Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer

    PubMed Central

    Deng, Junli; Wang, Li; Chen, Hongmin; Hao, Jingli; Ni, Jie; Chang, Lei; Duan, Wei; Graham, Peter; Li, Yong

    2016-01-01

    Chemoresistance is the main challenge for the recurrent ovarian cancer therapy and responsible for treatment failure and unfavorable clinical outcome. Understanding mechanisms of chemoresistance in ovarian cancer would help to predict disease progression, develop new therapies and personalize systemic therapy. In the last decade, accumulating evidence demonstrates that epithelial-mesenchymal transition and cancer stem cells play important roles in ovarian cancer chemoresistance and metastasis. Treatment of epithelial-mesenchymal transition and cancer stem cells holds promise for improving current ovarian cancer therapies and prolonging the survival of recurrent ovarian cancer patients in the future. In this review, we focus on the role of epithelial-mesenchymal transition and cancer stem cells in ovarian cancer chemoresistance and explore the therapeutic implications for developing epithelial-mesenchymal transition and cancer stem cells associated therapies for future ovarian cancer treatment. PMID:27304054

  1. Ovarian Germ Cell Tumors Treatment

    MedlinePlus

    ... Tube, & Primary Peritoneal Cancer Screening Research Ovarian Germ Cell Tumors Treatment (PDQ®)–Patient Version General Information About Ovarian Germ Cell Tumors Go to Health Professional Version Key Points ...

  2. Interleukin-6 as a therapeutic target in human ovarian cancer

    PubMed Central

    Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D. Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery; Vermeulen, Jessica; Singh, Naveena; Avril, Norbert; Cummings, Jeff; Rexhepaj, Elton; Jirström, Karin; Gallagher, William M; Brennan, Donal J.; McNeish, Iain A.; Balkwill, Fran

    2011-01-01

    Purpose We investigated whether inhibition of IL-6 has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. Experimental Design We combined pre-clinical and in silico experiments with a phase II clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Results Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases demonstrated that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signalling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, whilst seven others had periods of disease stabilization. In patients treated for six months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12 and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. Conclusions IL-6 stimulates inflammatory cytokine production, tumor angiogenesis and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralising anti-IL-6 antibody in pre-clinical and clinical studies. PMID:21795409

  3. Interleukin-6 as a therapeutic target in human ovarian cancer.

    PubMed

    Coward, Jermaine; Kulbe, Hagen; Chakravarty, Probir; Leader, David; Vassileva, Vessela; Leinster, D Andrew; Thompson, Richard; Schioppa, Tiziana; Nemeth, Jeffery; Vermeulen, Jessica; Singh, Naveena; Avril, Norbert; Cummings, Jeff; Rexhepaj, Elton; Jirström, Karin; Gallagher, William M; Brennan, Donal J; McNeish, Iain A; Balkwill, Frances R

    2011-09-15

    We investigated whether inhibition of interleukin 6 (IL-6) has therapeutic activity in ovarian cancer via abrogation of a tumor-promoting cytokine network. We combined preclinical and in silico experiments with a phase 2 clinical trial of the anti-IL-6 antibody siltuximab in patients with platinum-resistant ovarian cancer. Automated immunohistochemistry on tissue microarrays from 221 ovarian cancer cases showed that intensity of IL-6 staining in malignant cells significantly associated with poor prognosis. Treatment of ovarian cancer cells with siltuximab reduced constitutive cytokine and chemokine production and also inhibited IL-6 signaling, tumor growth, the tumor-associated macrophage infiltrate and angiogenesis in IL-6-producing intraperitoneal ovarian cancer xenografts. In the clinical trial, the primary endpoint was response rate as assessed by combined RECIST and CA125 criteria. One patient of eighteen evaluable had a partial response, while seven others had periods of disease stabilization. In patients treated for 6 months, there was a significant decline in plasma levels of IL-6-regulated CCL2, CXCL12, and VEGF. Gene expression levels of factors that were reduced by siltuximab treatment in the patients significantly correlated with high IL-6 pathway gene expression and macrophage markers in microarray analyses of ovarian cancer biopsies. IL-6 stimulates inflammatory cytokine production, tumor angiogenesis, and the tumor macrophage infiltrate in ovarian cancer and these actions can be inhibited by a neutralizing anti-IL-6 antibody in preclinical and clinical studies. ©2011 AACR.

  4. Genetic Modifiers of Ovarian Cancer

    DTIC Science & Technology

    2013-06-01

    cancer suggesting the presence of genetic modifiers of ovarian cancer in this population. A genome wide association study ( GWAS ) for ovarian cancer...cancer and 1,000 age-matched unaffected BRCA1 carriers. As outlined in detail in our previous annual report, we recently conducted a GWAS of BRCA1...between ovarian cancer risk and SNPs implicated in Aim 1 by genotyping 1,500 BRCA1 ovarian cancer cases and 1,500 unaffected BRCA1 carriers. GWAS

  5. Cognitive and Ocular Factors Jointly Determine Pupil Responses under Equiluminance

    PubMed Central

    Brascamp, Jan; Nuiten, Stijn; Hoppenbrouwers, Sylco; Theeuwes, Jan

    2016-01-01

    Changes in pupil diameter can reflect high-level cognitive signals that depend on central neuromodulatory mechanisms. However, brain mechanisms that adjust pupil size are also exquisitely sensitive to changes in luminance and other events that would be considered a nuisance in cognitive experiments recording pupil size. We implemented a simple auditory experiment involving no changes in visual stimulation. Using finite impulse-response fitting we found pupil responses triggered by different types of events. Among these are pupil responses to auditory events and associated surprise: cognitive effects. However, these cognitive responses were overshadowed by pupil responses associated with blinks and eye movements, both inevitable nuisance factors that lead to changes in effective luminance. Of note, these latter pupil responses were not recording artifacts caused by blinks and eye movements, but endogenous pupil responses that occurred in the wake of these events. Furthermore, we identified slow (tonic) changes in pupil size that differentially influenced faster (phasic) pupil responses. Fitting all pupil responses using gamma functions, we provide accurate characterisations of cognitive and non-cognitive response shapes, and quantify each response's dependence on tonic pupil size. These results allow us to create a set of recommendations for pupil size analysis in cognitive neuroscience, which we have implemented in freely available software. PMID:27191166

  6. Ovarian ectopic pregnancy in adolescence

    PubMed Central

    Andrade, Ana Gonçalves; Rocha, Sara; Marques, Catarina O; Simões, Mafalda; Martins, Isabel; Biscaia, Isabel; F Barros, Carlos

    2015-01-01

    Key Clinical Message Ovarian pregnancy is one of the rarest types of extrauterine pregnancy. Its preoperative diagnosis remains a challenge since it presents quite similarly to tubal pregnancy and complicated ovarian cysts. Although in most cases, histology is necessary to confirm the diagnosis, we present an ovarian pregnancy in a teenager, correctly diagnosed during ultrasound examination. PMID:26576271

  7. Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug☆

    PubMed Central

    Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

    2015-01-01

    Objective Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. Methods The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Results Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Conclusions Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. PMID:25172764

  8. Inhibition of epithelial ovarian cancer by Minnelide, a water-soluble pro-drug.

    PubMed

    Rivard, Colleen; Geller, Melissa; Schnettler, Erica; Saluja, Manju; Vogel, Rachel Isaksson; Saluja, Ashok; Ramakrishnan, Sundaram

    2014-11-01

    Minnelide is a water-soluble pro-drug of triptolide, a natural product. The goal of this study was to evaluate the effectiveness of Minnelide on ovarian cancer growth in vitro and in vivo. The effect of Minnelide on ovarian cancer cell proliferation was determined by real time electrical impedance measurements. Multiple mouse models with C200 and A2780 epithelial ovarian cancer cell lines were used to assess the efficacy of Minnelide in inhibiting ovarian cancer growth. Minnelide decreased cell viability of both platinum sensitive and resistant epithelial ovarian cancer cells in vitro. Minnelide with carboplatin showed additive effects in vitro. Minnelide monotherapy increased the survival of mice bearing established ovarian tumors. Minnelide, in combination with carboplatin and paclitaxel, improved overall survival of mice. Minnelide is a promising pro-drug for the treatment of ovarian cancer, especially when combined with standard chemotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. The genetic make-up of ovarian development and function: the focus on the transcription factor FOXL2.

    PubMed

    Elzaiat, M; Todeschini, A-L; Caburet, S; Veitia, R A

    2017-02-01

    In a 46 XY individual, the presence of the Y chromosome harboring the testis-determining factor (SRY) triggers testis determination and differentiation. In a 46 XX individual, the absence of SRY and the activation of genes associated with the female pathway lead to ovarian development. The latter process has long been considered as a default pathway. However, recent studies have cast doubts on this dogma. Here, after a brief overview of the main steps of ovarian development, we focus on three genes WNT4, RSPO1 and FOXL2 that are essential for ovarian determination, differentiation and/or maintenance. Special attention is paid to FOXL2 whose mutations are responsible for the blepharophimosis syndrome, often associated with female infertility, and for cancer. We highlight the cooperation of WNT4, RSPO1 and FOXL2 within a regulatory network and the need for further research to better understand their role in defining and maintaining ovarian identity. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Structural Analysis to Determine the Core of Hypoxia Response Network

    PubMed Central

    Heiner, Monika; Sriram, K.

    2010-01-01

    The advent of sophisticated molecular biology techniques allows to deduce the structure of complex biological networks. However, networks tend to be huge and impose computational challenges on traditional mathematical analysis due to their high dimension and lack of reliable kinetic data. To overcome this problem, complex biological networks are decomposed into modules that are assumed to capture essential aspects of the full network's dynamics. The question that begs for an answer is how to identify the core that is representative of a network's dynamics, its function and robustness. One of the powerful methods to probe into the structure of a network is Petri net analysis. Petri nets support network visualization and execution. They are also equipped with sound mathematical and formal reasoning based on which a network can be decomposed into modules. The structural analysis provides insight into the robustness and facilitates the identification of fragile nodes. The application of these techniques to a previously proposed hypoxia control network reveals three functional modules responsible for degrading the hypoxia-inducible factor (HIF). Interestingly, the structural analysis identifies superfluous network parts and suggests that the reversibility of the reactions are not important for the essential functionality. The core network is determined to be the union of the three reduced individual modules. The structural analysis results are confirmed by numerical integration of the differential equations induced by the individual modules as well as their composition. The structural analysis leads also to a coarse network structure highlighting the structural principles inherent in the three functional modules. Importantly, our analysis identifies the fragile node in this robust network without which the switch-like behavior is shown to be completely absent. PMID:20098728

  11. Ovarian and Uterine Grafts

    PubMed Central

    Cheval, Max

    1934-01-01

    Recent experience has convinced the author of the value of ovarian grafting. He gives the histories of a number of women upon whom he made implants of their own ovarian tissue in the course of operations for double oöphorectomy. The subsequent state of these patients is contrasted with that of women after castration without grafting. When the uterus was left in position menstruation was re-established in over 80% of the grafted cases. The author and his co-workers maintain that the vitality of autogenous grafts of ovarian substance is enhanced by hormones produced by the uterine mucosa. He therefore advocates that grafts of uterus be made in conjunction with ovarian implants whenever possible. Experiments carried out on animals have proved the correctness of this opinion. The results of a series of cases of combined ovarian and uterine graftings are recorded, and the technique of uterine mucosa implants is described. ImagesFig. 10Fig. 11Fig. 1Fig. 2Fig. 3Fig. 4Fig. 8Fig. 9Fig. 10Fig. 5Fig. 6 PMID:19989930

  12. Evaluation of 2-deoxy-2-[18F]fluoro-D-glucose- and 3'-deoxy-3'-[18F]fluorothymidine-positron emission tomography as biomarkers of therapy response in platinum-resistant ovarian cancer.

    PubMed

    Perumal, Meg; Stronach, Euan A; Gabra, Hani; Aboagye, Eric O

    2012-12-01

    We evaluated whether 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) could be used as imaging biomarkers of platinum resensitization in ovarian cancer. Paired platinum-sensitive and platinum-resistant ovarian cancer cells from the same patient, PEO1 and PEO4, grown as tumor xenografts in nude mice, were assessed by PET. The AKT inhibitor, API-2, resensitized platinum-resistant PEO4 tumors to cisplatin, leading to a markedly lower Ki67 labeling index (p ≤ 0.006, n = 6 per group). [(18)F]FDG-PET and [(18)F]FLT-PET imaging variables were lower after combination treatment compared with vehicle treatment (p ≤ 0.006, n = 6 per group). No changes were seen with either drug alone. PRAS40 phosphorylation status was a sensitive biochemical marker of pathway inhibition, whereas reductions thymidine kinase 1 expression defined the [(18)F]FLT response. Therapeutic inhibition of AKT activation in acquired platinum-resistant disease can be imaged noninvasively by [(18)F]FDG-PET and [(18)F]FLT-PET warranting further assessment.

  13. Akt isoform specific effects in ovarian cancer progression

    PubMed Central

    Linnerth-Petrik, Nicolle M.; Santry, Lisa A.; Moorehead, Roger; Jücker, Manfred

    2016-01-01

    Ovarian cancer remains a significant therapeutic problem and novel, effective therapies are needed. Akt is a serine-threonine kinase that is overexpressed in numerous cancers, including ovarian. Mammalian cells express three Akt isoforms which are encoded by distinct genes. Although there are several Akt inhibitors in clinical trials, most indiscriminately target all isoforms. Current in vitro data and animal knockout experiments suggest that the Akt isoforms may have divergent roles. In this paper, we determined the isoform-specific functions of Akt in ovarian cancer cell proliferation in vitro and in ovarian cancer progression in vivo. For in vitro experiments, murine and human ovarian cancer cells were treated with Akt inhibitors and cell viability was assessed. We used two different in vivo approaches to identify the roles of Akt isoforms in ovarian cancer progression and their influence on the primary tumor and tumor microenvironment. In one experiment, wild-type C57Bl6 mice were orthotopically injected with ID8 cells with stable knockdown of Akt isoforms. In a separate experiment, mice null for Akt 1-3 were orthotopically injected with WT ID8 cells (Figure 1). Our data show that inhibition of Akt1 significantly reduced ovarian cancer cell proliferation and inhibited tumor progression in vivo. Conversely, disruption of Akt2 increased tumor growth. Inhibition of Akt3 had an intermediate phenotype, but also increased growth of ovarian cancer cells. These data suggest that there is minimal redundancy between the Akt isoforms in ovarian cancer progression. These findings have important implications in the design of Akt inhibitors for the effective treatment of ovarian cancer. PMID:27533079

  14. Primary ovarian insufficiency in classic galactosemia: role of FSH dysfunction and timing of the lesion.

    PubMed

    Gubbels, Cynthia S; Land, Jolande A; Evers, Johannes L H; Bierau, Jörgen; Menheere, Paul P C A; Robben, Simon G F; Rubio-Gozalbo, M Estela

    2013-01-01

    FSH inactivity due to secondary hypoglycosylation has been suggested as a potential mechanism for primary ovarian insufficiency in classic galactosemia. To investigate the role of FSH and to gain insight in the timing of the damage, ovarian stimulation tests were performed and data on ovarian imaging collected. Fifteen patients with primary ovarian insufficiency underwent ovarian stimulation with gonadotropins. Only one patient showed a normal increase in estradiol level, all the others had a low or no estradiol response. Anti-Müllerian hormone measurement in all girls and women showed levels below the detection limit of 0.10 μg/l. Ovarian volumes were evaluated by MRI in 14 patients and compared to age matched controls, prepubertal controls and postmenopausal controls. The ovarian volumes of the galactosemic girls were smaller than those of the age matched controls (p = 0.001) and the prepubertal ovaries (p = 0.008), and did not differ significantly from postmenopausal ovarian volumes (p = 0.161). In conclusion we found no evidence that FSH inactivity plays a role in primary ovarian insufficiency in classic galactosemia. Moreover, ovarian imaging results point to an early onset of ovarian failure in this disease.

  15. Glutathione-deficient mice have increased sensitivity to transplacental benzo[a]pyrene-induced premature ovarian failure and ovarian tumorigenesis.

    PubMed

    Lim, Jinhwan; Lawson, Gregory W; Nakamura, Brooke N; Ortiz, Laura; Hur, Jin A; Kavanagh, Terrance J; Luderer, Ulrike

    2013-01-15

    Polycyclic aromatic hydrocarbons (PAH) such as benzo[a]pyrene (BaP) are ubiquitous environmental pollutants found in tobacco smoke, air pollution, and grilled foods. Prenatal exposure to BaP causes premature reproductive senescence in mice, and other PAHs are transplacental ovarian carcinogens. Glutathione (GSH) is critical for detoxification of the reactive metabolites of PAHs. Therefore, we hypothesized that mice that are genetically deficient in GSH synthesis, due to deletion of the modifier subunit of glutamate cysteine ligase (Gclm), the rate-limiting enzyme in GSH synthesis, have increased destruction of oogonia, premature ovarian failure, and ovarian tumorigenesis after transplacental BaP exposure compared with Gclm(+/+) females. Gclm(+/-) female and male mice were mated, and dams were treated with 0, 2, or 10 mg/kg/d BaP in sesame oil by gavage from gestational days 7 to 16. Compared with oil-treated F1 females of the same genotype, Gclm(-/-) prenatally BaP-treated females had significantly greater decrements in offspring production than Gclm(+/+) BaP-treated females. Similarly, we observed significant BaP dose × Gclm genotype interactions on ovarian follicle counts and ovarian tumor multiplicity at 7.5 months of age, with Gclm(-/-) females having greater decrements in follicle numbers and more ovarian tumors in response to prenatal BaP exposure than Gclm(+/+) females. The ovarian tumors were positive for the epithelial marker cytokeratin. Our results show that prenatal exposure of females to BaP causes premature ovarian failure and ovarian tumorigenesis and that embryonic GSH deficiency due to deletion of Gclm increases sensitivity to these transplacental ovarian effects of BaP.

  16. Xenobiotic Effects on Ovarian Preantral Follicles1

    PubMed Central

    Mark-Kappeler, Connie J.; Hoyer, Patricia B.; Devine, Patrick J.

    2011-01-01

    Women are born with a finite population of ovarian follicles, which are slowly depleted during their reproductive years until reproductive failure (menopause) occurs. The rate of loss of primordial follicles is determined by genetic and environmental influences, but certain toxic exposures can accelerate this process. Ionizing radiation reduces preantral follicle numbers in rodents and humans in a dose-dependent manner. Cigarette smoking is linked to menopause occurring 1–4 yr earlier than with nonsmokers, and components of smoke, polycyclic aromatic hydrocarbons, can cause follicle depletion in rodents or in ovaries in vitro. Chemotherapeutic agents, such as alkylating drugs and cisplatin, also cause loss of preantral ovarian follicles. Effects depend on dose, type, and reactivity of the drug, and the age of the individual. Evidence suggests DNA damage may underlie follicle loss induced by one common alkylating drug, cyclophosphamide. Occupational exposures have also been linked to ovarian damage. In an industrial setting, 2-bromopropane caused infertility in men and women, and it can induce ovarian follicle depletion in rats. Solvents, such as butadiene, 4-vinylcyclohexene, and their diepoxides, can also cause specific preantral follicle depletion. The mechanism(s) underlying effects of the latter compound may involve alterations in apoptosis, survival factors such as KIT/Kit Ligand, and/or the cellular signaling that maintains primordial follicle dormancy. Estrogenic endocrine disruptors may alter follicle formation/development and impair fertility or normal development of offspring. Thus, specific exposures are known or suspected of detrimentally impacting preantral ovarian follicles, leading to early ovarian failure. PMID:21697514

  17. Saturated fatty acids as possible important metabolites for epithelial ovarian cancer based on the free and esterified fatty acid profiles determined by GC-MS analysis.

    PubMed

    Yin, Rui; Yang, Tongshu; Su, Hui; Ying, Li; Liu, Liyan; Sun, Changhao

    2016-09-26

    The aims were to investigate the serum free fatty acid (FFA) and esterified fatty acid (EFA) profiles and to identify biomarkers that can be used to identify patients with epithelial ovarian cancer (EOC) based on the metabolomics approach. We applied a targeted gas chromatography-mass spectrometry metabolomics approach to serum samples from 40 EOC patients and 35 healthy controls for achieving the FFA and EFA profiles. These metabolite profiles were processed using multivariate analysis to obtain potential biomarkers. And then, some independent samples were chosen to validate these potential biomarkers. There were higher saturated fatty acids and lower unsaturated fatty acids in EOC patients when compared with the healthy controls. EFA (C16:0), EFA (C18:0) and FFA (C16:0) were identified as potential biomarkers that distinguished EOC from the healthy controls. The areas under the curve from the EFA (C16:0), EFA (C18:0) and FFA (C16:0) in validated study were 0.745, 0.701, 0.682, respectively. Our study provides useful information to bridge the gaps in our understanding to the fatty acids metabolic alterations associated with EOC, and this study has demonstrated saturated fatty acid biomarkers might be helpful for the detection and characterization of EOC patients.

  18. Screening for ovarian cancer.

    PubMed

    Menon, Usha; Jacobs, Ian

    2002-08-01

    There has been considerable interest in the prospect of early detection of ovarian cancer through screening asymptomatic women, in both the general and 'high-risk' populations. Over the last decade screening strategies using the serum marker CA126 and transvaginal ultrasound have been refined and encouraging data have emerged on the impact of screening on ovarian cancer survival rates. Two randomized controlled trials are now underway in the general population to establish the impact of screening on ovarian cancer mortality while comprehensively tackling the issues of compliance, health economics and physical and psychological morbidity. In addition, trials in the high-risk population aimed at optimizing the current strategy have commenced in both the USA and the UK.

  19. Ovarian innervation develops before initiation of folliculogenesis in the rat.

    PubMed

    Malamed, S; Gibney, J A; Ojeda, S R

    1992-10-01

    Sympathetic neurotransmitters have been shown to be present in the ovary of the rat during early postnatal development and to affect steroidogenesis before the ovary becomes responsive to gonadotropins, and before the first primordial follicles are formed. This study was undertaken to determine if development of the ovarian innervation is an event that antedates the initiation of folliculogenesis in the rat, Rattus norvegicus. Serial sections of postnatal ovaries revealed a negligible frequency of follicles 24 h after birth (about 1 primordial follicle per ovary). Twelve hours later there were about 500 follicles per ovary, a number that more than doubled to about 1300 during the subsequent 12 h, indicating that an explosive period of follicular differentiation occurs between the end of postnatal days 1 and 2. Electron microscopy demonstrated that before birth the ovaries are already innervated by fibers containing clear and dense-core vesicles. Immunohistochemistry performed on either fetal (day 19) or newborn (less than 15h after birth) ovaries showed the presence of catecholaminergic nerves, identified by their content of immunoreactive tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. While some of these fibers innervate blood vessels, others are associated with primordial ovarian cells, thereby suggesting their participation in non-vascular functions. Since prefollicular ovaries are insensitive to gonadotropins, the results suggest that the developing ovary becomes subjected to direct neurogenic influences before it acquires responsiveness to gonadotropins.

  20. IL-12 Expressing oncolytic herpes simplex virus promotes anti-tumor activity and immunologic control of metastatic ovarian cancer in mice.

    PubMed

    Thomas, Eric D; Meza-Perez, Selene; Bevis, Kerri S; Randall, Troy D; Gillespie, G Yancey; Langford, Catherine; Alvarez, Ronald D

    2016-10-27

    Despite advances in surgical aggressiveness and conventional chemotherapy, ovarian cancer remains the most lethal cause of gynecologic cancer mortality; consequently there is a need for new therapeutic agents and innovative treatment paradigms for the treatment of ovarian cancer. Several studies have demonstrated that ovarian cancer is an immunogenic disease and immunotherapy represents a promising and novel approach that has not been completely evaluated in ovarian cancer. Our objective was to evaluate the anti-tumor activity of an oncolytic herpes simplex virus "armed" with murine interleukin-12 and its ability to elicit tumor-specific immune responses. We evaluated the ability of interleukin-12-expressing and control oncolytic herpes simplex virus to kill murine and human ovarian cancer cell lines in vitro. We also administered interleukin-12-expressing oncolytic herpes simplex virus to the peritoneal cavity of mice that had developed spontaneous, metastatic ovarian cancer and determined overall survival and tumor burden at 95 days. We used flow cytometry to quantify the tumor antigen-specific CD8(+) T cell response in the omentum and peritoneal cavity. All ovarian cancer cell lines demonstrated susceptibility to oncolytic herpes simplex virus in vitro. Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus demonstrated a more robust tumor antigen-specific CD8(+) T-cell immune response in the omentum (471.6 cells vs 33.1 cells; p = 0.02) and peritoneal cavity (962.3 cells vs 179.5 cells; p = 0.05). Compared to controls, mice treated with interleukin-12-expressing oncolytic herpes simplex virus were more likely to control ovarian cancer metastases (81.2 % vs 18.2 %; p = 0.008) and had a significantly longer overall survival (p = 0.02). Finally, five of 6 mice treated with interleukin-12-expressing oHSV had no evidence of metastatic tumor when euthanized at 6 months, compared to two of 4 mice treated

  1. Is assessment of anti-Müllerian hormone and/or antral follicle count useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH and GnRH antagonists? A prospective observational study.

    PubMed

    Ganidou, Maria A; Kolibianakis, Efstratios M; Venetis, Christos A; Gerou, Spiros; Makedos, Georgios A; Klearchou, Nikolaos; Tarlatzis, Basil C

    2014-11-01

    The purpose of this prospective observational study was to evaluate whether the assessment of AMH and AFC is useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH (rec-FSH) and GnRH antagonists. A base model including age and basal FSH as independent predictors of COCs could explain 15% of the variance observed in the number of COCs retrieved (p = 0.002). The addition of AFC did not increase significantly the predictive ability of the above model, whereas the addition of AMH increased the performance of the base model by 13% (p < 0.001). Logistic regression analysis showed that only when AMH was added to the base model, including age and FSH, its predictive capacity for high ovarian response was statistically significant (F-test: p = 0.001; c-statistic: 0.80, 95% CI: 0.70-0.88), but this was not the case for poor ovarian response. In conclusion, the addition of AMH, but not of AFC, to a model including female age and basal FSH, is useful in the prediction of ovarian response in expected normal responders treated with a fixed dose of recombinant FSH and GnRH antagonists.

  2. Role of human epididymis protein 4 in chemoresistance and prognosis of epithelial ovarian cancer.

    PubMed

    Lee, Seungho; Choi, Seowon; Lee, Yookyung; Chung, Donghae; Hong, Suntaek; Park, Nohhyun

    2017-01-01

    Human epididymis protein 4 (HE4) is a novel biomarker for epithelial ovarian cancer. This study was designed to evaluate the role of HE4 in chemo-response against anti-cancer drugs and prognosis of epithelial ovarian cancer. HE4-depleted cells and HE4-overexpressing cells were generated. The effect of HE4 gene silencing and overexpression was examined using a cell viability assay after exposure to chemotherapeutic agents and the signaling pathway. We studied the expression of HE4 in ovarian cancer tissue and the prognostic significance. Cytoplasmic staining was graded for intensity and percentage of positive cells. The grades were multiplied to determine an H-score. Knockdown of HE4 in OVCAR-3 cells resulted in reduction in cell growth and increased sensitivity to paclitaxel and cisplatin compared to control cells. This effect originated from the decreased activation of cell-growth-related signaling, such as AKT and Erk mediated by epidermal growth factor (EGF), while overexpression of HE4 resulted in enhanced cell growth and suppressed the anti-tumorigenic activity of paclitaxel. Activation of AKT and Erk pathways was enhanced in HE4-overexpressing cells compared to control cells. Based on the results of multivariate analysis, the risk of death was significantly higher in patients with an H-score > 4. HE4 induces chemoresistance against anti-cancer drugs and activates the AKT and Erk pathways to enhance tumor survival. HE4 expression in ovarian cancer tissue is associated with a worse prognosis for epithelial ovarian cancer patients. © 2016 Japan Society of Obstetrics and Gynecology.

  3. Genetic testing for breast-ovarian cancer susceptibility: a regional trial.

    PubMed

    Loader, S; Levenkron, J C; Rowley, P T

    1998-01-01

    To evaluate receptivity to testing for a genetic susceptibility to breast-ovarian cancer, information is needed on the response when the offer is open to all qualifying women in a given region. To qualify in this trial, a woman who had not had breast or ovarian cancer had to have at least two first-degree relatives or one first- and one second-degree relative with breast and/or ovarian cancer, whereas a woman who had had breast or ovarian cancer had to have at least one first-degree relative with breast or ovarian cancer and a first- or second-degree relative without cancer willing to be tested. Of 140 women qualifying and interested enough to return questionnaires requesting baseline information, 111 were referred by their physician and 29 were identified from a regional tumor registry. Of these 140, 112 came for pretest education and 98 of these chose to be tested. Thus, the acceptance rate was 70% for all those returning baseline questionnaires, but 88% for those interested enough to come for pretest education. The most common reasons for accepting testing were to take extra precautions if a mutation were found (42.9%) and to determine if offspring were at risk (24.5%). The most common reasons for declining were anxiety and absence of specific interventions. Factors predicting who chose testing were years of education (p < 0.005) and family closeness (p < 0.02). Fourteen deleterious BRCA1 or BRCA2 mutations were found in 13 of the 87 families actually tested. If the criteria for testing had been three or more affected family members rather than two or more, the number of families tested would have been reduced by 46%, but the number of families found to have a deleterious mutation would have been reduced by only 9%.

  4. Ovarian tumor characterization using 3D ultrasound.

    PubMed

    Acharya, U Rajendra; Sree, S Vinitha; Krishnan, M Muthu Rama; Saba, Luca; Molinari, Filippo; Guerriero, Stefano; Suri, Jasjit S

    2012-12-01

    Among gynecological malignancies, ovarian cancer is the most frequent cause of death. Preoperative determination of whether a tumor is benign or malignant has often been found to be difficult. Because of such inconclusive findings from ultrasound images and other tests, many patients with benign conditions have been offered unnecessary surgeries thereby increasing patient anxiety and healthcare cost. The key objective of our work is to develop an adjunct Computer Aided Diagnostic (CAD) technique that uses ultrasound images of the ovary and image mining algorithms to accurately classify benign and malignant ovarian tumor images. In this algorithm, we extract texture features based on Local Binary Patterns (LBP) and Laws Texture Energ