tbuckley/cabot-search huggingface dataset:
Abstract 2070: HMGB1 governs p53 to autophagic degradation via its nucleus-to-cytoplasm transport
Authors: Qiaojun He, Peihua Luo, Xiaochun Yang, Qinjie Weng, Ling Ding, Bo Yang
Journal: Cancer Research (2017)

Abstract P53 is under exquisitely fine regulation and acts as a transcription factor that regulates the expression of thousands of genes that control apoptosis, necroptosis, ferrotosis, cell cycle arrest, senescence, metabolism and fertility. Regulation of p53 turnover is essential not only for the response to chemotherapeutic drugs or radiation in cancer cell but also to keep p53 activity under control in a normal cell. Moreover, .p53 is found to be overactivated in various diseases including idiopathic pulmonary fibrosis (IPF), alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD). Promoting hyperactivated-p53 degradation can combat these diseases. However, the strategies that based on known proteasome-dependent degradation only can stabilize the expression level of p53 such as nutlins (inhibit the interaction between mdm2 and tumor suppressor p53). Autophagy-lysosomal degradation is the other pathway for controlling cellular protein stability. More and more researches have established that numerous proteins can be degraded through both proteasome and autophagy-lysosome pathways. However, very little is known to date about p53 turnover through autophagy-lysosome pathway. Here we discover that the activation of p53 autophagic degradation during an oral small molecule receptor tyrosine kinase inhibitor sunitinib in p53 wt cancer cells and normal cells. Mechanistically, the nucleus-to-cytoplasm shift is essential for the autophagic degradation of p53 induced by sunitinib, however, does not require p53 nuclear export signals. Indeed, p53 degradation is achieved by the nucleus-to-cytoplasm transport of its nuclear binding target HMGB1, shifting the distribution of p53 from the nucleus to the cytoplasm. Then cytoplasmic p53 directly interacts with the autophagy cargo receptor p62 to promote degradation. Importantly, inhibition of HMGB1 sensitizes cancer cell to sunitinib. Taken together, our study identified an alternative p53 protein turnover mechanism induced by sunitinib, thus not only elucidating the underlying mechanisms that limit sunitinib efficacy in cancer therapy but also opening an avenue for expanding the clinical indications of sunitinib. Note: This abstract was not presented at the meeting. Citation Format: Qiaojun He, Peihua Luo, Xiaochun Yang, Qinjie Weng, Ling Ding, Bo Yang. HMGB1 governs p53 to autophagic degradation via its nucleus-to-cytoplasm transport [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2070. doi:10.1158/1538-7445.AM2017-2070
A Review of Some Spontaneous Neoplasms in Mice&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/xref&gt;
Authors: Stuart W. Lippincott, Jesse E. Edwards, Hugh G. Grady, Harold L. Stewart
Journal: JNCI Journal of the National Cancer Institute (1942)

Journal Article A Review of Some Spontaneous Neoplasms in Mice Get access Stuart W. Lippincott, Stuart W. Lippincott passed assistant surgeon Search for other works by this author on: Oxford Academic PubMed Google Scholar Jesse E. Edwards, Jesse E. Edwards research fellow Search for other works by this author on: Oxford Academic PubMed Google Scholar Hugh G. Grady, Hugh G. Grady acting assistant surgeon Search for other works by this author on: Oxford Academic PubMed Google Scholar Harold L. Stewart Harold L. Stewart senior pathologist National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 3, Issue 2, October 1942, Pages 199–210, https://doi.org/10.1093/jnci/3.2.199 Published: 01 October 1942
Abstract 5174: Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells
Authors: Luciana Madeira Da Silva, Elaine Gavin, Kevin J. Lee, Veronica Ramírez-Alcántara, Kristy L. Berry, Holly T. Taylor, Alla Musiyenko, Ileana V. Aragon, Adam B. Keeton, Jennifer Scalici, Rodney P. Rocconi, Gary A. Piazza
Journal: Cancer Research (2017)

Abstract Canonical Wnt/β-catenin signaling is known to be associated with platinum resistance in ovarian cancer in which inhibitors hold promise for the treatment of refractory disease. Phosphodiesterase 10A (PDE10A) is a dual cyclic AMP and cyclic GMP phosphodiesterase isozyme recently implicated in colon cancer. PDE10A inhibition in colon cancer cells by siRNA or small molecule inhibitors increased cGMP levels and activated PKG to inhibit β-catenin signaling. A novel PDE10 inhibitor, ADT-061, was identified by screening a library of indene derivatives, and showed strong antineoplastic activity in the Apc+/min-FCCC mouse (Lee K et al., unpublished data). Cyclic GMP and phosphodiesterases participate in the ovarian follicular development, although little is known about PDE10A expression in ovaries, especially with regard to a potential role in ovarian tumorigenesis. PDE10A protein was found to be expressed in various established ovarian cancer cell lines at higher levels than immortalized or primary ovarian surface epithelial cell lines. Pf-2545920, a known PDE10A inhibitor, and ADT-061 inhibited the growth of multiple ovarian tumor cell lines with IC50s around 20µM and 0.5µM, respectively. Both compounds induced apoptosis after 24h treatment, as measured by PI/Annexin-V staining and PARP cleavage. Pf-2545920 and ADT-061 induced phosphorylation of VASP at Ser157 and Ser239 in various ovarian cancer cell lines, indicating activation of cyclic AMP and cyclic GMP signaling, respectively. Treatment also decreased levels of β-catenin and downstream targets of TCF-dependent transcription, including c-MYC, survivin and cyclin-D1. Homozygous knockout PDE10A clones of OV-90 ovarian cancer cells obtained using CRISPR/Cas9 showed decreased clonogenic potential, decreased Pf-2545920-mediated VASP phosphorylation and β-catenin, c-MYC and survivin expression. Ongoing efforts are focused on the development of more potent ADT-061 analogs. These observations support further study of a role of PDE10 in ovarian tumorigenesis and the development of ADT-061 or analogs for the treatment of refractory ovarian cancer as well as the prevention of malignant recurrence. Citation Format: Luciana Madeira Da Silva, Elaine Gavin, Kevin J. Lee, Veronica Ramírez-Alcántara, Kristy L. Berry, Holly T. Taylor, Alla Musiyenko, Ileana V. Aragon, Adam B. Keeton, Jennifer Scalici, Rodney P. Rocconi, Gary A. Piazza. Phosphodiesterase 10A inhibition as a novel approach to suppress β-catenin signaling in ovarian cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5174. doi:10.1158/1538-7445.AM2017-5174
Abstract 2037: Oral nitroxoline in combination with intravesical bacille calmette-guerin (BCG) shows synergistic antitumor efficacy in mouse bladder cancer orthotopic xenograft
Authors: Qiang Li, Kevin Pan, Xiezhao Li, Naijin Xu, Peng Huang
Journal: Cancer Research (2017)

Abstract Nitroxoline, an antibiotic used to treat urinary tract infection, had previously been identified as a MetAP2 inhibitor and found to show antitumor efficacy in mouse models of human breast cancer xenograft and bladder cancer orthotopic xenograft [1]. Our purpose in this study was to evaluate the feasibility of combining oral nitroxoline with intravesical BCG, the first-line therapy for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC), in mouse bladder cancer orthotopic xenograft. The luciferase-expressing murine bladder cancer cell line MBT-2-Luc cells was transurethrally implanted in the bladder of syngeneic female C3H/He mice. The animals were randomly divided into groups and treated with phosphate-buffered saline (PBS), oral nitroxoline, intravesical BCG alone, and a combination as described in methods. The IVIS spectrum images analyses of luciferin-stained tumor at 21 days after inoculation revealed that combining oral nitroxoline with intravesical BCG showed synergistically enhanced antitumor efficacy and prolonged long-term survival, implicating the potential of combining bladder cancer treatment using oral nitroxoline with intravesical BCG in the clinical setting. The mechanism behind this observation is currently under investigated. Citation Format: Qiang Li, Kevin Pan, Xiezhao Li, Naijin Xu, Peng Huang. Oral nitroxoline in combination with intravesical bacille calmette-guerin (BCG) shows synergistic antitumor efficacy in mouse bladder cancer orthotopic xenograft [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2037. doi:10.1158/1538-7445.AM2017-2037
Abstract 746: TaqMan Rare Mutation Assays targeting the TERT promoter region
Authors: Marion Laig, Kamini Varma, Vidya Venkatesh
Journal: Cancer Research (2017)

Abstract The enzyme Telomerase maintains telomeres at the ends of chromosomes. The Telomerase Reverse Transcriptase (TERT) gene codes for the enzyme’s catalytic domain and is not expressed in normal somatic cells. As a consequence, normal cells acquire senescence by shortening of their telomeres during cell division and eventually undergo apoptosis. In contrast to normal somatic cells, expression of TERT is reinstated in cancer cells causing escape from senescence and apoptosis by maintaining the telomeres. It has recently been shown that mutations in the TERT promoter region play a key role in regulating and reinstating TERT expression. 90% of cancers carry a mutation in the TERT promoter region. Mutations like C228T and C250T create new binding site for the E26 transformation-specific (ETS) transcription factor that regulates TERT expression. Experimental evidence showed that the ETS factor GA-binding protein, alpha subunit (GABPA) binds to the de novo ETS motif and activates TERT transcription in cancer cells. We undertook a project designing TaqMan Rare Mutation assays addressing mutations in the TERT promoter. These assays are TaqMan SNP Genotyping assays that are optimized for use in digital PCR with the Applied Biosystems QuantStudio 3D. In digital PCR, partitioning the sample into many individual reaction wells facilitates detection and quantification of rare mutant alleles. TaqMan SNP Genotyping Assays ensure reliable discrimination of mutant and wild-type allele. This will enable easy and sensitive detection of TERT promoter mutations in cancer research samples. These assays are suitable for detection in liquid biopsy applications with cell free DNA (cfDNA). Assay design proved to be challenging due to high GC content and repetitive elements in this region of the TERT gene and required varying both the assay design and experimental cycling conditions. Template for wet-lab testing was synthetic plasmid carrying the mutation spiked into wild-type genomic DNA and wild-type genomic DNA control. The result was a TaqMan Rare Mutation assay detecting the C228T mutation in the TERT promoter region. We showed that designing TaqMan Rare Mutation Assays for digital PCR is feasible for the challenging TERT promoter region. Work addressing additional mutations in this region is ongoing. For Research Use Only. Not for use in diagnostic procedures. Citation Format: Marion Laig, Kamini Varma, Vidya Venkatesh. TaqMan Rare Mutation Assays targeting the TERT promoter region [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 746. doi:10.1158/1538-7445.AM2017-746
Abstract 936: Single cell analysis reveals cancer stem cell heterogeneities in hepatocellular carcinoma
Authors: Hongping Zheng, Yotsawat Pomyen, Maria Hernandez, Caiyi Li, Ferenc Livak, Tim Greten, Anuradha Budhu, Xin Wang
Journal: Cancer Research (2017)

Abstract Tumor heterogeneity represents a major obstacle to effective cancer treatment and personalized medicine. Hepatocellular carcinoma (HCC) is clinically and biologically heterogeneous, which is partly attributed to the presence of hepatic cancer stem cells (CSCs). CSC surface makers can have overlapping expression or exclusive expression of different subpopulations of hepatic CSCs, and these cells may contain different oncogenic changes. The existence of various CSC surface-marked subpopulations might pose a problem for CSC targeted therapeutics. Little is known about whether there are shared or distinct pathways in different subpopulations. Moreover, it remains unknown whether heterogeneity exists within certain subpopulations. Thus, we propose to profile the global transcriptome of surface-marked CSCs (EpCAM+, CD133+ and CD24+) at the single-cell level using index flow cytometric sorting and single-cell RNA sequencing technology. We statistically compared mRNA transcriptomes of individual single cells of triple positive (EpCAM+/ CD133+ /CD24+) CSCs and triple negative (EpCAM-/ CD133- /CD24-) cells. Further, we compared the triple positive and the triple negative cells at the single cell level in terms of their self-renew capability in both normoxic and hypoxic conditions. Our results show that at the single cell level, the transcriptomic profiles show a high-degree of heterogeneity in HCC cell lines, meanwhile, there is a dramatic difference between triple positive and triple negative cells in their transcriptomic profiles. There is a high-degree of intra-tumor and inter-tumor heterogeneity observed in single cell transcriptomes of HCC patients’ samples. Triple positive CSC single cells show continuous rather than discrete stemness-related gene expression patterns. In parallel, the self-renewal capability of triple positive cells also exhibits heterogeneity, while triple negative cells show little self-renewal capability. Thus, our single cell analysis study reveals molecular and biological heterogeneity of cancer stem cells in HCC, which may provide insight into the underlying mechanisms of how CSCs contribute to tumor heterogeneity and underscore key pathways and novel targets for hepatic CSC therapy. Citation Format: Hongping Zheng, Yotsawat Pomyen, Maria Hernandez, Caiyi Li, Ferenc Livak, Tim Greten, Anuradha Budhu, Xin Wang. Single cell analysis reveals cancer stem cell heterogeneities in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 936. doi:10.1158/1538-7445.AM2017-936
Abstract 4324: Estrogen promotes proliferation and apoptosis of endometrial carcinoma cell lines Ishikawa and HEC1A via endometrial stromal cells
Authors: Xiang Tao, Jian Wu, Yinhua Yu
Journal: Cancer Research (2017)

Abstract Endometrial carcinoma is the leading malignancies of women in Western countries and the second leading cancer of female in China. As endometrial stromal cells (ESCs) are sharply decreased in endometrial carcinoma (EC) compared to normal endometrium, it is interested to explore the roll of ESCs in the tumorigenesis of endometrium. Unopposed estrogen is considered as the etiology of endometrioid carcinoma, but the underlying mechanism is needed to further explore. This study is to determine the biological effects of primary cultured ESCs on two endometrial cancer cell lines-Ishikawa and HEC1A. ESCs from normal, atypical hyperplastic and malignant endometrial specimens were collected, validated by immunohistochemistry and cultured in vitro, which were maintained in a medium containing 10 nM estradiol (E2) for three months to simulate the unopposed estrogen stimulation of EC patients. Microarray were performed to detect the alteration of gene expression, which were then confirmed by real time RT-PCR. Co-culture of ESC and EC cell lines were performed by Transwell plate. Cell proliferation was analyzed by CCK8 assay. Apoptosis was analyzed by flow cytometry based on PI/Anexin V staining. Our results showed E2 promoted the proliferation of three types of ESCs. E2 has no direct effect on cancer cell lines Ishikawa and HEC1A, but when they co-cultured with ESCs, which were stimulated by E2, the proliferation of cancer cells was promoted by all three type of ESCs. Moor interestedly, we found that the much obvious promoted effects were occurred by the ESCs that extracted from malignant samples. Estrogen could also reduce the apoptosis of both cancer cell lines when co-culturing with ESCs from normal specimen. Gene microarray and real time RT-PCR indicated that collagen 9 were up-regulated 2.3 times when ESCs cells treated by E2. In conclusion, Estrogen altered the microenvironment of stromal cells, which could lead to the proliferation of endometrial carcinoma cells via paracrine function. The alteration of collagen synthesis by ESCs might contribute to this communication between the epithelial and mesenchymal cells. Citation Format: Xiang Tao, Jian Wu, Yinhua Yu. Estrogen promotes proliferation and apoptosis of endometrial carcinoma cell lines Ishikawa and HEC1A via endometrial stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2017-4324
The Paradox of Mindfulness: Seamus Heaney’s “St Kevin and the Blackbird”
Authors: Kimberly R. Myers
Journal: JAMA (2017)

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Abstract 256A: Validation of methyl donors between two food measurements in a colorectal cancer study
Authors: Lufei Young, S. Pamela K. Shiao
Journal: Cancer Research (2017)

Abstract Purpose: The purpose of this study was to validate methyl donor intakes between 30-day food frequency questionnaire (FFQ) and 24-hour food record (FR) in a colorectal cancer study. Background: Dietary methyl donors play pivotal roles in cancer prevention by promoting adequate metabolism and DNA methylation. The FFQ and 24-hour FR are the most commonly used methods to assess adequate nutrient intake, including methyl donors and other vital micronutrients that are essential to promote metabolism and methylation. While FFQ provides best estimates in dietary intakes, a 24-hour food record is less time consuming for subject burden. Methods: A total of 134 participants’ dietary data were collected using FFQ and 24-hour FR by using US Department of Agriculture computerized programs. Bland and Altman methodology was used to validate the bias and agreement between these two measurements. Results: Overall, the 24-hour measurements presented underestimated values across all nutrients in comparison to FFQ measurements. Using a 10% criterion on the differences between the two measurements, the percentage bias for 24-hour FR compared to 30-day FFQ was acceptable for most B vitamins, including B1 (-6.9 ±0.15), B2 (-8.66± 0.12), B3 (-9.25± 0.12), B6 (-5.02, ± 0.14), and B9 (folate: -7.90 ±0.24). However, the bias was greater for protein based methyl donors, including B12 (-17.23± 0.14), choline (-13.38± 0.11), Glycine (-17.53± 0.10), and Methionine (-18.88± 0.09). The correlations between the two measurements on all methyl donors ranged from 0.92 to 0.99. The precisions for all measurements based on the standard error (SE) were less than and within 0.03% (0.007 -0.021%). And, the agreements between the two measurements were less than and within 10% for Glycine and methionine (8.96 - 9.58%), based on the standard deviation (SD); however, greater than 10% for other protein based methyl donors including choline and other B vitamins (10.5-24.11%). Conclusion: Proper dietary intakes of methyl donors are vital for cancer prevention. These findings point out the importance of further validation and use of more accurate food measurement to monitor dietary intake, and the interpretation of nutrient reports with caution. Citation Format: Lufei Young, S. Pamela K. Shiao. Validation of methyl donors between two food measurements in a colorectal cancer study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 256A. doi:10.1158/1538-7445.AM2017-256A