tbuckley/cabot-search huggingface dataset:
Abstract 1368: 4NQO shows formation of yH2AX foci, oxidative base damage and activates DNA repair pathway preferentially in HPV positive HNSCC cells
Authors: Gauri Shishodia, Rhodee Ric G. Toledo, Xiahuao Rong, Adam Y. Xiao, Lynn Harrison, Cherie Ann Nathan
Journal: Cancer Research (2020)

Abstract Background: There is an epidemic of HPV associated head and neck squamous cell carcinoma (HNSCC) There is controversy as to whether HPV positive SCC patients who have a &amp;gt;10 pack year smoking history have a worse prognosis than HPV associated non-smokers. Tobacco exposure is associated with alteration of DNA damage repair (DDR) pathway which is often activated in several cancers including HNSCC. A mutational profile of HPV associated smokers determined there was no significant difference in the mutational profile between HPV associated non-smokers and smokers. Hence we wanted to test this observation by analyzing the effects of 4NQO, a mutagen and carcinogen which serves as a surrogate for tobacco exposure, in HPV positive and HPV negative HNSCC cells. Methods: Protein and mRNA expression were analyzed by western blotting and real time PCR respectively. yH2AX staining and oxidative DNA damage analysis were performed using immunofluorescence and FPG-modified alkaline comet assay respectively. Results: Our preliminary data shows that 4NQO activates DDR pathway preferably in NOK E6/E7 and HPV positive UMSCC47 and SCC104 HNSCC cells as seen by increased phosphorylation of BRCA1, Rad50 and RAD51, chk1 and increased p21 levels in a time- and concentration-dependent fashion. Real time PCR data showed higher mRNA transcript levels of RAD51 and BRCA1 in NOK E6/E7 and HPV positive UMSCC47 and SCC104 HNSCC cells as compared to NOK and HPV negative SCC40 HNSCC cells upon 4NQO treatment. 4NQO causes yH2AX foci formation suggesting double strand breaks (DSBs) formation and an increase in DNA damage in HNSCC cells. 4NQO increased oxidative base damage in NOK E6/E7, UMSCC47 and SCC104 HPV positive HNSCC cells, and to a lesser degree in NOK and SCC40 HPV negative HNSCC cells. Conclusion: Our preliminary study shows for the first time that HPV E6/E7 oncogenes promote DNA repair in NOK and HPV positive HNSCC cells in response to 4NQO treatment. This could explain why HPV associated HNSCC have a better prognosis irrespective of smoking history. Citation Format: Gauri Shishodia, Rhodee Ric G. Toledo, Xiahuao Rong, Adam Y. Xiao, Lynn Harrison, Cherie Ann Nathan. 4NQO shows formation of yH2AX foci, oxidative base damage and activates DNA repair pathway preferentially in HPV positive HNSCC cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1368.
Abstract 3438: Hypoxia inhibits BMP4-induced astrocytic differentiation in glioma stem cells
Authors: Ronald S. Wu, Elisabeth Liedtke, Sheila Mansouri, Samantha Brazier, Paul Guilhamon, Nicole I. Park, Eric Chen, Mathieu Lupien, Daniel D. De Carvalho, Peter G. Dirks, Gelareh Zadeh, Bradley G. Wouters
Journal: Cancer Research (2020)

Abstract The tumor microenvironment is an important contributor to malignancy in glioblastoma (GBM) by influencing stemness properties in glioma stem cells (GSCs) and their capacity for differentiation into various cell types. Tumor hypoxia is a common feature of the GBM microenvironment and can influence cell state through a variety of processes including the inhibition of oxygen-dependent lysine histone demethylases (KDMs) and subsequent epigenetic changes required for differentiation or maintenance of the stem cell state. However, the precise mechanisms underlying hypoxic restriction of differentiation to specific neural lineages is unclear. Here, we show that hypoxia suppresses astrocytic differentiation induced by bone morphogenetic protein 4 (BMP4) in patient-derived GSCs. In 8/10 patient derived GSC lines, BMP4 induced expression of astrocytic markers, such as glial fibrillary acidic protein, and this induction was repressed by hypoxia in 7/10 lines. Interestingly, significant anti-proliferative effects of BMP4 induced differentiation were only observed in 3/10 lines and was rescued in only one GSC line by hypoxia, suggesting that these processes are uncoupled. Although hypoxia may directly limit the activity of oxygen-dependent KDMs important in this process, levels of S-2-hydroxyglutarate (S-2HG), an endogenous KDM inhibitor, were also increased in 5/8 GSC lines under hypoxia. Exogenous treatment with S-2HG or a small molecule KDM6 family inhibitor, phenocopied the repressive effects of hypoxia on BMP4 induced differentiation. In patient tumors, hypoxic areas surrounding pseudopalisading necrosis showed high expression of hypoxia markers, and these hypoxia markers were anti-correlated with markers of astrocytic differentiation. Together, these results demonstrate that the hypoxic tumor microenvironment in GBM, through multiple mechanisms limiting oxygen-dependent KDM activity, promote maintenance of the malignant stemness state by inhibiting astrocytic differentiation. This study implicates tumour hypoxia as a key regulator of stemness and a therapeutic target to promote differentiation in GBM. Treatment strategies that target hypoxic cells are urgently needed to overcome these challenges. Citation Format: Ronald S. Wu, Elisabeth Liedtke, Sheila Mansouri, Samantha Brazier, Paul Guilhamon, Nicole I. Park, Eric Chen, Mathieu Lupien, Daniel D. De Carvalho, Peter G. Dirks, Gelareh Zadeh, Bradley G. Wouters. Hypoxia inhibits BMP4-induced astrocytic differentiation in glioma stem cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3438.
Abstract 1: Sulindac plus phospholipid is effective for polyp reduction and safer than sulindac alone
Authors: Jennifer Sarah Davis, Preeti Kanikarla, Patrick L. Yu, Mihai Gagea, Dexing Fang, Manu Sebastian, Peiying Yang, Ernest Hawk, Roderick Dashwood, Lenard M. Lichtenberger, David Menter, Scott Kopetz
Journal: Cancer Research (2020)

Abstract Purpose: To evaluate the chemoprevention efficacy and relative safety of sulindac combined with a phospholipid compared to sulindac alone. Methods: Apcmin/+ mice on the C57/B6 background were randomized to receive oral gavage of sulindac, sulindac combined with the phospholipid (phosphatidyl choline, sulindac-PC), saline or no treatment, daily for twenty-one days. At the end of the treatment period, polyp burden and gastric integrity were assessed in a blinded Following formalin fixation, the stomach from each animal was embedded in paraffin and sectioned for microscopic evaluation. In addition to mucosal ulceration, three measures of gastric inflammation were taken. To test biological activity of sulindac and sulindac-PC, nuclear β-catenin immunohistochemistry was performed on small intestinal polyps. Results: Both sulindac and sulindac-PC treated animals had significantly decreased polyp burden compared to controls (Table 1). Additionally, sulindac-PC treated mice had significantly (p=0.02) lower gastric inflammation scores (1.00 ± 0.63) compared to sulindac alone (2.14 ± 0.90). Two out of seven sulindac treated mice were found to have gastric ulcers, compared to zero out of six sulindac-PC treated mice, though this difference was not statistically significant. Both sulindac and sulindac-PC treated mice had significantly lower nuclear β-catenin staining compared to control treated mice (Table 1). Conclusions: Our findings suggest the addition of a phospholipid as an effective strategy to reduce gastric toxicity of non-steroidal anti-inflammatory drugs, such as sulindac, while maintaining chemopreventive efficacy. Citation Format: Jennifer Sarah Davis, Preeti Kanikarla, Patrick L. Yu, Mihai Gagea, Dexing Fang, Manu Sebastian, Peiying Yang, Ernest Hawk, Roderick Dashwood, Lenard M. Lichtenberger, David Menter, Scott Kopetz. Sulindac plus phospholipid is effective for polyp reduction and safer than sulindac alone [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1.
Abstract 47: Mutation in homologous recombination as a prognostic factor independent of TCGA molecular subtypes in endometrial cancer
Authors: Luyang Zhao, Yibo Dai, Yuanjing Hu, Zhiqi Wang, Chengcheng Li, Guoqiang Wang, Jianliu Wang
Journal: Cancer Research (2020)

Abstract Background: Endometrial cancers have been categorized into four genomic classes by The Cancer Genome Atlas Research Network (TCGA) with comprehensive genomic analysis. However, TCGA molecular subtypes are hard to utilize in clinic as the expensive cost and a simply version of POLE, TP53 genes cannot fully differentiate the four subtypes. Therefore, more convenient and reliable biomarkers need to be identified for clinical practice. Methods: Whole-exome sequencing and RNA sequencing data for 529 patients with endometrial carcinomas were downloaded from TCGA. Mutations in 62 genes of homologous recombination repair (HR) signaling were defined as HR mutation. Associations between HR mutation and survival and RNA expression were analyzed. Results: HR mutation was associated with a prolonged disease specific survival (DSS) (HR, 0.47; 95% CI, 0.28-0.79; P &amp;lt;0.05), progression-free survival (PFS) (HR, 0.50; 95% CI, 0.35-0.72; P &amp;lt;0.05) and overall survival (OS) (HR, 0.48; 95% CI, 0.31-0.73; P &amp;lt;0.05) in endometrial cancers. HR mutation was related with clinical characteristics including FIGO stage (P&amp;lt;0.05), tumor grade (P&amp;lt;0.05) and histological types (P&amp;lt;0.05). HR mutation was enriched in MSI (hypermutated) group (49%) and copy-number low group (19.6%). In the multivariable cox proportional hazards regression model including FIGO 2008, histology types, tumor grade and TCGA subtypes, the association between HR mutation and PFS was still significant (HR, 0.22; 95% CI, 0.05-0.88; P = 0.03), which indicating the HR mutation is an independent prognostic factor for PFS. Gene set enrichment analysis suggested that HR mutation was involved with the increase of genes related to activated T cells, immune cytolytic activity, and IFN-γ release. Conclusion: HR mutation was related with a favorable prognosis through increasing T cells signature. Identification of HR mutation by genomic profiling provides a potentially novel and convenient approach for endometrial cancer patients to predict the prognosis independent of TCGA four subtype classifications Citation Format: Luyang Zhao, Yibo Dai, Yuanjing Hu, Zhiqi Wang, Chengcheng Li, Guoqiang Wang, Jianliu Wang. Mutation in homologous recombination as a prognostic factor independent of TCGA molecular subtypes in endometrial cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 47.
Abstract 379: Myeloperoxidase-produced HOCl is a paracrine effector linking myeloid cells to NF-κB signaling in melanoma, mediating anti-tumor responses during early melanoma progression
Authors: Tracy W. Liu, Seth T. Gammon, Ping Yang, David T. Fuentes, David Piwnica-Worms
Journal: Cancer Research (2020)

Abstract The myeloperoxidase (MPO) system of myeloid-derived cells (MDCs) is central to cellular innate immunity and the microbicidal activities of phagocytes, while also impacting the pathogenesis of many disorders, including cancer. Upon MDC activation, MPO is secreted into phagosomes, catalyzing the production of hypochlorous acid (HOCl). HOCl is a potent chlorinating oxidant with significant biological effects, but the mechanisms by which HOCl impacts cancer growth remain unresolved. Herein, we demonstrate that the myeloid lineage-restricted MPO-HOCl system has anti-tumor effects during early melanoma progression. Orthotopic melanomas grew slower in immuno-competent host mice wild type for MPO+/+ compared to syngeneic MPO-null (MPO-/-) animals. Using a specific and potent inhibitor of MPO, 4-aminobenzoic acid hydrazide (4-ABAH), melanoma tumor growth in MPO+/+ mice continuously administered 4-ABAH, pharmacologically mimicked the MPO-/- phenotype. Real-time intravital tumor imaging in vivo using skinfold window chamber animal models as well as live cell co-culture studies revealed a cell-cell proximity-dependent association between MDC-derived MPO activity and blockade of ligand-induced IκBα degradation in tumor cells. Real-time bioluminescent imaging and quantitative monitoring of the canonical NF-κB pathway was assessed in melanoma cells stably expressing bioluminescent reporters: a transcriptionally-activated NF-κB-promoter-driven Firefly luciferase (FLuc) reporter or a fusion reporter under the control of an NF-κB-responsive promoter fused to IκBα-FLuc reporter. HOCl was shown to directly inhibit IκB kinase (IKK) activity, thereby decreasing NF-κB transcriptional activation within melanomas, increasing circulating levels of the myeloid-attracting cytokines CXCL1 and CXCL5, enhancing local infiltration of CD8+ cytotoxic T cells, and dampening tumor growth. Overall, these data reveal a novel role for MDC-derived HOCl as a small molecule paracrine signaling factor that trans-inhibits IKK in melanoma cells, mediating anti-tumor responses during early tumor progression. Citation Format: Tracy W. Liu, Seth T. Gammon, Ping Yang, David T. Fuentes, David Piwnica-Worms. Myeloperoxidase-produced HOCl is a paracrine effector linking myeloid cells to NF-κB signaling in melanoma, mediating anti-tumor responses during early melanoma progression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 379.
Abstract 862: A method to create aggregate histogram representations for machine learning from small sample size medical sensor time series
Authors: Nick Moss, Ingrid Oakley-Girvan, Michelle R. Longmire
Journal: Cancer Research (2020)

Abstract Background: Machine learning has been used to successfully develop biomarkers from data collected from a wide range of commodity and specialized sensor devices. Typical machine learning algorithms, such as deep learning, require several thousand to on the order of millions of samples of data to work most effectively. However, in many studies with limited numbers of patients and data samples, such methods cannot be used. Objective: To solve this problem, we have developed a specialized algorithm that can convert time series signals into a set of histogram signatures that can then be used with unsupervised methods such as clustering to create biomarkers. Methods: Our methods decompose the time series data into time windows and analyze aggregate mean and variance and other statistical qualities over these windows. Results: We will describe our approach and show how we have applied it along with genetic algorithms to perform auto-tuning for novel biomarkers and endpoints. Conclusions: We will be able to develop a highly accurate biomarker to detect gate imbalance and impairment from limited accelerometer data. Citation Format: Nick Moss, Ingrid Oakley-Girvan, Michelle R. Longmire. A method to create aggregate histogram representations for machine learning from small sample size medical sensor time series [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 862.
Abstract 3054: Targeting TGF-β signaling for obesity/insulin resistance-associated hepatocellular carcinoma
Authors: Jian Chen, Xiaoping Su, Andres Rojas, Robert S Bresalier, John R. Stroehlein, Sai-ching Yeung
Journal: Cancer Research (2020)

Abstract Background: Recently, obesity, insulin resistance/type 2 diabetes mellitus and fatty liver disease, i.e., key components of the metabolic syndrome, have been recognized as risk factors for hepatocellular carcinoma (HCC). Obesity and dysmetabolism serve as drivers of oncogenesis in the setting of abnormal hepatic morphology and physiology, and hepatic steatosis may provide the promoting microenvironment for the development of HCC. Dysregulated signaling in the transforming growth factor (TGF)-β pathway plays a central role in immunomodulation, inflammation, and fibrogenesis in the HCC microenvironment. We used a carcinogen Diethylnitrosamine (DEN)-induced HCC mouse model in genetically obese mice [heterozygous Agouti yellow (Ay/a)] and haplo-knock out of Smad3 (a kinase downstream of type II receptor for TGFβ to study the detailed mechanism by which Smad3-dependent TGF-β signaling regulates obesity-associated dysmetabolism in HCC, and to determine whether inhibition of TGF-β signaling could inhibit obesity-associated HCC. Methods: Ay/a mice in C57B/L genetic background were bred with Smad3 knockout mouse (Smad3+/−). Obese and insulin-resistant Ay/a mice were treated with DEN (i.p. 25mg/kg) at 14 days of age to induce HCC. Ay/a mice and DEN-induce HCC mice were treated with TGF-β receptor 2 inhibitor (EW7919, 20 mg/kg orally 3 times/week for 8 weeks). We performed RNA sequencing analysis for 40 mouse liver samples from the groups of mice above. Results: 1. Haplodeficiency of Smad3 significantly decreased obesity Ay/a mouse weight and suppressed fatty liver development. 2. Treatment of TGF-β receptor 2 inhibitor to Ay mice successfully blocked weight gain in Ay/a mice. 3. DEN-induced hepatocarcinogenesis in Ay/a mice occurred significantly earlier than in lean (a/a) C57B/L mice. 4. Inhibition of TGF-β signaling by Smad3 haplodeficiency significantly upregulated lipid catabolic processes and downregulated cytokine-induce leukocyte migration in the fatty livers of Ay/a mice. 5. Inhibition of TGF-β signaling by genetic or pharmacologic inhibitors significantly suppressed HCC development in Ay/a mice. Conclusion: We demonstrated a specific cancer promoting role of TGF-β in metabolic reprogramming in liver cancer cells, highlighting the TGF-β signaling pathway as a potential therapeutic target in obesity/insulin resistance-associated HCC. Citation Format: Jian Chen, Xiaoping Su, Andres Rojas, Robert S Bresalier, John R. Stroehlein, Sai-ching Yeung. Targeting TGF-β signaling for obesity/insulin resistance-associated hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3054.
Abstract 4686: Core transcriptional regulatory circuitry FOXA1-MAX-SP1 promotes malignancy of hepatocellular carcinoma
Authors: Li Peng, Xiaoqing Yuan, Zhen Chen, Chaoyang Zhang, Duanqing Tian, Dong Yin, De-Chen Lin
Journal: Cancer Research (2020)

Abstract Background: Super-enhancers (SEs) are large clusters of transcriptionally active enhancers. Functionally, they are capable of driving the expression of key genes that control cell identity, which are also particularly important for tumor biology. This study is aimed at probing the biological function and mechanisms of the hyper-activation of the SEs associated core transcriptional regulatory circuitry (CRC) constituted by FOXA1-MAX-SP1 in hepatocellular carcinoma. Results: ChIP-seq analysis of H3K27ac showed that the expression of three transcription factors FOXA1, MAX and SP1 is driven by super-enhancers in hepatocellular carcinoma cells. Notably, these three transcription factors also regulate large number of super-enhancers, whose characteristics fit the mathematical model of the core transcriptional regulatory circuitry (CRC). ChIP-seq analysis of FOXA1, MAX, SP1, H3K27ac, H3K4me1 and H3K4me3 confirmed the occupancy of FOXA1, MAX and SP1 at super-enhancers and promoters of some genes, including FOXA1, MAX and SP1. Also, FOXA1, MAX and SP1 have a positive correlation with each other in human hepatocellular carcinoma tissue. In addition, CCK8 assay showed that FOXA1, MAX and SP1 could promote cell growth of HCC cells. Relative open chromatin at FOXA1, MAX and SP1 genes mirrored their more active transcriptional state in HCC patients from TCGA ATAC-seq data. The mRNA expression of these three TFs were increased, which predict a worse prognosis of HCC patients. Conclusion: FOXA1-MAX-SP1 regulate super-enhancers and may form a core transcriptional regulatory circuitry, so as to promote malignancy of hepatocellular carcinoma. They are potential therapeutic targets and prognostic biomarkers for hepatocellular carcinoma. This work was supported by the National Natural Science Foundation of China (81802812 and 81972658), the Natural Science Foundation of Guangdong Province (2018A030313129 and 2019A1515012114). Citation Format: Li Peng, Xiaoqing Yuan, Zhen Chen, Chaoyang Zhang, Duanqing Tian, Dong Yin, De-Chen Lin. Core transcriptional regulatory circuitry FOXA1-MAX-SP1 promotes malignancy of hepatocellular carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4686.
Abstract 1480: CCL4 promotes oral squamous cell carcinoma angiogenesis by targeting the angiopoietin-2 signal pathway
Authors: Ming-Yu Lien
Journal: Cancer Research (2020)

Abstract The inflammatory chemokine (C-C motif) ligand 4 (CCL4) plays an important role in the pathogenesis and progression of cancer, with higher serum CCL4 levels in patients with oral squamous cell carcinoma (OSCC) marking a more advanced stage of disease. OSCC accounts for approximately 95% of oral cancer in Taiwan and this disease has a poor prognosis, with aggressive local invasion and metastasis predisposing to recurrence and additional morbidity. Angiogenesis, a physiological process that enables new blood vessels to form from pre-existing vessels, is involved in the growth, maintenance, and metastasis of most tumors. Angiopoietin-2 (ANGPT2) induces angiogenesis and is a potent endothelial cell-specific mitogen. Until now, it has been unclear as to whether levels of CCL4 expression are a marker of angiogenic activity in patients with OSCC and are correlated with higher levels of ANGPT2 expression. Our investigations have found that treating OSCC cells with CCL4 increases ANGPT2 expression and that CCL4 treatment promotes angiogenesis in a murine model of OSCC. Thus, CCL4 may be a novel molecular therapeutic target for inhibiting angiogenesis and metastasis in OSCC. Citation Format: Ming-Yu Lien. CCL4 promotes oral squamous cell carcinoma angiogenesis by targeting the angiopoietin-2 signal pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1480.