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Decoy Receptor 3 (DcR3) Inhibits Intratumoral Lymphocytic Infiltration By Inhibiting LIGHT Induced Chemokine Production In Ovarian Cancer
Abstracts / Gynecologic Oncology 125 (2012) S3–S167
Results: We assessed the impact of neoadjuvant chemotherapy on the selected genes and microRNAs. Among the cell growth and proliferation genes MKI67, PLK1, PBK were reduced. Deactivation of the TUBB3 survival pathway, which was reduced while its negative regulator GNAI1 was increased. ERBB2 resulted downregulated in the neoadjuvant setting, while HGF and PTEN were increased. MicroRNAs expression broadly increased, with the only exception of miR-20a and miR-141. Patients exhibiting high levels of COL11A1 and PLK1 were poor performers, while the opposite occurred for GLI1. At the micro-RNA level the best predictors were miR-193a-5p, miR-375 and miR-20a. The poor performers (miR-193a-5p, miR-375) were featured by high levels of the micro-RNA while the opposite was evident for miR-20a. Conclusions: Use of the nanofluidic platform may provide deeper insight into the specific roles of clinically relevant major molecular networks. Chemotherapy induced modification of genes and microRNA expression can be used as a model to develop future prognostic biomarkers and therapeutic modalities.
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significantly more likely to use NSAIDS while Japanese (68% vs 32%) women were significantly less likely to use the medications. In addition, users were slightly heavier and non-users had menopause at a slightly older age. Use of aspirin, acetaminophen or other NSAID whether non-users, current or former user and whether short or longer duration had no impact on the relative risk for the development of ovarian cancer. Only very short duration of acetaminophen use (b1 yr) was found to reduce the risk of ovarian cancer (RR = 0.59). Analysis of NSAID use by race or histological subtype found no impact on risk of ovarian cancer. Conclusions: NSAID use appears to have no effect on the future development of epithelial ovarian cancer. doi:10.1016/j.ygyno.2011.12.231
231 Decoy receptor 3 (DcR3) inhibits intratumoral lymphocytic infiltration by inhibiting LIGHT induced chemokine production in ovarian cancer N. Onujiogu, M. Felder, A. Kapur, A. Ziebarth, J. Connor. University of Wisconsin, Madison, WI.
doi:10.1016/j.ygyno.2011.12.230
230 NSAIDS do not prevent ovarian cancer M. Carney, M. Goodman, G. Lurie, R. Weise. University of Hawaii, Honolulu, HI. Objective: NSAID use has been linked to the reduction of cancer risk in several cancers including colon. One theory for the development of ovarian cancer involves the inflammatory process which could be directly impacted with NSAID use. The purpose of this study was to examine the relationship of NSAID use and the risk for the development of ovarian cancer. Methods: This Multiethnic Cohort Study is a prospective study of 74,078 women aged 45–75 years residing in Hawaii and California recruited between 1993 and 1996. Subjects were asked via questionnaire demographics including race/ethnicity and details regarding whether they had ever taken an NSAID at least two times per week for one or more months including aspirin, acetaminophen, or other NSAID pain relief medication. Follow-up started on the date of baseline questionnaire completion and ended on the date of EOC diagnosis, death, or end of study follow-up (December 31, 2007), whichever came first. Incident cases of EOC and histologies were identified through record linkage with the Hawaii Tumor Registry, the Cancer Surveillance Program for Los Angeles County, and the California State Cancer Registry, which are all part of the NCI's SEER Program. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals using age as the time scale. Multivariable models adjusted for age, race/ethnicity, age at menarche, duration of oral contraceptive use in months, type of postmenopausal hormone use, and parity. Results: Nearly 36,000 women reported no use of NSAIDS while 38,000 reported using NSAIDS at some point during the study period. Demographics were balanced between the two groups except African American (35% vs 65%) and Latina women (40% vs 60%) were
Objective: Decoy Receptor 3 (DcR3) is present in ovarian cancer and is known to inhibit key apoptotic pathways including HveA/LTβR -LIGHT. CD8+ tumor infiltrating lymphocytes(TILs) have been correlated with improved clinical outcomes in ovarian cancer, yet the mechanism is unknown. Our objective was to determine if there is a correlation between CD8+ TILs and ascites DcR3 levels in advanced ovarian cancer and to investigate possible mechanisms. Methods: CD8+ tumor infiltrating lymphocytes (TILs) were identified in ovarian cancer tissue by Immunohistochemistry (IHC). The number of lymphocytes were counted and cases were classified as positive (N5) or negative (≤5) per high power field. Ascites fluid was tested for DcR3 by ELISA and reported in pg/ml. Ovarian cancer clinical samples were assessed for LIGHT expression by IHC, flow cytometry and RT-PCR. Primary peritoneal cells from ovarian cancer were stimulated with interferon and LIGHT with and without DcR3 and chemokine production was examined by ELISA. Peritoneal cells were also co-cultured with cancer cells that express cell surface LIGHT and either produce or do not produce DcR3. Once again chemokine production was examined by ELISA. Results: Of 40 cases reviewed, 36 were adequate for IHC evaluation. Of these 36, 13 (36%) were negative for CD8+ TILs and 23 (64%) were positive. DcR3 was detected in all cases, with levels ranging from 77 pg/mL to 13,000 pg/mL. The cohort was divided into tertiles based on DcR3 level. Ninety two percent of the patients with the lowest DcR3 levels were positive for TILs compared to only 33% of patients with the highest DcR3 level (p = 0.008). Of the 36 patients, 3 (8.3%) were without evidence of disease. The average CD8+ TILs count was 55.8 in this group compared to 11.4 for the group who were either dead of their disease or alive with disease (p = 0.0001). Patient samples treated with interferon and LIGHT expressed over 4000 pg/ mL of chemokine CXCL9. This was completely inhibited by the addition of DcR3 p b 0.001. Similar results were seen in co-culture experiments where DcR3 producing cells inhibit CXCL9 production from patient samples but DcR3 negative cells do not. This pattern was seen in four of the five patient samples tested. Conclusions: TILs are inversely related to DcR3 levels in ovarian cancer. LIGHT is present in ovarian cancer and can induce chemokine production, a function that is inhibited in the presence of DcR3. The LIGHT/DcR3 interaction is a possible mechanism of TIL inhibition in ovarian cancer. doi:10.1016/j.ygyno.2011.12.232
Results: We assessed the impact of neoadjuvant chemotherapy on the selected genes and microRNAs. Among the cell growth and proliferation genes MKI67, PLK1, PBK were reduced. Deactivation of the TUBB3 survival pathway, which was reduced while its negative regulator GNAI1 was increased. ERBB2 resulted downregulated in the neoadjuvant setting, while HGF and PTEN were increased. MicroRNAs expression broadly increased, with the only exception of miR-20a and miR-141. Patients exhibiting high levels of COL11A1 and PLK1 were poor performers, while the opposite occurred for GLI1. At the micro-RNA level the best predictors were miR-193a-5p, miR-375 and miR-20a. The poor performers (miR-193a-5p, miR-375) were featured by high levels of the micro-RNA while the opposite was evident for miR-20a. Conclusions: Use of the nanofluidic platform may provide deeper insight into the specific roles of clinically relevant major molecular networks. Chemotherapy induced modification of genes and microRNA expression can be used as a model to develop future prognostic biomarkers and therapeutic modalities.
S97
significantly more likely to use NSAIDS while Japanese (68% vs 32%) women were significantly less likely to use the medications. In addition, users were slightly heavier and non-users had menopause at a slightly older age. Use of aspirin, acetaminophen or other NSAID whether non-users, current or former user and whether short or longer duration had no impact on the relative risk for the development of ovarian cancer. Only very short duration of acetaminophen use (b1 yr) was found to reduce the risk of ovarian cancer (RR = 0.59). Analysis of NSAID use by race or histological subtype found no impact on risk of ovarian cancer. Conclusions: NSAID use appears to have no effect on the future development of epithelial ovarian cancer. doi:10.1016/j.ygyno.2011.12.231
231 Decoy receptor 3 (DcR3) inhibits intratumoral lymphocytic infiltration by inhibiting LIGHT induced chemokine production in ovarian cancer N. Onujiogu, M. Felder, A. Kapur, A. Ziebarth, J. Connor. University of Wisconsin, Madison, WI.
doi:10.1016/j.ygyno.2011.12.230
230 NSAIDS do not prevent ovarian cancer M. Carney, M. Goodman, G. Lurie, R. Weise. University of Hawaii, Honolulu, HI. Objective: NSAID use has been linked to the reduction of cancer risk in several cancers including colon. One theory for the development of ovarian cancer involves the inflammatory process which could be directly impacted with NSAID use. The purpose of this study was to examine the relationship of NSAID use and the risk for the development of ovarian cancer. Methods: This Multiethnic Cohort Study is a prospective study of 74,078 women aged 45–75 years residing in Hawaii and California recruited between 1993 and 1996. Subjects were asked via questionnaire demographics including race/ethnicity and details regarding whether they had ever taken an NSAID at least two times per week for one or more months including aspirin, acetaminophen, or other NSAID pain relief medication. Follow-up started on the date of baseline questionnaire completion and ended on the date of EOC diagnosis, death, or end of study follow-up (December 31, 2007), whichever came first. Incident cases of EOC and histologies were identified through record linkage with the Hawaii Tumor Registry, the Cancer Surveillance Program for Los Angeles County, and the California State Cancer Registry, which are all part of the NCI's SEER Program. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals using age as the time scale. Multivariable models adjusted for age, race/ethnicity, age at menarche, duration of oral contraceptive use in months, type of postmenopausal hormone use, and parity. Results: Nearly 36,000 women reported no use of NSAIDS while 38,000 reported using NSAIDS at some point during the study period. Demographics were balanced between the two groups except African American (35% vs 65%) and Latina women (40% vs 60%) were
Objective: Decoy Receptor 3 (DcR3) is present in ovarian cancer and is known to inhibit key apoptotic pathways including HveA/LTβR -LIGHT. CD8+ tumor infiltrating lymphocytes(TILs) have been correlated with improved clinical outcomes in ovarian cancer, yet the mechanism is unknown. Our objective was to determine if there is a correlation between CD8+ TILs and ascites DcR3 levels in advanced ovarian cancer and to investigate possible mechanisms. Methods: CD8+ tumor infiltrating lymphocytes (TILs) were identified in ovarian cancer tissue by Immunohistochemistry (IHC). The number of lymphocytes were counted and cases were classified as positive (N5) or negative (≤5) per high power field. Ascites fluid was tested for DcR3 by ELISA and reported in pg/ml. Ovarian cancer clinical samples were assessed for LIGHT expression by IHC, flow cytometry and RT-PCR. Primary peritoneal cells from ovarian cancer were stimulated with interferon and LIGHT with and without DcR3 and chemokine production was examined by ELISA. Peritoneal cells were also co-cultured with cancer cells that express cell surface LIGHT and either produce or do not produce DcR3. Once again chemokine production was examined by ELISA. Results: Of 40 cases reviewed, 36 were adequate for IHC evaluation. Of these 36, 13 (36%) were negative for CD8+ TILs and 23 (64%) were positive. DcR3 was detected in all cases, with levels ranging from 77 pg/mL to 13,000 pg/mL. The cohort was divided into tertiles based on DcR3 level. Ninety two percent of the patients with the lowest DcR3 levels were positive for TILs compared to only 33% of patients with the highest DcR3 level (p = 0.008). Of the 36 patients, 3 (8.3%) were without evidence of disease. The average CD8+ TILs count was 55.8 in this group compared to 11.4 for the group who were either dead of their disease or alive with disease (p = 0.0001). Patient samples treated with interferon and LIGHT expressed over 4000 pg/ mL of chemokine CXCL9. This was completely inhibited by the addition of DcR3 p b 0.001. Similar results were seen in co-culture experiments where DcR3 producing cells inhibit CXCL9 production from patient samples but DcR3 negative cells do not. This pattern was seen in four of the five patient samples tested. Conclusions: TILs are inversely related to DcR3 levels in ovarian cancer. LIGHT is present in ovarian cancer and can induce chemokine production, a function that is inhibited in the presence of DcR3. The LIGHT/DcR3 interaction is a possible mechanism of TIL inhibition in ovarian cancer. doi:10.1016/j.ygyno.2011.12.232