bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6: Metabolomics of Gleason score in prostate tumor tissue and serum
Authors: Penney Kathryn , Tyekucheva Svitlana , Loda Massimo 
Published: July 2016

Abstract
Background: Gleason score is currently the best clinical predictor of prostate cancer specific-mortality. Identifying biomarkers associated with Gleason score can improve prediction and advance the understanding of the biology of aggressive disease. Using gene expression data, we previously determined that metabolism pathways, including pyrimidine, propanoate, and beta-alanine, were differentially expressed in high and low grade tumors. The goal of this study is to identify metabolites that differ in low and high Gleason score tumors and in blood from these patients.
Methods: Metabolic profiling was performed on Gleason score 6 (n = 53) and Gleason score ≥8 (n = 32) radical prostatectomy tumor tissue specimens, and on serum samples from the time of diagnosis (n = 30 Gleason score 6 and n = 19 Gleason score ≥8) from the DF/HCC Prostate Cancer SPORE Cohort. Samples were prepared for analysis by Metabolon, Inc. with their standard solvent extraction method to recover small molecules. Metabolites were identified and quantified by gas and liquid chromatography and mass spectrometry. Missing values were calculated using k-nearest neighbor imputation, and sample values were normalized across batches. The metabolite levels were compared across Gleason score 6 and Gleason score ≥8 tumors and serum using a Wilcoxon test.
Results: In the tumor tissue, 207 metabolites were identified. Of these, 30 were present in significantly different amounts in high and low Gleason score tumors, including previously reported citrate (p = 0.002) and spermine (p = 0.003). In a pathway analysis, the propanoate pathway was significantly different in high and low Gleason (p = 0.03), but not the pyrimidine or beta-alanine pathways (p&gt;0.05). In serum, 15 individual metabolites had significantly different levels, including uridine (p = 0.008) and N-acetylserine (p = 0.0001).
Conclusions: Metabolite levels do differ in high and low Gleason score prostate tumor tissue. The novel serum results suggest that metabolites in blood may serve as biomarkers of tumor differentiation. Our ongoing research will build prediction models, and will determine if the blood metabolites can indicate the presence of high-Gleason score tumor not detected at biopsy and could serve as biomarkers for monitoring disease progression in active surveillance patients.
Citation Format: Kathryn Penney, Svitlana Tyekucheva, Massimo Loda. Metabolomics of Gleason score in prostate tumor tissue and serum. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 6.
Abstract 606: Similar 3D pharmacodynamic (3D-PD) responses of human tumor spheroids and xenografts to topoisomerase 1 inhibitor-induced DNA damage
Authors: Evans David M. , Delosh Rene , Laudeman Julie , Ogle Chad , Reinhart Russell , Selby Michael , Thomas Silvers , Kinders Robert , Navas Tony , Lawrence Scott , Monks Anne , Rapisarda Annamaria , Parchment Ralph E. , Doroshow James H. , Teicher Beverly 
Published: July 2016

Abstract
Three-dimensional (3D) cultures have been proposed as higher fidelity models of in vivo tumors than 2D cultures. To determine whether this idea extends to drug pharmacodynamics, we examined whether 3D cultures of the human melanoma line A375 (grown as tumor spheroids) could replicate the timing and magnitude of the nuclear γH2AX response to the topoisomerase 1 inhibitor, topotecan observed in A375 tumor xenografts (Kinders et al, Clin Can Res 2010). The appearance of γH2AX-positive nuclear foci has been used as a biomarker for drug- and radiation-induced double-strand breaks in DNA; we reported previously that treatment of nu/nu mice harboring A375 xenografts with a single-dose of topotecan induced nuclear γH2AX foci in a dose- and time-dependent manner, which peaked 4 hours after drug administration. A375 spheroids were generated by seeding cells into ULA U-bottom plates; 4 hours of exposure to 0.1 μM topotecan elicited a γH2AX signal in these 3D cultures while cell viability and intracellular ATP levels remained unchanged, indicating a DNA damage repair response at the maximally tolerated topotecan concentration for human hematopoietic cells (Erickson-Miller et al, Can Chemo Pharmacol 2009). Extending drug exposure to 24 hours caused substantial loss of viable cells (calcein AM+) and 50% decline in ATP levels but no further increase in γH2AX. In contrast, the HT29 tumor line was refractory to topotecan in vivo, and exposing 3D cultures of HT-29 spheroids to 0.1 μM topotecan for 24 hours elicited a strong nuclear γH2AX biomarker response in only a small fraction of cells at the surface of the spheroids. Longer exposure durations or supra-pharmacological concentrations (1 μM) of topotecan were required to achieve a strong nuclear γH2AX response in HT-29 spheroids. These results support the hypothesis that the 3D pharmacodynamics (PD) of drug response is similar to PD drug response in vivo for the camptothecin class of topoisomerase 1 inhibitors. Funded by NCI Contract No. HHSN261200800001E.
Citation Format: David M. Evans, Rene Delosh, Julie Laudeman, Chad Ogle, Russell Reinhart, Michael Selby, Silvers Thomas, Robert Kinders, Tony Navas, Scott Lawrence, Anne Monks, Annamaria Rapisarda, Ralph E. Parchment, James H. Doroshow, Beverly Teicher. Similar 3D pharmacodynamic (3D-PD) responses of human tumor spheroids and xenografts to topoisomerase 1 inhibitor-induced DNA damage. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 606.
Abstract 610: Effect of scaffold and growth factors on anti-cancer drug screening with multicellular spheroids: mimicking in vivo response
Authors: Masuda Norio , Rahman M. Mamunur , Arai Kazuya , Mizuno Atsushi , Itoh Manabu 
Published: July 2016

Abstract
Background:
For in vitro cancer research, cancer microenvironment is being increasingly recognized as a key factor. In the past, several 3D cell culture models have been tested as the powerful method for reproducing cancer microenvironment. However, in some cases, the growth and drug sensitivity of cells grown on anchorage-independent 3D culture models have been different to that of cells grown in vivo. Further, development of the 3D culture model including the physical (the cell-ECM interaction (scaffold)) and chemical factor (cytokine) are essential for mimicking cancer microenvironment in vitro. Therefore, we explored the effect of the growth factor dependent proliferation and drug sensitivity in scaffold/scaffold-free culture models, and try to understand which method is mimicking in vivo response due to stimulation and suitable for anti-cancer drug development.
Methods:
We cultured lung cancer, breast cancer, pancreatic cancer and ovarian cancer cell line on monolayer, Matrigel (ECM-embedded 3D culture, scaffold type), NanoCuluture Plate (NCP, a gel-free scaffold type 3D culture plate) and Low adhesion round-bottom plate (scaffold-free 3D culture plate). For growth curve experiment upon addition of growth factors (EGF, HB-EGF, FGF, HRG), we evaluated cell viabilities by ATP assay in several cancer cell lines. We examined drug sensitivities of cancer cell lines against clinically active anti-cancer agents by addition of growth factors.
Results:
Growth factor promoted the proliferation of cancer cell lines cultured on NCP while it was not enhanced the cell growth when cultured on 2D, Matrigel and Low adhesion round-bottom plate. In drug response, the cells grown on NCP by growth factor stimulation was more sensitive to drug than 2D and other 3D culture models.
Conclusion:
Differences of the cell growth and drug sensitivity were appeared by effect of scaffold and growth factor. Growth factor dependent cell proliferation and drug sensitivity on NCP were similar to in vivo behavior (1). These results demonstrated that scaffold and growth factor are the novel approach to be mimicking the cancer microenvironment in vitro. Therefore, it is obvious that NCP can be used as a suitable 3D culture model for mimicking in vivo response and anti-cancer drug development.
1. J Cell Sci. 2009 Dec 1;122(Pt 23):4277-86.
Citation Format: Norio Masuda, M. Mamunur Rahman, Kazuya Arai, Atsushi Mizuno, Manabu Itoh. Effect of scaffold and growth factors on anti-cancer drug screening with multicellular spheroids: mimicking in vivo response. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 610.
Abstract 612: Identification of selective inhibitors of diffuse-type gastric cancer cells by screening of annotated compounds
Authors: Shimada Shu , Akiyama Yoshimitsu , Fukamachi Hiroshi , Yuasa Yasuhito , Tanaka Shinji 
Published: July 2016

Abstract
Diffuse-type gastric cancer (DGC) exhibits rapid disease progression and a poor prognosis. We have reported an E-cadherin/p53 double conditional knockout (DCKO) mouse line as the first genetically engineered one, which morphologically and molecularly recapitulates human DGC. We have also established mouse gastric cancer (GC) cell lines from DGC of the DCKO mice, demonstrating strong resistance to cytotoxic anti-cancer agents and high tumorigenic property when subcutaneously injected to nude mice. Then, we performed a synthetic lethal screening of 1535 annotated chemical compounds, and identified 27 candidates with selective inhibitory activity against the GC cell lines. These candidate drugs were classified into some classes, and members of the most potent class specifically attenuated cell proliferation of the GC cell lines by induction of apoptosis as well as suppressing tumor growth in vivo. Expectedly, E-cadherin-mutant and -low human gastric cancer cell lines were more sensitive to them in contrast to E-cadherin-intact ones. These findings may lead to development of novel drugs and discovery of potential targets in human DGC.
Citation Format: Shu Shimada, Yoshimitsu Akiyama, Hiroshi Fukamachi, Yasuhito Yuasa, Shinji Tanaka. Identification of selective inhibitors of diffuse-type gastric cancer cells by screening of annotated compounds. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 612.
Abstract 613: Astrocytes and endothelial colony forming cells (ECFCs) influence the migration and drug response of glioblastoma cells in a 3D culture model
Authors: Herrera-Perez Marisol , Fishel Melissa , Harbin Sherry , Rickus Jenna 
Published: July 2016

Abstract
Glioblastoma, a brain cancer with low prognosis, is characterized by rapid infiltration and drug resistance that leads to tumor reappearance. Cell-extrinsic factors, such as the development of a supportive microenvironment and synergistic relationships between normal cells and GBM play an important role in the tumor successful progression. Despite the importance of the microenvironment as a regulator of tumor response, there is a lack of predictive in vitro models that represent the dimensionality and characteristics of the glioma microenvironment. To this end, we developed a 3D in vitro model that recapitulates the composition and physical features of the GBM microenvironment by generating a composite matrix of a hyaluronan supported by collagen. Human astrocytes and endothelial colony forming cells (ECFCs) were incorporated into the matrix and co-cultured with GBM cells to evaluate the effect of normal cells on the GBM 3D cell migration and drug response. Time-lapse microscopy was used to evaluate the 3D migration distance, velocity and persistence of GBM cell lines GBM10, GBM43 and GBAM1 (CD133+) during 18h after drug treatment with temozolomide and a STAT3-inhibitor. Survival of GBM cells was also evaluated 18h and 72 h after drug treatment. All results were compared to standard monolayer culture. Presence of astrocytes and ECFCs increased GBM net migration distance and velocity in the 3D model and in 2D monolayer culture. Additionally, viability of GBM after drug treatment was higher when astrocytes and ECFCs were present in the 3D model compared to only GBM 3D culture and standard monolayer culture. Our results support the importance of the 3D-microenvironment as modulator of tumor response and provide a tunable in vitro platform for primary brain tumor studies aimed to compliment in vivo model observations.
Citation Format: Marisol Herrera-Perez, Melissa Fishel, Sherry Harbin, Jenna Rickus. Astrocytes and endothelial colony forming cells (ECFCs) influence the migration and drug response of glioblastoma cells in a 3D culture model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 613.
Abstract 63: A transposon-based forward genetic screen for steatosis-associated liver cancer drivers
Authors: Tschida Barbara R. , Temiz N. Alpay , Yang Ju D. , Keng Vincent W. , Largaespada David A. 
Published: July 2016

Abstract
Hepatocellular carcinoma (HCC), or liver cancer, is the second leading cause of death from cancer worldwide (Ferlay et al, Lyon, France: International Agency for Research on Cancer, 2013). HCC is linked with hepatic steatosis, or fatty liver disease, the most common chronic liver disease in the US. Both hepatic steatosis and HCC are increasing in prevalence in the US. However, the molecular mechanisms that cause HCC in a steatotic liver are not entirely understood. To uncover mutations promoting cancer in fatty livers and elucidate the role of steatosis in HCC, we performed a forward genetic screen using the conditional Sleeping Beauty (SB) transposon insertional mutagenesis system in mice treated with ethanol and a choline deficient diet to induce steatosis. Mice developed hepatic steatosis and liver cancer without sex bias, modeling the pattern seen in humans in whom HCC's with steatosis as a preceding condition are represented by a nearly equal number of males and females. We found that hepatic steatosis caused a downregulation of liver Foxa1 expression and increased Foxa2 inactivating phosphorylation, thus providing a molecular explanation for the loss of gender bias in our mouse model. Transposon insertion sites were mapped from the mouse HCC tumors, and genes near or in which more insertions were observed than expected by chance were identified as common insertion sites (CIS), which we consider putative steatosis-associated liver cancer genes. Wnt/b-catenin signaling, which defines a subclass of HCC and can induce tumors in mice without sex bias, was one of the top CIS associated pathways identified. Interestingly, alpha-adrenergic and dopamine signaling were also among the top steatosis-specific CIS associated pathways, suggesting a role for the sympathetic nervous system and cAMP signaling in fatty liver-associated cancer. Further studies are underway to test the roles of the pathways and individual genes identified in this study in driving HCC. Our studies implicate Wnt/beta-catenin and sympathetic nervous system signaling in steatosis-associated HCC and suggest methods for treatment or prevention in such cases.
Citation Format: Barbara R. Tschida, N. Alpay Temiz, Ju D. Yang, Vincent W. Keng, David A. Largaespada. A transposon-based forward genetic screen for steatosis-associated liver cancer drivers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 63.
Abstract 638: Clinical characteristics of breast cancer xenograft models
Authors: den Brok Wendie D. , Chia Stephen , Bates Cherie , Kalloger Steve , Aparicio Samuel , Mar Mar , Gelmon Karen , Eirew Peter 
Published: July 2016

Abstract
Purpose: We have expertise in breast cancer xenograft models and have previously published data on clonal dynamics. Our aim was to explore clinical characteristics of those patients (pts) whose breast cancer tumours engrafted versus those that did not.
Methods: Tissue from pts enrolled in a locally advanced/metastatic (MBC) study and a breast tumour tissue repository between Sept. 2008 and July 2014 underwent xenografting using NodScid/IL2rgKO (NSG) mice. Xenografts were passaged when tumour volume reached 1 cm3. Mice were sacrificed if no engraftment by 12 months (mos). Pt charts were reviewed to determine biomarker status (hormone receptor [HR], HER2), grade, LVI, time free from disease/progression, and pathologic complete response (pCR) for pts receiving neoadjuvant therapy.
Results: A total of 64 pts had known xenograft status: 32 engrafters, 32 non-engrafters. Biomarker status did not predict likelihood of engraftment (p = .0695) and is shown in Table 1 along with site/timing of biopsy for tissue engraftment within biomarker groups. When HER2+ cases are excluded from analysis, the HR-/HER2- phenotype yields a 72% probability of engraftment compared to 39% for the HR+/HER2- group (p = .0418). For engrafters, 22/32 (68%) of pts had or went on to have relapsed or de novo MBC. For non-engrafters, 7/32 (22%) had or went on to have relapsed disease (p = .0004). Grade and LVI did not predict engraftment (p = .1806 and p = .8657 respectively). No grade 1 tumours engrafted (n = 3). There were 25 pts who received neoadjuvant chemotherapy: 14 engrafters, 11 non-engrafters. None of the engrafters achieved a pCR; 3 non-engrafters achieved a pCR. Median time to engraftment was 5 mos for pts with relapsed/advanced disease vs 9.8 mos for pts who did not relapse however, treatment was variable.
Conclusion: This preliminary study highlights potential differences in clinical characteristics of engrafters vs non-engrafters in breast cancer xenograft models and warrants further exploration. (Funded by CBCRA, BCCF) TABLE 1.Biomarker status, tissue site/type in attempted xenografts.Engrafter (N = 32) N, (%)Non-engrafter (N = 32) N, (%)HR+/HER2-14 (44)22 (69)Tissue from:Primary tumour419Recurrence23Advanced dz on therapy80HR-/HER2-13 (40)5 (16)Tissue from:Primary tumour114Recurrence21Advanced dz on therapy00HER2+/HR+0 (0)2 (9)Tissue from:Primary tumour02Recurrence00Advanced dz on therapy00HER2+/HR-5 (16)3 (9)Tissue from:Primary tumour42Recurrence01Advanced dz on therapy10
Citation Format: Wendie D. den Brok, Stephen Chia, Cherie Bates, Steve Kalloger, Samuel Aparicio, Mar Mar, Karen Gelmon, Peter Eirew. Clinical characteristics of breast cancer xenograft models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 638.
Abstract 657: N-Myc and STAT Interactor knock out in the mammary epithelium prompts hyper-proliferation
Authors: Pruitt Hawley C. , Metge Brandon J. , Bailey Sarah K. , Shevde Lalita A. , Samant Rajeev S. 
Published: July 2016

Abstract
N-Myc and STAT Interactor (NMI) is an evolutionarily conserved protein that is widely expressed in fetal and adult tissues. Early studies implicated its role in regulating the activities of transcription factors (such as MYC, STATs, BRCA1, TIP60 etc.) critical to tumor progression and metastasis. However, the functional relevance of these regulatory activities of NMI remains unknown. Recent findings from our lab have revealed that NMI protein expression is decreased by 70% in primary tumor specimens from patients with metastatic breast cancer. Most recently, we have found that lack of NMI expression in breast cancer cells confers resistance to chemotherapy by blocking autophagy-induced cell death. Thus the status of NMI expression in breast cancer patients may be an important clinical consideration. Additionally, our functional studies have demonstrated that loss of NMI expression allows manifestation of TGFβ and Wnt driven EMT that results in increased invasion and metastatic dissemination. Overall, we have noticed a profound impact of NMI on multiple developmental signaling pathways that are essential for mammary development as well as tumor progression.
To further elucidate the biological role of NMI, we have created a genetically engineered mammary specific Nmi knock out model. We observed that in normal murine mammary tissue Nmi is expressed in the mammary epithelium during all stages of mammary development. However, it's expression is strikingly induced at the onset of pregnancy, implicating an important role of NMI in mammary ductal development and/or lactation. Remarkably, the Nmi knock out mice exhibit distinctly increased number of alveolar structures (30% more than in control mice) during lactation. Moreover, these Nmi-/- mammary glands also show 20% more proliferating mammary epithelial cells (MECs) compared to respective littermate controls. In addition, 3D-alveologenesis of Nmi knock out MECs is highly responsive to induction by growth factors such as TGFα and FGFs when compared to MECs from littermate controls. Hyper-proliferative phenotype has been implicated as one of the key factors for breast cancer initiation as well as progression. Overall, our work describes a direct evidence for the role of NMI as a key regulator of mammary epithelial cell proliferation.
Citation Format: Hawley C. Pruitt, Brandon J. Metge, Sarah K. Bailey, Lalita A. Shevde, Rajeev S. Samant. N-Myc and STAT Interactor knock out in the mammary epithelium prompts hyper-proliferation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 657.
Abstract 659: Novel refinements for the autochthonous mouse model of cancer
Authors: Cabeceiras Peter K. , Joshi Nikhil S. , Jacks Tyler 
Published: July 2016

Abstract
There are many levels of genetic regulation at play in autochthonous mouse models of cancer. For instance, mouse models can be programed to knockout tumor suppressor genes and enable transcription of oncogenes in order to cause normal cells to transform into cancer cells that can eventually form tumors and metastasize. Concurrently to this, a gene of interest (GOI) under the control of a tetracycline-response element (TRE) promoter can be studied in a doxycycline-dependent fashion. The GOI under the control of the TRE promoter will be transcribed only in the presence of a transcriptional activator fusion protein, rtTA, and a chemical compound, doxycycline. Unfortunately, it is extremely difficult to limit the doxycycline-dependent expression of the GOI only to cancer cells, so normal cells will invariably express the GOI. This inaccuracy can limit the translation of results from mouse model to human patient. In the interest of engineering models that closely recapitulate the disease in question, we propose to limit the expression of rtTA and the GOI to cancer cells by linking rtTA expression to cell cycle regulation. The cell cycle is leveraged because rapid division and proliferation are characteristics intrinsic to proliferative cancer cells, and some cell cycle proteins are abundantly expressed in cancer cells but not expressed in normal cells. By fusing rtTA to cell cycle proteins that are expressed in cycling cancer cells, we hope to improve the accuracy and capabilities of the autochthonous mouse model of cancer.
Citation Format: Peter K. Cabeceiras, Nikhil S. Joshi, Tyler Jacks. Novel refinements for the autochthonous mouse model of cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 659.