bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR10: Serine biosynthesis from glucose regulates folate availability
Authors: Lewis Caroline A. , Fiske Brian P. , Pacold Michael E. , Hosios Aaron M. , Mattaini Katherine R. , Sabatini David M. , Heiden Matthew G. Vander 
Published: May 2016

Abstract
It has been established that de novo serine biosynthesis is important for some cancers. We have previously shown that phosphoglycerate dehydrogenase (PHGDH), the enzyme responsible for catalyzing the first step in glycolytic serine biosynthesis, is amplified in certain cancers, including breast cancer and melanoma. Knockdown of PHGDH results in decreased proliferation of PHGDH-amplified cells, demonstrating a dependence on PHDGH in these cells; however, it has not been possible to rescue this defect with exogenous serine, suggesting that glycolytic serine biosynthesis has an alternate function in cells. Here we have investigated four mutually exclusive hypotheses each consistent with the inability of serine to rescue decreased glycolytic serine biosynthesis: 1: There exists an alternative function of PHGDH; 2: Pathway activity is important for TCA cycle anapleurosis; 3: Metabolic channeling of de novo serine; and 4: A unique product of this pathway other than serine is critical for proliferation. Using a combination of genetic and biochemical approaches, we show that flux through the serine biosynthesis pathway is required for cytosolic serine-glycine conversion via serine hydroxymethyltransferase 1 (SHMT1). In many cells flux through SHMT1 occurs in the glycine-to-serine direction, including PHDGH-dependent cell lines, and loss of PHGDH activity results in wasting of folates from the one-carbon pool to make serine. This reduces availability of one-carbon units in the folate pool for nucleotide biosynthesis, resulting in S-phase arrest and eventual cell death. These data link serine biosynthesis from glucose with the regulation of one-carbon folate metabolism, and provide an explanation for why cancer cells are dependent on de novo serine production even when serine is abundant.
Citation Format: Caroline A. Lewis, Brian P. Fiske, Michael E. Pacold, Aaron M. Hosios, Katherine R. Mattaini, David M. Sabatini, Matthew G. Vander Heiden. Serine biosynthesis from glucose regulates folate availability. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr PR10.
Abstract A13: Transferrin facilitates the formation of DNA-double strand breaks via transferrin receptor 1 in fallopian tube epithelial cells.
Authors: Shigeta Shogo , Toyoshima Masafumi , Kitatani Kazuyuki , Ishibashi Masumi , Usui Toshinori , Yaegashi Nobuo 
Published: May 2016

Abstract
Objectives: High-grade serous ovarian cancer (HGSOC) is now believed to arise from fallopian tube epithelium (FTE), and p53 signatures are indicated to be the early oncogenic change in HGSOC. Although accumulation of DNA-double strand breaks (DNA-DSBs) are frequently observed in p53 signatures, the mechanism of DNA-DSBs formation in FTE has not been revealed yet. Hydroxyl radicals, which strongly induce DNA-DSBs, are the most active reactive oxygen species (ROS) in a living organism, and hydroxyl radicals are produced in a Fenton reaction catalyzed by free iron ions. Focusing on transferrin, which is a transporter of iron ion and exists abundantly in the follicular fluid or retrograde menstrual blood, we inspected the role of transferrin and transferrin receptor family in DNA-DSBs formation at FTE.
Materials and methods: The expressions of transferrin receptor 1(TfR1) and 2 (TfR2) in human FTE were assessed by immunohistochemistry. Immortalized fallopian tube secretory epithelial cells (kindly provided by Dr. Ronny Drapkin, Dana-Farber Cancer institute) and A2780 ovarian cancer cells were cultured with holo-transferrin or vehicle, and the extent of DNA-DSBs was compared. γH2AX was adopted as a marker of DNA-DSBs. ROS were also measured to verify whether transferrin promotes a Fenton reaction. The involvement of TfR1 and TfR2 were assessed with siRNA knockdown strategy. Further, the ex vivo study were performed using murine fallopian tubes.
Results: In immunohistochemistry, both TfR1 and TfR2 were ubiquitously positive in human FTE. Transferrin administration significantly increased the γH2AX expression in these cells and led ROS formation. In addition, transferrin treatment also amplified hydrogen peroxide-inducing γH2AX expression. TfR1 knockdown cancelled the uptake of transferrin, subsequent γH2AX expression and ROS formation but TfR2 knockdown didn't. Also we confirmed that transferrin treatment facilitated γH2AX formation in murine FTE ex vivo.
Conclusion: We identified transferrin-TfR1 axis facilitates DNA-DSBs by promoting a Fenton reaction. It is possible that FTE exposed to the extracellular transferrin highly concentrated in the follicular fluid or retrograde menstrual blood is deeply involved with the carcinogenesis of HGSOC.
Citation Format: Shogo Shigeta, Masafumi Toyoshima, Kazuyuki Kitatani, Masumi Ishibashi, Toshinori Usui, Nobuo Yaegashi. Transferrin facilitates the formation of DNA-double strand breaks via transferrin receptor 1 in fallopian tube epithelial cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A13.
Abstract A16: Regulation of TRAIL and NF-kappaB pathways in ovarian cancer.
Authors: Anees Mariam , Batool Umaima , Bukhari Sidra , Yousaf Sohail 
Published: May 2016

Abstract
Objective: The equilibrium between apoptotic and survival pathways determines the fate of cells. Dysregulation in any one mechanism often leads to cancer. The present study was designed to determine the crosstalk between TRAIL and NF-kappaB pathways through study of the much controversial role of DcR2 in the induction of NF-kappaB.
Methodology: A total of 50 epithelial ovarian tissue samples were used for immunohistochemical staining of DcR2 and NF-kappaB (p65) proteins along with the other players of TRAIL pathway including DR4, DR5, DcR1, FLIP and TRAIL. Correlations were drawn and survival analysis was performed using Kaplan Meier's method.
Results: A total of 72% ovarian carcinomas showed positive DR4 expression, 68% showed positive DR5 expression, 42% showed positive DcR1 expression, 48% showed positive DcR2 expression, 44% had positive FLIP expression, 46% had positive TRAIL expression in epithelium while 28% had positive TRAIL expression in stroma. NF-kappaB was positive in 46% of the tissue samples. A strong but non-significant correlation was seen between DcR2 and NF-kappaB expression. Interestingly a similar correlation was also found between DR4 and NF-kappaB expression. Survival analysis showed better survival for patients with positive NF-kappaB expression as compared to negative expression.
Conclusion: Coexpression of DcR2 and NF-kappaB suggests a potential therapeutic approach of targeting NF-kappaB through TRAIL pathway by using anti-DcR2 antibodies. However, the study may be elaborated with increased sample size to get significant results.
Note: This abstract was not presented at the conference.
Citation Format: Mariam Anees, Umaima Batool, Sidra Bukhari, Sohail Yousaf. Regulation of TRAIL and NF-kappaB pathways in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A16.
Abstract A21: Ovarian tumor cells' adhesion and cell signaling pathways are regulated by ARID3B.
Authors: Bobbs Alexander S. , Hallas William Morgan , Dahl. Karen D. Cowden 
Published: May 2016

Abstract
Patients with ovarian cancer are often diagnosed with late-stage metastatic cancer resulting in poor survival rates. To improve both diagnostics and therapeutics, we need to increase our understanding of the genetic programming that leads to metastatic ovarian cancer. We found that the DNA-binding protein AT-Rich Interactive Domain 3B (ARID3B) is over-expressed in ovarian cancer. Nuclear expression of ARID3B correlates with relapse following chemotherapy. Furthermore, ARID3B increases tumor growth in a xenograft model of ovarian cancer. We hypothesize that ARID3B modulates adhesion and survival by regulating genes in the Wnt and TNF pathways. We identified and validated direct target genes of ARID3B by chromatin immunoprecipitation (ChIP), and characterized the binding site for ARID3B. ARID3B regulates target genes in the Wnt signaling pathway including Wnt5A, FZD5, and APC. ARID3B increases adhesion to extra-cellular matrix at least in part through regulation of FZD5. In addition to regulation of adhesion through Wnt signaling, we found that decreased ARID3B leads to a reduction in fibronectin and vitronectin adhesion. ARID3B also seems to play a role in regulating cell death and survival. We found that ARID3B regulates genes in the TNF and TRAIL signaling pathways. In particular, TNF, TNFR2, and TRAIL are ARID3B regulated genes. We are investigating the impact of TNF and TRAIL regulation on cell death and survival. This study directly demonstrates that ARID3B is a transcription factor that regulates target expression of key components of the Wnt and TNF signaling pathways.
Citation Format: Alexander S. Bobbs, William Morgan Hallas, Karen D. Cowden Dahl. Ovarian tumor cells' adhesion and cell signaling pathways are regulated by ARID3B. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A21.
Abstract A24: Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance.
Authors: Cutter Noelle L. , Walther Tyler , Gallagher Liam , Lucito Robert , Wrzeszczynski Kazimierz 
Published: May 2016

Abstract
Epithelial ovarian cancer (EOC) is the leading cause of gynecologic cancer mortality worldwide. These cancers are highly heterogeneous and while chemotherapy is the preferred treatment many patients are intrinsically resistant or quickly develop resistance. Furthermore, all tumors that recur ultimately become resistant. Understanding the molecular alterations of primary tumor cells has become a common method to identify genes critical to the development of a drug-resistance phenotype and progression of cancer and could lead to the development of novel therapeutic strategies for successful treatment of patients. DNA copy number alterations are a common occurrence in all cancers. Specific chromosomal regions and focal points favor either gains or losses in DNA and are important in the regulation of various oncogenes and tumor suppressors. Contributions from The Cancer Genome Atlas as well as recent bioinformatic results have identified key players involved in ovarian cancer deregulation. Specifically, we examined the datasets to identify copy number alterations in genes that segregate with platinum response, and further filtered with expression data to identify genes that were amplified.
Our analysis revealed correlations for expression and CNV for several genes. Of the genes identified in the screen we further characterized one gene involved in hypoxia, HIF1α. Hypoxia is a microenvironmental factor which plays a critical role in the development and progression of cancer, chemoresistance, and poor survival. Epithelial-to-mesenchymal transition (EMT) is the process by which adherent epithelial cells convert to motile mesenchymal cells and is now known to also occur in a variety of diseases including the progression of cancer. EMT may reflect an adaptation of cancer cells to survive cytotoxic drug activity, and may thus be responsible for chemosensitivity. Our results have indicated that the gain of HIF1α decreased the level of apoptosis in response to carboplatin. Furthermore, ovarian cell lines undergoing hypoxia are more invasive, have migratory ability, and display a transformed EMT phenotype. Taken together, we provide the evidence of a role for HIF1α as an important regulator of chemoresistance in ovarian cancer and hypothesize EMT as the underlying mechanisms. These results suggest that the inactivation of HIF-1α signaling by novel strategies may be a potential targeted therapeutic approach for overcoming EMT and chemoresistance induced by hypoxia.
Note: This abstract was not presented at the conference.
Citation Format: Noelle L. Cutter, Tyler Walther, Liam Gallagher, Robert Lucito, Kazimierz Wrzeszczynski. Hypoxia signaling pathway plays a role in ovarian cancer chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A24.
Abstract A81: Targeting of free fatty acid signaling in ovarian cancer may serve as a potential therapeutic approach.
Authors: Munkarah Adnan , Hamid Suhail , Chhina Jasdeep , Mert Ismail , Jackson LaToya , Hensley-Alford Sharon , Chitale Dhananjay , Giri Shailendra , Rattan Ramandeep 
Published: May 2016

Abstract
Recent studies have revealed an association between adipocyte driven free fatty acids (FFA) and the aggressiveness of epithelial ovarian cancer (EOC). Adipocyte derived free fatty acids (FFA) seem to promote epithelial ovarian cancer (EOC) growth and progression by acting as mitochondrial fuel source to support the energy requirements of EOC cells. Apart from acting as a fuel source, FFA may also enhance tumor growth through other signaling pathways that can promote proliferation and regulate metabolism. Recently, a family of FFA activated G-protein coupled receptors (FFAR/GPCRs) was identified, including: FFAR1/GPR40, FFAR2/GPR42, FFAR3/GPR41, FFAR4/GPR120 and GPR84. Using RT-PCR, we have found that exposing EOC cells to adipocytes results in overexpression of FFAR1/GPR40 in multiple ovarian cancer cell lines (ID8, A2780, C200, OVCAR3 and SKOV3). In mRNA extracted from formalin-fixed paraffin embedded tumor specimens, approximately 80% of high-grade serous ovarian carcinomas exhibited increased FFAR1 expression. Additionally, analysis of TCGA database revealed that patients with tumors exhibiting increased mRNA expression of FFAR1/GPR40 had poor overall survival and progression free survival. We have also found that targeting FFAR1 using its specific antagonist GW1100 inhibited the proliferation of A2780, ID8, C200, OVCAR3 and SKOV3 cell lines and resulted in downstream inhibition of insulin secretion and the Akt signaling pathway. On the other hand, treatment of the same cells with the FFAR1 agonist ,CAY10587, had no effect on proliferation. Thus, we conclude that FFAR1 may play an important role in the regulation of FFA mediated EOC cell proliferation. Targeting of FFAR1/GPR40 may be an attractive strategy in EOC, particularly for EOC patients presenting with high adiposity.
Citation Format: Adnan Munkarah, Suhail Hamid, Jasdeep Chhina, Ismail Mert, LaToya Jackson, Sharon Hensley-Alford, Dhananjay Chitale, Shailendra Giri, Ramandeep Rattan. Targeting of free fatty acid signaling in ovarian cancer may serve as a potential therapeutic approach. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A81.
Abstract B11: Mutational heterogeneity in non-serous ovarian cancers.
Authors: Teer Jaime , Yoder Sean , Gjyshi Anxhela , Zhang Chaomei , Monteiro Alvaro 
Published: May 2016

Abstract
Background: The mutational landscape of non-serous ovarian carcinomas is underexplored despite their substantial contribution to ovarian cancer morbidity and mortality. In this study we report whole exome sequencing analysis of 10 non-serous ovarian tumors and matched normal samples. We also report targeted gene sequencing results of an additional 28 non-serous tumor samples targeting 1,321 genes selected for their involvement in cancer.
Methods: Whole exome capture was performed using Roche NimbleGen SeqCap EZ, followed by sequencing of captured libraries using an Illumina HiScan platform. Target gene capture was performed using SureSelect custom designs, using GAIIx sequencing technology. Sequences from both experimental procedures were aligned to the human genome using the Burrows-Wheeler Aligner and the Genome Analysis ToolKit was used for insertion/deletion realignment, quality score calibration, and variant identification. Mutations were detected with MuTect or Strelka (whole exome) or GATK (target gene).
Results: We annotated 32,965 somatic mutations (829-15,737 per tumor) for an overall rate of mutation 12.2 per Mb. Interestingly, a BRCA2 frameshift mutation was observed in mucinous tumors; although inherited BRCA mutations have not been previously observed in mucinous histology. TP53 mutations were much less common than observed in high-grade serous ovarian cancers. PTEN stood out as a gene containing truncating mutations in many samples. We confirmed FOXL2 importance in granulosa, KRAS in mucinous histology and identified POLE mutations in endometrioid ovarian samples. Finally, we report comparative analysis of our results to The Cancer Genome Atlas (TCGA) database.
Conclusion: In summary, we report that non-serous ovarian tumors are mutationally distinct from serous ovarian tumors, having a mutational profile more similar to non-serous endometrial cancers.
Citation Format: Jaime Teer, Sean Yoder, Anxhela Gjyshi, Chaomei Zhang, Alvaro Monteiro. Mutational heterogeneity in non-serous ovarian cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B11.
Abstract B35: Ovarian cancer incidence projections in the United States: Expected increases through 2030.
Authors: Stewart Sherri L. , Thompson Trevor D. , Weir Hannah K. , Rim Sun Hee 
Published: May 2016

Abstract
Background: Several reports have shown that age-standardized ovarian cancer rates are decreasing in recent years in the United States. While these reported rates are useful to compare trends across certain groups, they do not always accurately convey the burden of ovarian cancer, nor do they provide information on the actual numbers of ovarian cases diagnosed each year. Since age is the greatest risk factor for ovarian cancer, and the older population of the Unites States is growing, the accurate assessment of future ovarian cancer trends is important in order to plan for clinical care needs and allocate resources effectively.
Objective: To assess future trends in the United States ovarian cancer burden by projecting the number of new cases of ovarian and fallopian tube cancer cases diagnosed through the year 2030.
Methods: We used observed incidence data from 1982-2011 from the SEER program, and population projections based on the 2010 US Census to predict ovarian and fallopian tube cancer cases and rates through 2030. Cases of both ovarian and fallopian tube cancers were included to account for misclassification that often occurs between the two cancer sites and also because some ovarian cases are thought to originate in the fallopian tube. Predictions were made using age-period-cohort regression models implemented in the Nordpred software.
Results: The number of ovarian cancer cases is estimated to increase from 23,215 in 2012 to 27,666 in 2030, for a 19.2% total increase in new cases of ovarian cancer in 2030. Fallopian tube cancer cases are expected to increase from 1,621 in 2012 to 3,686 in 2030. Together, 31,352 cases of ovarian and fallopian tube cancers are projected to be diagnosed in 2030, for an overall expected increase of 26.2% for these cancers.
Discussion: Given the expected increase in cancer cases, prioritizing resources for ovarian cancer control is warranted. Continued training and outreach of gynecologic oncologists to ensure ovarian cancer patients receive optimal treatment is necessary. Systems changes that ensure referral and accessibility to gynecologic oncologists are also needed. Additional research into genetic and other factors that predispose individuals to ovarian cancer, and the continued characterization of symptoms may help to identify cases earlier, potentially resulting in more treatment options for ovarian cancer patients.
Citation Format: Sherri L. Stewart, Trevor D. Thompson, Hannah K. Weir, Sun Hee Rim. Ovarian cancer incidence projections in the United States: Expected increases through 2030. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B35.
Abstract B37: Menstrual cycle characteristics, PCOS, and ovarian cancer risk.
Authors: Harris Holly R. , Titus Linda J. , Cramer Daniel W. , Terry Kathryn L. 
Published: May 2016

Abstract
Background: Long and irregular menstrual cycles, a hallmark of polycystic ovary syndrome (PCOS), have been associated with higher androgen and lower sex hormone binding globulin levels (SHBG) and this altered hormonal environment may increase the risk of specific histologic subtypes of ovarian cancer.
Methods: We investigated the association between menstrual cycle characteristics and PCOS among 2071 women with epithelial ovarian cancer and 2100 controls in the New England Case-Control Study (1992-2008). Women self-reported menstrual cycle irregularity, menstrual cycle length, and previous diagnosis of PCOS. We used unconditional logistic regression models to calculate odds ratios (OR) and 95% confidence intervals (95% CIs) for ovarian cancer risk overall, and polytomous logistic regression to evaluate whether the associations differed across histologic subtypes.
Results: Overall, we observed no difference in ovarian cancer risk between women who reported periods that were never regular and women who did not report menstrual cycle irregularity (multivariable OR=0.87; 95% CI=0.69-1.10). A similar association was observed for those reporting an average menstrual cycle length of greater than 35 days with a multivariable OR of 0.87 (95% CI=0.47-1.60). In addition, no association was observed with self-reported PCOS and ovarian cancer (multivariable OR=0.96; 95% CI=0.60-1.54). When we examined the associations by histologic subtype, we observed significant differences in the association with menstrual cycle irregularity as the exposure (pheterogeneity=0.007) but not for cycle length &gt;35 days or self-reported PCOS. Menstrual cycle irregularity was protective for serous invasive tumors (OR=0.66; 95% CI=0.47-0.91) but was associated with a non-significant increase in risk of serous borderline tumors (OR=1.32; 95% CI=0.86-2.03).
Conclusions: Our results suggest that menstrual cycle characteristics may have influences on ovarian cancer risk that vary by histologic subtype. Future research in a large collaborative consortium may help clarify these associations.
Citation Format: Holly R. Harris, Linda J. Titus, Daniel W. Cramer, Kathryn L. Terry. Menstrual cycle characteristics, PCOS, and ovarian cancer risk. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B37.