bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1850: Evaluation of Pim-1 kinase inhibition in a preclinical model of mouse prostate cancer
Authors: De Velasco Marco A. , Oki Takashi , Kura Yurie , Ando Naomi , Fukushima Emiko , Davies Barry R. , Huszar Dennis , Yamamoto Yutaka , Hatanaka Yuji , Shimizu Nobutaka , Yoshimura Kazuhiro , Nozawa Masahiro , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2015

Abstract
Pim-1 is a serine/threonine kinase that is in involved in the transcription of genes that regulate apoptosis and cell cycle progression. Pim-1 has been shown to be overexpressed in a variety of cancers and has been implicated in human prostate tumorigenesis. The aim of our study was to clarify the role of Pim-1 during the prostate tumorigenesis and determine its potential as a molecular target for therapy. To accomplish this goal, we carried out a series of experiments using a genetically engineered mouse model of prostate cancer driven by the conditional inactivation of PTEN. High levels of Pim-1 were observed during the early stages of the tumorigenesis process which decreased as tumors progressed. Expression of Pim-1 was localized in the nucleus and cytoplasm of prostatic intraepithelial neoplasia (PIN), well-differentiated, and moderately-differentiated tumors. In poorly-differentiated tumors, Pim-1expression was heterogeneously expressed at lower levels and was predominantly localized to the cytoplasm of cancer cells. Levels of Pim-1 expression were increased in tumors from mice after surgical castration. To evaluate the therapeutic potential of Pim-1as a target for prostate cancer, we tested the antitumor effects of AZD1208, a highly potent Pim kinase inhibitor, on a panel of cell lines derived from castration-naïve and castration-resistant mouse prostate cancer. AZD1208 inhibited the tumor cell growth of several cell lines and demonstrated higher sensitivity to those derived from castration resistant tumors. In vivo, drug intervention studies show that treatment with AZD1208 reduced tumor growth of castration-naïve and castration-resistant prostate tumors by 12.1 (P = 0.162) and 24.3% (P&lt;0.001), respectively. These findings provide further support for a role of Pim-1 during prostate tumorigenesis and could thus serve as a rational target for the development of novel combination strategies.
Citation Format: Marco A. De Velasco, Takashi Oki, Yurie Kura, Naomi Ando, Emiko Fukushima, Barry R. Davies, Dennis Huszar, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Evaluation of Pim-1 kinase inhibition in a preclinical model of mouse prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1850. doi:10.1158/1538-7445.AM2015-1850
Abstract 1864: Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models
Authors: Zhou Wei , Blake Robert A. , Nonomiya Jim , Qian Jing , Kategaya Lorna , Wertz Ingrid , Daemen Anneleen , O'Brien Thomas , Sensintaffar John , Moon Michael , Nannini Michelle A. , Oeh Jason , Sampath Deepak , Wang Xiaojing , Smith Nicholas , Brigham Daniel , Joseph James , Hager Jeffrey H. , Friedman Lori S. 
Published: August 2015

Abstract
The majority of breast cancers express and rely on ERα for tumor growth, thus endocrine therapy is the mainstay of ER-positive breast cancer treatment. Despite the effectiveness of current therapies, many patients relapse with tumors still dependent on ER for growth via both estrogen-dependent and estrogen-independent mechanisms. Acquired mutations in ESR1 were recently identified in the ligand-binding domain of ERα in patients who progressed after aromatase inhibitors and tamoxifen. It is estimated that more than 20% of relapsed ER-positive breast cancer patients acquire activating mutations in ESR1. We created a variety of model systems to study the functional consequences of ESR1 mutations. In stable overexpressing cell lines, the mutant ER protein eventually becomes down-regulated, thus we generated cell lines with dox-inducible and CRISPR engineered ESR1 hotspot mutations. We confirmed ligand-independent transcriptional activity of ESR1 hotspot mutations including Y537S and D538G. Cell lines and patient derived xenograft (PDX) models were utilized in ER ChIP-seq studies. Additionally, we investigated therapeutic response and resistance in the context of ESR1 activating mutations for tamoxifen, fulvestrant, and next generation oral SERDs including ARN-810, also known as GDC-0810. ARN-810 is efficacious in MCF7 ESR1 Y537S xenografts and WHIM20 Y537S PDX tumors, indicating that SERDs may be effective for ER mutants.
Citation Format: Wei Zhou, Robert A. Blake, Jim Nonomiya, Jing Qian, Lorna Kategaya, Ingrid Wertz, Anneleen Daemen, Thomas O'Brien, John Sensintaffar, Michael Moon, Michelle A. Nannini, Jason Oeh, Deepak Sampath, Xiaojing Wang, Nicholas Smith, Daniel Brigham, James Joseph, Jeffrey H. Hager, Lori S. Friedman. Selective estrogen receptor degrader (SERD) activity in ESR1 mutant models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1864. doi:10.1158/1538-7445.AM2015-1864
Abstract 1887: Calcium intake and milk product consumption in association with risk for colorectal adenomas
Authors: Um Caroline , Fedirko Veronika , Flanders W Dana , Bostick Roberd M. 
Published: August 2015

Abstract
Calcium intake has been consistently, albeit modestly associated with lower risk of colorectal cancer and adenomas, and supplemental calcium reduced adenoma recurrence in large randomized controlled trials. Milk-based dairy products are the major source of dietary calcium in the US, but the association between milk product consumption and colorectal cancer is unclear. Conventionally produced milk contains significant levels of insulin-like growth factor 1 (IGF-1) from the use of bovine somatotropin hormone. Calcium intake has been positively associated with IGF-1 and IGF-1 binding protein 3 (IGFBP-3) levels. Higher circulating levels of IGF-1 and the IGF-1:IGFBP-3 ratio have been associated with higher risk of certain cancers, including breast, prostate, and colorectal, as well as with adenomatous polyps.
To investigate associations of calcium and milk product intakes with risk for colorectal neoplasms, we pooled data from three colonoscopy-based case-control studies of incident, sporadic colorectal adenoma (n = 786 cases, 2,020 controls) conducted between 1991 and 2002, and analyzed the data using multivariable unconditional logistic regression. Dietary and supplemental intakes in all three studies were assessed using Willett food frequency questionnaires. For indirect indicators of IGF-1 intake from milk products, dietary calcium-adjusted residuals were calculated for total milk products and non-fat milk. For total, dietary, and supplemental calcium intakes, the multivariable-adjusted odds ratios (ORs) comparing the highest to the lowest quintiles of intake were 0.87 (95% confidence interval [CI] 0.63-1.20), 0.91 (95% CI 0.65-1.28), and 0.96 (95% CI 0.70-1.31), respectively. The corresponding ORs for consumption of total milk products, total milk, non-fat milk, total milk product residuals, and non-fat milk residuals were, 1.01 (95% CI 0.74-1.36), 0.97 (95% CI 0.73-1.29), 0.95 (95% CI 0.71-1.25), 0.92 (95% CI 0.70-1.22), and 0.97 (95% CI 0.70-1.34), respectively. For those who consumed any whole milk relative to those who consumed none, the OR was 1.15 (95% CI 0.89-1.50).
These results are consistent with previous findings of modestly lower risk with higher total (dietary plus supplemental) calcium intakes, but suggest that neither the consumption of specific milk products nor all milk products combined, nor the non-calcium components of milk products are associated with risk for sporadic colorectal adenoma.
Citation Format: Caroline Um, Veronika Fedirko, W Dana Flanders, Roberd M. Bostick. Calcium intake and milk product consumption in association with risk for colorectal adenomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1887. doi:10.1158/1538-7445.AM2015-1887
Abstract 1912: Reduction of microRNA-21 by vitamin D compounds during ductal carcinoma in situ transition to invasive ductal carcinoma
Authors: Wahler Joseph , Cheng Larry C. , Maehr Hubert , Uskokovic Milan , Suh Nanjoo 
Published: August 2015

Abstract
MicroRNAs (miRNAs) are small RNA molecules of approximately 22 nucleotides in lengths that can negatively control target gene expression post-transcriptionally. There are currently more than one hundred known human miRNAs. miRNAs have been shown to play an important role in the development and progression of various types of cancer. In breast cancer, ductal carcinoma in situ (DCIS) is an early non-invasive precursor, which is known to progress to invasive ductal carcinoma (IDC) if left untreated. The involvement of miRNAs in the breast cancer progression from DCIS to IDC is still not well understood, and potential regulation of miRNAs by vitamin D compounds during the progression has not been tested. We have previously reported that a novel Gemini vitamin D analog, 1α,25-dihydroxy-20R-21(3-hydroxy-3-deuteromethyl-4,4,4-trideuterobutyl)-23-yne-26,27-hexafluoro-cholecalciferol (BXL0124), inhibits the progression of DCIS to IDC in vivo. To identify miRNAs that could potentially be involved in DCIS progression to IDC, we utilized the MCF10DCIS.com xenograft tumors. MCF10DCIS.com cells (10^6 cells/mouse) were injected subcutaneously into the rear flanks of nu/nu mice. The mice were then treated with BXL0124 (0.1 μg/kg) for 5 weeks. The critical DCIS to IDC transition occurred between weeks 3 and 4 in the in vivo lesions, and several microRNAs were assessed with respect to the DCIS to IDC transition at weeks 3 and 4. Among many miRNAs analyzed, miR-21, miR-24, and miR-140 were up-regulated in IDC lesions compared to DCIS lesions, whereas no marked changes were observed with respect to miR-200c, miR-let-7a, miR-26a, miR-34a, and miR-182. One of the miRNAs identified miR-21, is a well-known oncomir and overexpressed in breast carcinoma, mediating cell survival, proliferation, and metastasis. The increased expression of miR-21 was significant when DCIS lesions progressed to IDC, and this effect was diminished by the treatment with Gemini vitamin D, BXL0124, at week 4. In conclusion, vitamin D compounds reduce the levels of miR-21 during DCIS transition to IDC, potentially contributing to its preventive effects in breast cancer progression. Further investigation of the mechanisms of action by which vitamin D compounds regulate miR-21 should be considered. (This work was supported in part by the National Institutes of Health National Cancer Institute R01-CA127645 and the National Institute of Environmental Health Sciences Grant ES005022).
Citation Format: Joseph Wahler, Larry C. Cheng, Hubert Maehr, Milan Uskokovic, Nanjoo Suh. Reduction of microRNA-21 by vitamin D compounds during ductal carcinoma in situ transition to invasive ductal carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1912. doi:10.1158/1538-7445.AM2015-1912
Abstract 1917: Targeting wildtype and L858R/T790M mutant EGFR by isoliquiritigenin induces apoptosis and Inhibits tumor growth of NSCLC
Authors: Lee Mee-Hyun , Jung Sung Keun , Lim Do Young , Cho Yong-Yeon , Lee Cheol-Jung , Song Ji-Hong , Kim Myoung Ok , Kim Sung-Hyun , Bode Ann M. , Dong Zigang 
Published: August 2015

Abstract
Genetic alteration of epidermal growth factor receptor (EGFR) is a high risk factor of non-small-cell lung cancer (NSCLC). Isoliquiritigenin (ILQ), a chalcone derivative, reported anti-cancer activities. In this study, we investigated the effects of ILQ on the growth of tyrosine kinase inhibitor -sensitive and -resistant NSCLC cells and elucidated its molecular mechanisms. Treatment with ILQ inhibited growth and induced apoptosis in both tyrosine kinase inhibitor-sensitive (HCC827, H1650; delE746-A750 EGFR) and -resistant (H1975; L858R/T790M EGFR) NSCLC cells. However, ILQ didn't showed the inhibitory effects of cell growth and induction of apoptosis in Met amplified-HCC827GR or K-ras mutated-A549 cells. ILQ induced apoptotic markers, the cleavage of caspase-3 and poly-(ADP ribose)-polymerase, increased expression of Bim and reduced expression of Bcl-2. ILQ inhibited the catalytic activity of both wildtype and double mutant (L858R/T790M) EGFR by kinase assay. Treatment with ILQ inhibited the anchorage-independent growth of NIH3T3 cells stably transfected with either wildtype or double-mutant EGFR with or without EGF stimulation. ILQ also reduced the phosphorylation of Akt and ERK1/2 in both TKI-sensitive and -resistant NSCLC cells in the western blotting analysis. ILQ directly bound both wildtype and double-mutant EGFR by ATP-competitive manner. Computational docking model expected that ILQ interacted with Glu762 and Met793 sites of wildtype EGFR and Lys745, Met793 and Asp855 of mutant EGFR. ILQ attenuated the tumor growth of H1975 cell xenografted athymic mice in vivo, which was caused by decreased expression of Ki-67 and diminished phosphorylation of Akt and ERK1/2. Taken together, ILQ suppresses NSCLC cell growth by directly targeting wildtype or mutant EGFR.
Citation Format: Mee-Hyun Lee, Sung Keun Jung, Do Young Lim, Yong-Yeon Cho, Cheol-Jung Lee, Ji-Hong Song, Myoung Ok Kim, Sung-Hyun Kim, Ann M. Bode, Zigang Dong. Targeting wildtype and L858R/T790M mutant EGFR by isoliquiritigenin induces apoptosis and Inhibits tumor growth of NSCLC. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1917. doi:10.1158/1538-7445.AM2015-1917
Abstract 1919: Warfarin-dependent gamma-carboxylation regulates androgen receptor activity
Authors: Tew Ben Yi , Hong Teresa , Pal Sumanta K. , Kalkum Markus , Jones Jeremy 
Published: August 2015

Abstract
The anti-coagulant warfarin prevents the gamma-carboxylation (gla) of target proteins by interfering with the vitamin K cycle through its inhibition of the vitamin K epoxide reductase (VKOR). Most known gla proteins are found in the blood clotting cascade, but we demonstrate using immunoprecipitation and mass spectrometry that the androgen receptor (AR) can also be gamma-carboxylated. This modification occurs at amino acid 2E and can be prevented by warfarin treatment. This residue has been found to be mutated in partial androgen insensitivity syndrome patients. Warfarin, likely through its ability to control carboxylation, alters AR conformation and inhibits AR transcriptional activity, as does siRNA-mediated knockdown of VKOR, the target of warfarin. We further demonstrate that warfarin treatment reduces AR target gene expression in benign mouse prostate tissue in vivo. Interestingly, retrospective studies have shown that prolonged use of warfarin reduces the incidence of prostate cancer, an effect that is not observed for other cancers. In a small series of patients at our institution, we found that one allele of a functional SNP in VKOR is found at a significantly higher rate in prostate cancer patients than would be expected in the general population. We also found that VKOR is highly expressed in normal human prostate epithelia but is lost in cancerous tissue, a pattern of expression that appears to be unique to prostate cancer. We hypothesize that the lower prostate cancer incidence observed in men taking warfarin is due to the ability of warfarin to reduce AR activity, similar to the effect of 5-alpha reductase inhibitors. Importantly, we show for the first time that a nuclear receptor and transcription factor can be regulated by gamma-carboxylation.
Citation Format: Ben Yi Tew, Teresa Hong, Sumanta K. Pal, Markus Kalkum, Jeremy Jones. Warfarin-dependent gamma-carboxylation regulates androgen receptor activity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1919. doi:10.1158/1538-7445.AM2015-1919
Abstract 193: Epigenetic regulation of Notch1 signaling-driven melanoma progression
Authors: Yin Ling , Huang Qinghua , Livingstone Alan S. , Velazquez Omaida C. , Liu Zhao-Jun 
Published: August 2015

Abstract
Objectives. Aberrant Notch signaling promotes melanoma progression, yet the underlying molecular mechanism remains largely unknown. We hypothesized a potential involvement of epigenetic mechanism in this process and sought to identify Notch-regulated miRNAs and their functional targets.
Methods. Notch-regulated miRNAs were identified by examining miRNA profiles in response to Notch activation/inhibition in human melanoma cells using RT2-miRNAArray. The role of specific miRNA in mediating the oncogenic effect of the Notch signaling was studied by testing whether alteration of miRNA expression could reverse the Notch's effects on melanoma cell growth, survival and colony-formation in vitro, and lung metastasis in vivo. The targets of the Notch-regulated miRNA were identified by searching miRNA target database and validated by immunoblot. The roles of miRNA targets in mediating the Notch's oncogenic effects were further assessed by in vitro colony-formation and in vivo lung metastasis assays.
Results. Notch activation down-regulated mi143 in melanoma cells. Reconstituted expression of mi143 antagonized Notch1's oncogenic effect. The anti-oncogenic effect of mi143 is mediated by inhibiting Notch1-induced expression of FGF-1, uPA and uPAR since expression of these targets was up-regulated by the Notch1 activation while down-regulated by reconstituted overexpression of mi143. Supplementation of exogenous FGF-1 or reconstituted expression of uPA/uPAR, but not uPA alone, reversed the suppressive effect of mir143 on Notch-enhanced melanoma cells colony formation in soft-agar or lung metastasis in SCID mice.
Conclusions. Notch activation up-regulates expression of FGF-1, uPA and uPAR through down-regulating mi143 expression in melanoma cells. mi143 is responsible for mediating aberrant Notch signaling-driven melanoma progression. The effect of down-regulated mi143 is transmitted through elevated FGF-1 and enhanced uPA-uPAR signaling activity, but not enzyme activity of uPA. This study unveils novel Notch1/mi143/FGF-1 and Notch1/mi143/uPA-uPAR cascades and uncovers an epigenetic mechanism underlying the oncogenic effect of Notch signaling, and provides potential novel targets for melanoma prognosis and therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Ling Yin, Qinghua Huang, Alan S. Livingstone, Omaida C. Velazquez, Zhao-Jun Liu. Epigenetic regulation of Notch1 signaling-driven melanoma progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 193. doi:10.1158/1538-7445.AM2015-193
Abstract 1934: Improved deconvolution of heterogeneous tumor data to reconstruct clonal evolution from bulk genomic samples
Authors: Roman Theodore , Schwartz Russell 
Published: August 2015

Abstract
Intratumor heterogeneity has long been a confounding factor in interpreting cancer genomic data, but has also been useful in reconstructing progression processes based on variation between clonal populations in single tumors. We previously developed a strategy of applying computational deconvolution algorithms to gene expression or DNA copy number data to reconstruct models of progression of cell populations from bulk tumor samples. Many tools have since been proposed for similar deconvolution analysis, but all are limited by the computational difficulty of unambiguously distinguishing small cell populations and variants from noise in genomic assays. We present a novel approach to infer tumor progression pathways from deconvolved genomic data designed to leverage the fact that tumors that partition into subtypes with similar evolutionary trajectories would be expected to lead to a mathematical substructure in the genomic data, known as a simplicial complex, which can be modeled computationally to better deconvolve cell populations across tumor types. We have developed a computational pipeline to perform tumor deconvolution while taking into consideration this kind of mathematical structure. The pipeline clusters tumors to identify genetically distinct subgroups, fits mixture models to these subgroups, and uses overlap between them to infer a refined deconvolution of major cellular populations and possible pathways of progression between them.
We apply our methods to a set of RNASeq data from the TCGA breast cancer data set and to synthetic data modeling distinct scenarios of tumor progression. We first compare our methods on the synthetic data to our earlier work and to a comparative Gaussian mixture model. All methods perform comparably on unstructured data but the new method substantially outperforms the others on data consistent with simple scenarios for tumor progression along multiple discrete subtypes. The novel method, however, shows lower tolerance for noisy data than a Gaussian mixture model. Application to the TCGA RNASeq data showed our method could partition tumors into discrete subcategories associated with HER2+, ER/PR+, and triple-negative status and could exploit the resulting substructure of the data to deconvolve tumor data and infer progression models reflecting partial sharing of progression states between subtypes. Gene enrichment analysis showed association of deconvolved cell populations with a variety of gene functional categories suggestive of distinct progression mechanisms of the subtypes.
Citation Format: Theodore Roman, Russell Schwartz. Improved deconvolution of heterogeneous tumor data to reconstruct clonal evolution from bulk genomic samples. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1934. doi:10.1158/1538-7445.AM2015-1934