bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR06: Identification of metabolic dependencies in tuberous sclerosis and lymphangioleiomyomatosis
Authors: Filippakis Harilaos , Khabibullin Damir , Priolo Carmen , Henske Elizabeth P. 
Published: May 2016

Abstract
The mammalian target of rapamycin complex (mTORC1) is constitutively active in many human cancers and in Tuberous Sclerosis Complex (TSC). Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease of women in which TSC2-deficient cells metastasize to the lungs, causing cystic lung destruction. LAM can lead to oxygen dependency and death in young women. Inhibition of mTORC1 has a cytostatic effect in LAM and TSC, decreasing the size of kidney and brain tumors and stabilizing lung function. Lifelong therapy appears to be required, since tumors regrow upon treatment cessation.
Hyperactive mTORC1 leads to low autophagic flux, contributing to the metabolic dependencies of TSC-deficient cells. Previously we found that the survival of TSC2-deficient cells is autophagy dependent. A Phase I clinical trial is currently underway testing the combination of rapamycin and hydroxychloroquine (which inhibits autophagy) in LAM. To further define autophagy dependent cellular pathways in TSC2-deficient cells we utilized the L1000 high-throughput gene expression assay. TSC2-null patient-derived cells were treated with chloroquine (CQ, 5 uM) for 24 hrs or 72 hrs. Pathway enrichment analysis revealed that the cholesterol biosynthesis pathway is significantly induced upon CQ treatment. TSC2-deficient cells exhibit differential sensitivity to the combination of CQ and a HMG-CoA reductase inhibitor supporting the L1000 finding.
In parallel, we performed a high throughput synthetic lethality screen of TSC2-deficient and TSC2-expressing cells in the presence or absence of CQ. Four libraries consisting of 4,500 compounds were screened. Six compounds exhibited synergy with CQ by suppressing ATP levels in TSC2-deficient cells but not TSC2-expressing cells. Follow-up analyses of these compounds are ongoing.
In conclusion we utilized gene expression profiling and a high throughput drug screen to identify genetic and chemical perturbations that act synergistically with autophagy inhibition to target TSC2-deficient cells. Abundant data suggests that TSC2-deficient cells can be exploited through their autophagy-dependent metabolic vulnerabilities. Our long-term goal is to identify novel cytocidal therapeutic strategies for clinical translation in TSC and LAM.
Citation Format: Harilaos Filippakis, Damir Khabibullin, Carmen Priolo, Elizabeth P. Henske. Identification of metabolic dependencies in tuberous sclerosis and lymphangioleiomyomatosis. [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 PR06.
Abstract PR07: Functional identification of a mitochondrial glutamine carrier using isotope tracers
Authors: Metallo Christian 
Published: May 2016

Abstract
Mitochondria are the central metabolic hub of cells, and cells have the ability to metabolize numerous substrates in biochemical pathways within these organelles. Glutamine is a vital nutrient that serves as both nitrogen carrier and anaperotic substrate for mammalian cells. Various cancer cells exhibit dependence on glutaminolysis to fuel bioenergetic and biosynthetic metabolic pathways. This pathway is catalyzed, in part, via mitochondrial glutaminase; however, the mechanism through which glutamine is transported into the matrix is not well known. In fact, the function of nearly half the known mitochondrial solute carriers (SLC25 family) is yet to be described. Using a combination of cell engineering strategies, metabolic tracing using 15N and 13C labeled substrates, and respirometry applied to both intact and permeabilized cultures we have identified a putative mitochondrial glutamine carrier (MQC). Knockdown of this carrier decreases cell growth and drives cells to use alternate pathways for oxidation of glutamine in the TCA cycle. Cancer cells treated with inhibitors of glutaminase exhibit a similar metabolic phenotype as demonstrated via 13C tracing. These results functionally identify a critical node in mitochondrial metabolism and further highlight the utility of metabolic tracing and mass spectrometry for elucidating metabolic function.
Citation Format: Christian Metallo. Functional identification of a mitochondrial glutamine carrier using isotope tracers. [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 PR07.
Abstract A28: Osteopontin splicing isoforms expression is modulated by partial epithelial mesenchymal transition in ovarian carcinoma cells.
Authors: Celestino Ingridy , Guimarães Isabella S. , Rangel Leticia B. A. , Gimba Etel R. P. 
Published: May 2016

Abstract
In ovarian carcinoma (OC), invasive cell properties are supported by epithelial mesenchymal transition (EMT). We previously demonstrated that OPNc, one of the glycophosphoprotein osteopontin splicing isoforms (OPN-SI), activates OC progression. However , the involvement of these OPN-SI in EMT in OC cells has not previously been addressed. We aimed to evaluate the expression of OPN-SI in OC cells induced to EMT by TGFβ. ES2 and A2780 OC cell lines were treated with 10ng/ml of TGFβ in order to induce EMT. The expression of OPN-SI and EMT epithelial (E) (Claudin-3, Claudin-4 and E-cadherin) and mesenchymal (M) (slug, vimentin and N-cadherin) markers was tested by quantitative real time PCR. In both cell lines, OPNa is overexpressed in relation to OPNb and OPNc. Upon treatment with TGFβ, in A2780 cells we observed an upregulation of OPNc. Conversely, OPNa and OPNb were downregulated. In ES2 cells, TGFβ also induced OPNc upregulation, but OPNb expression is activated as well, while OPNa expression is inhibited. In order to validate EMT induction by TGFβ, we tested the expression of E and M markers. In A2780 cells, TGFβ induce the downregulation of E-cadherin, but Claudin-3 and Claudin-4 are upregulated. In ES2 cells, Claudin-3 expression is downregulated in this condition. After TGFβ treatment, in A2780 cells all M markers are downregulated, while in ES2 cells, only N-cadherin expression has been inhibited. Our data indicate that the expression of OPN-SI is modulated by EMT induced by TGFβ and that mostly the oncogenic OPNc is upregulated in this condition. Our data evidence that the expression of OPN-SI is modulated by a partial EMT phenotype induced by TGFβ, which is cell-type specific, and that OPN-SI, specially OPNc, could contribute to this key step on tumor progression in OC cells.
Citation Format: Ingridy Celestino, Isabella S. Guimarães, Leticia B. A. Rangel, Etel R. P. Gimba. Osteopontin splicing isoforms expression is modulated by partial epithelial mesenchymal transition in ovarian carcinoma 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 A28.
Abstract A34: Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis.
Authors: Sapoznik Stav , Bahar-Shany Keren , Brand Hadar , Pinto Yishay , Gabay Orshay , Glick-Saar Efrat , Dor Chen , Zadok Oranit , Barshack Iris , Zundelevich Adi , Gal-Yam Einav Nili , Yung Yuval , Hourvitz Ariel , Korach Jacob , Beiner Mario , Jacob Jasmine , Levanon Erez Y. , Barak Michal , Aviel-Ronen Sarit , Levanon Keren 
Published: May 2016

Abstract
In recent years, the notion that serous ovarian carcinoma results from ovulation-induced inflammation of the fallopian tube epithelial cells (FTECs) has gained evidence. However, the mechanistic pathway that leads to mutagenesis and genomic instability has not been revealed yet. The mutator enzyme activation-induced cytidine deaminase (AID), which is known to be involved in the process of immunoglobulin somatic hypermutations, has also been recently implicated in inflammation-induced epithelial malignancies. In the current study, we propose that AID is a mechanistic link between ovulation-induced inflammation in FTECs and the genotoxic damage that leads to serous carcinogenesis.
We tested at the expression of AID in human fallopian tube tissues from patients with various gynecological pathologies, as well as in cultured FTECs in an experimental model mimicking normal ovulation. We also looked at the functional effects of AID up regulation in vitro by analyzing double strand DNA breaks, abasic sites, hypomethylation and chromosomal rearrangements. We also performed a comprehensive bioinformatic analysis of somatic mutations patterns in publically available serous carcinoma sequencing data in search of AID mutational fingerprints.
We show that AID, previously shown to be functional only in B lymphocytes, is expressed in human FTECs under physiological conditions, is induced in vitro upon ovulatory-like stimulation and is elevated in vivo under carcinogenesis-associated circumstances. We also report that AID activity results in epigenetic, genetic and genomic damage in FTECs.
Overall, our data provides new insights on the etiology of serous ovarian carcinogenesis and may set the ground for innovative approaches aimed at prevention and early-detection.
Citation Format: Stav Sapoznik, Keren Bahar-Shany, Hadar Brand, Yishay Pinto, Orshay Gabay, Efrat Glick-Saar, Chen Dor, Oranit Zadok, Iris Barshack, Adi Zundelevich, Einav Nili Gal-Yam, Yuval Yung, Ariel Hourvitz, Jacob Korach, Mario Beiner, Jasmine Jacob, Erez Y. Levanon, Michal Barak, Sarit Aviel-Ronen, Keren Levanon. Activation-induced cytidine deaminase links ovulation-induced inflammation and serous carcinogenesis. [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 A34.
Abstract A41: The heat shock transcription factor HSF1 induces ovarian cancer epithelial-mesenchymal transition in a 3-D spheroid growth model.
Authors: Paullin Trillitye , Powell Chase , Christopher Menzie , Hill Robert , Martyniuk Christopher , Westerheide Sandy 
Published: May 2016

Abstract
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. Compared to other cancers, ovarian cancer has very limited treatment options to date, with cisplatin and paclitaxel being the most common and efficient. Recently, a significant increase in heat shock factor 1 (HSF1) expression has been found in highly malignant ovarian cancer. HSF1 is the regulator of the heat shock response (HSR) and promotes the transcription of heat shock proteins (HSPs). Previous studies have shown that HSF1-induced chaperone activity may act to stabilize multiple oncogenes within many different cancer types. This leads to cancer proliferation, reduced apoptosis, and metastasis. In this study, we examine gene expression changes through microarray analysis in spheroid versus monolayer ovarian cancer cells treated with TGFβ to induce EMT. Interestingly, EMT and stress response pathways, including the heat shock response, were all significantly affected by 3D growth. HSF1 knockdown was utilized in both 2D and 3D cultures to further study this response. HSF1 knockdown is shown to inhibit ovarian cancer progression in both monolayer and spheroid model cells. Moreover, HSF1 knockdown in spheroid cells has a significantly greater impact on EMT markers than it does in 2D cultures. This indicates HSF1 may be a utilized as a target for chemotherapeutics in ovarian cancer patients and could potentially have implications in other such hormonal cancers.
Citation Format: Trillitye Paullin, Chase Powell, Menzie Christopher, Robert Hill, Christopher Martyniuk, Sandy Westerheide. The heat shock transcription factor HSF1 induces ovarian cancer epithelial-mesenchymal transition in a 3-D spheroid growth model. [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 A41.
Abstract B17: Type 2 diabetes, metformin, and ovarian cancer survival: An analysis of tumor registry and electronic medical record data.
Authors: Keene Spencer , Stansel Samantha P. , Clayton Leshaun , Jiang Min , Aldrich Melinda , Xu Hua , Warner Jeremy , Denny Joshua , Khabele Dineo , Beeghly-Fadiel Alicia 
Published: May 2016

Abstract
Background: Type 2 Diabetes Mellitus (T2D) is associated with increased cancer risk and higher cancer mortality. Metformin, a common T2D treatment, is associated with improved survival for several cancers. With a five year survival of 42%, repurposing metformin to improve ovarian cancer prognosis is attractive. However, only a few studies to date have evaluated associations between T2D, metformin use, and ovarian cancer survival.
Methods: We evaluated tumor registry confirmed ovarian and fallopian tube cancer cases from the Vanderbilt University Medical Center. Metformin use was determined from electronic medical records (EMR) using MedEx. For validation, natural language processing EMR review was conducted for 50 subjects. Cox proportional hazards regression was used to evaluate associations with overall survival and calculate Hazard Ratios (HR) and corresponding 95% Confidence Intervals (CI); models included adjustment for age, stage, histologic subtype, and body-mass index (BMI).
Results: Tumor registry data and EMR was available for 372 invasive epithelial ovarian cancer cases. Forty (10.8%) had T2D, and 20 had metformin use (5.4%). MedEx and EMR reviewed metformin use was highly concordant (Kappa=0.96). Associations with overall survival were suggestive but non-significant for T2D (HR: 0.80, 95% CI: 0.51-1.25) and metformin use, either among only T2D cases (HR: 0.73, 95% CI: 0.29-1.84) or among all ovarian cancer cases (HR: 0.61, 95% CI: 0.31-1.21). Two or more years of metformin use was significantly associated with better survival compared to cases without metformin use (HR: 0.28, 95% CI: 0.09-0.89). Exploratory analyses suggested better survival among serous cases and worse survival among non-serous cases for both T2D and metformin, but associations were not significant. Analyses to address survival time bias yielded results comparable to our primary findings.
Conclusions: Ovarian cancer cases with metformin use had marginally better overall survival. While not significant, these associations indicate that metformin may have utility repurposed as a treatment for ovarian cancer. Larger studies are needed to determine if associations differ by histology, and if metformin may be beneficial to all ovarian cancer subtypes.
Citation Format: Spencer Keene, Samantha P. Stansel, Leshaun Clayton, Min Jiang, Melinda Aldrich, Hua Xu, Jeremy Warner, Joshua Denny, Dineo Khabele, Alicia Beeghly-Fadiel. Type 2 diabetes, metformin, and ovarian cancer survival: An analysis of tumor registry and electronic medical record data. [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 B17.
Abstract B30: Dietary fat intake and ovarian cancer risk.
Authors: Rice Megan , Tworoger Shelley 
Published: May 2016

Abstract
Purpose: Prevention recommendations for ovarian cancer have been limited because few confirmed risk factors are modifiable. While dietary fat intake has been proposed as a potential risk factor, results have been inconsistent possibly due to limitations of when diet was assessed (e.g., baseline only). Therefore, in two large prospective cohort studies, we examined the association between ovarian cancer risk and dietary fat intake, including cumulative average intake (long-term intake) as well as simple updated intake (recent intake).
Methods: We assessed recent (2-6 years prior to diagnosis) as well as long-term (cumulative average) dietary fat intake among 65,590 women in the Nurses' Health Study (NHS) and NHSII using food frequency questionnaires administered every 2-4 years beginning in 1984 and 1991 respectively. We examined intakes of total fat as well as specific types of fat (i.e., animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans fat). We identified 536 cases of ovarian cancer throughout follow-up with information on recent diet. We used Cox proportional hazards regression to estimate the associations between dietary fat intake and risk of ovarian cancer.
Results: While recent total fat intake was not associated with ovarian cancer risk (RR comparing extreme quartiles= 1.05, 95%CI: 0.81-1.36), higher recent polyunsaturated fat intake was associated with a higher risk of ovarian cancer (RR comparing extreme quartiles=1.45, 95%CI: 1.08-1.94). However, there were no significant associations between cumulative average intakes of dietary fat and risk of ovarian cancer. For example, women in the highest quartile of cumulative average polyunsaturated fat intake had a non-significant 20% higher risk of ovarian cancer compared to those in the lowest quartile (95%CI: 0.88-1.62, p-trend=0.39).
Conclusion: While there were no significant associations between long-term dietary fat intake and risk of ovarian cancer in the NHS and NHSII, higher recent intake of polyunsaturated fat was associated with a higher risk of ovarian cancer. Future work will assess whether these associations vary histologic subtypes and by ER and PR expression in ovarian tumors.
Citation Format: Megan Rice, Shelley Tworoger. Dietary fat intake 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 B30.
Abstract B43: Characterization of ovarian cancer cells as in vivo models for preclinical studies.
Authors: Hernandez Lidia , Kim Marianne K. , Lyle L Tiffany , Steeg Patricia S. , Annunziata Christina M. 
Published: May 2016

Abstract
Women are most often diagnosed with ovarian cancer in late stages of the disease, making this malignancy the most common cause of death from gynecological cancers in the United States. Identification of factors associated with disease subtypes and clinical outcome is critical to enable pathway-targeted therapeutic advances. As with other systems, the value of cell lines for in vitro and pre-clinical work lies in choosing groups of cell lines with similar characteristics. To date, selection of cell lines has been based on criteria such as patient history, histological subtype at diagnosis, mutation patterns, signaling patterns and tumorigenicity in mice. Most available ovarian cancer cell lines were generated decades ago and variable information exists as to these parameters. In recent years, several studies have reported comprehensive data gathered for the most commonly available ovarian cancer cell lines. While these reviews have established greater consensus regarding the molecular characteristics of these cell lines, data on in vivo tumorigenicity of these cell lines is still only sporadically available, making it difficult to translate in vitro work to xenograft models. We have studied the tumorigenicity of 16 commonly used ovarian cancer cell lines introduced through three distinct anatomical locations: subcutaneous, intraperitoneal, and ovary intrabursal injection. We also characterized these cell lines according to gene expression profiles and phospho-proteomics, in order to create an integrated panel of information by which to choose cells logically for specific research questions. Here we report a comprehensive analysis of in vivo growth patterns and histopathology, linked to molecular characteristics. This will provide a valuable resource to the ovarian cancer research community, and better guiding the choice of cell lines for in vitro studies that can be translated efficiently into xenograft testing.
Citation Format: Lidia Hernandez, Marianne K. Kim, L Tiffany Lyle, Patricia S. Steeg, Christina M. Annunziata. Characterization of ovarian cancer cells as in vivo models for preclinical studies. [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 B43.