tbuckley/cabot-search huggingface dataset:
Abstract 3012: Long-term aspirin use and total and cancer-specific mortality
Authors: Yin Cao, Meir Stampfer, Walter Willett, Donna Spiegelman, JoAnn Manson, Eric Rimm, Molin Wang, Shuji Ogino, Charles Fuchs, Edward Giovannucci, Andrew Chan
Journal: Cancer Research (2017)

Abstract Background: Long-term follow of clinical trials of aspirin for the prevention of cardiovascular disease have shown that aspirin may be associated with a reduced risk of death from cancer, including colorectal, esophageal, and lung cancer, and possibly breast and prostate cancer. However, the potential benefits of aspirin use, at a range of doses and duration of use, on total and cancer-specific mortality have not been examined in large prospective cohort studies with long-term follow-up. Methods: We examined the association between aspirin use and subsequent total and cancer-specific mortality, at a range of doses and duration of use, among 86,206 women in the Nurses' Health Study (1980-2012) and 43,977 men in the Health Professionals Follow-up Study (1986-2012). Participants with a history of cancer, heart disease, or stroke were excluded. Aspirin use was assessed at baseline and updated every 2 years with greater than 90% follow-up. Cox proportional hazards models were used to compute hazard ratios as estimates for age- and multivariable-adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: During up to 32 years of follow-up, 22,094 women and 14,749 men died, and 8,271 women and 4,591 men died of cancer. Compared with nonregular use, regular aspirin use was associated with lower risk of total mortality (multivariable-adjusted RR 0.93; 95% CI 0.90-0.95 for women and RR 0.89; 95% CI 0.86-0.93 for men), which was primarily due to a lower risk of dying from any cancer (RR 0.93; 95% CI 0.89-0.97 for women and RR 0.85; 95% CI 0.80-0.90 for men), especially colorectal cancers (RR 0.69; 95% CI 0.59-0.81 for women and RR 0.70; 95% CI 0.57-0.85 for men), breast cancers (RR 0.89; 95% CI 0.79-0.99), prostate cancers (RR 0.77; 95% CI 0.65-0.90), and lung cancers in men (RR 0.86; 95% CI 0.74-0.99). The benefit of aspirin on cancer mortality appeared evident with use of at least 0.5 to 1.5 standard aspirin tablets per week for both men and women; and the minimum duration of regular use associated with lower cancer mortality was 6 years. Conclusions: Long-term aspirin use was associated with reduced risk of total mortality, primary due to reduced risk of dying from cancers. Citation Format: Yin Cao, Meir Stampfer, Walter Willett, Donna Spiegelman, JoAnn Manson, Eric Rimm, Molin Wang, Shuji Ogino, Charles Fuchs, Edward Giovannucci, Andrew Chan. Long-term aspirin use and total and cancer-specific mortality [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 3012. doi:10.1158/1538-7445.AM2017-3012
Abstract 3443: Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 in hepatocellular carcinoma
Authors: Felice H. Tsang, Daniel W. Ho, Irene O. Ng, Jack C. Wong
Journal: Cancer Research (2017)

Abstract Hepatocellular carcinoma (HCC) is one of the most common and lethal cancers worldwide. Due to the asymptomatic nature of HCC, many patients were diagnosed at advance stages and available therapeutic options are very limited. Therefore, a better understanding of the molecular mechanism underlying hepatocarcinogenesis is urgently needed and is crucial for the development of effective treatment. Long intervening non-coding RNAs (lincRNAs) are emerging class of regulatory RNA involved in diverse molecular processes. In this study, we aimed to interrogate lincRNAs expression in HCC and identify novel lincRNAs that contribute to hepatocarcinogenesis. To investigate the global expression profile of lincRNAs in human HCCs, next-generation transcriptome sequencing (RNA-Seq) was performed in 16 pairs of HBV-associated primary HCCs and their corresponding non-tumorous liver tissues. Interestingly, the lincRNA expressions in human HCCs can be unambiguously segregated from their non-tumorous counterparts by unsupervised clustering analysis, suggesting that global lincRNA expression profiles between tumors and non-tumors were remarkably different. From this analysis, we identified linc-CHD1L-1 as the most significant up-regulated lincRNA in HCCs. Clinically, linc-CHD1L-1 was overexpressed in over 80% of HCC patients. Linc-CHD1L-1 expression level in tumors was also shown to be a promising marker for HCC diagnosis. Functionally, knockdown of linc-CHD1L-1 by shRNAs had significantly reduced HCC cell proliferation and cell migration in vitro. Besides, knockdown of linc-CHD1L-1 in HCC cells also substantially abrogated tumorigenicity in subcutaneous tumor model. Mechanistically, the expression of linc-CHD1L-1 was significantly and positively correlated to the expression of its neighboring genes located on the chromosome 1q. Knockout of linc-CHD1L-1 by CRISPR/Cas9 also significantly repressed its neighboring genes expression, suggesting that linc-CHD1L-1 may positively regulate gene expression in a cis-manner. Finally, DAVID pathway analysis performed on linc-CHD1L co-expressed protein coding genes further suggested that linc-CHD1L-1 was significantly co-expressed with genes that are involved in transcription and chromatin modifications. In conclusion, overexpression of linc-CHD1L-1 contributes to hepatocarcinogenesis by promoting HCC cell proliferation and migration through transcriptional and epigenetic mechanisms. Citation Format: Felice H. Tsang, Daniel W. Ho, Irene O. Ng, Jack C. Wong. Functional and mechanistic characterization of oncogenic long intervening non-coding RNA Linc-CHD1L-1 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 3443. doi:10.1158/1538-7445.AM2017-3443
Abstract 365: Cross-talk between BRAF and Hippo/YAP1 signaling in melanoma
Authors: Mohan Kumar Durai Raj, Jonathan Nguyen, Namrata Bora-singhal, Jane Messina, Geoffrey Gibney, Srikumar Chellappan
Journal: Cancer Research (2017)

Abstract Hippo/YAP1 signaling pathway is a tumor suppressive pathway that controls the organ size by modulating the cell growth, proliferation and apoptosis and is conserved from Drosophila to mammals. In mammals, the Hippo tumor suppressor pathway consists of cascade of kinases in which MST1/2 phosphorylates and activates LATS1/2. The latter phosphorylates the oncogenic transcriptional coactivators YAP1 and TAZ, leading to their cytoplasmic retention by 14-3-3 proteins and/or degradation. Inactivation of MST and LATS kinases allows YAP1 and/ or TAZ nuclear translocation and subsequent activation of their target genes. Deregulation of Hippo pathway can induce tumors in model organisms and occurs in wide range of human cancers including melanoma. Merlin, a key component of this pathway which inhibits YAP1, is mutated/deleted in 8% of melanoma. Majority of uveal melanomas are driven by Gq/11 mutations that trigger YAP1 nuclear translocation, promoting tumor growth. High levels of YAP1 in BRAFV600E mutant tumors confer resistance to RAF- and MEK- targeted therapy in patients. Our results show that YAP1 level is elevated in melanoma and the YAP1 inhibitor verteporfin alone or in combination with B-RAF inhibitor PLX4720 reduces the viability, invasion and anchorage-independent growth of B-RAF V600E mutant SK-MEL-28 and SK-MEL-5 cells. In addition, verteporfin treatment also reduced the viability of PLX4720 resistant 1205 cells. Western blot analysis of verteporfin and PLX4720 treated SK-MEL-28 and SK-MEL-5 cells displayed reduced levels of YAP1, B-RAF, pERK, MEK and pMEK. We also report a novel physical interaction between YAP1 and B-RAF; this could be detected using double immunofluorescence and immunoprecipitation-western blotting techniques in both B-RAF V600E mutant and N-Ras mutant melanoma cells. Proximity ligation assays on tissue microarray showed that YAP1-B-RAF interaction is elevated in metastatic melanoma compared to normal skin. These novel findings highlight the crosstalk between B-RAF and Hippo/YAP1 signaling which might have a potential role in melanoma development and progression. Further, experiments are in progress to elucidate the functional significance of YAP1-B-RAF interaction in melanoma. Citation Format: Mohan Kumar Durai Raj, Jonathan Nguyen, Namrata Bora-singhal, Jane Messina, Geoffrey Gibney, Srikumar Chellappan. Cross-talk between BRAF and Hippo/YAP1 signaling in melanoma [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 365. doi:10.1158/1538-7445.AM2017-365
Abstract 2637: Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell carcinoma
Authors: Linda Tran, Clint T. Allen, So-Jin Park, Roy Xiao, Carter Van Waes, Nicole C. Schmitt
Journal: Cancer Research (2017)

Abstract Rationale: Cisplatin, which remains the most commonly used systemic drug for head and neck squamous cell carcinoma (HNSCC), reduces numbers of circulating immune cells. However, recent studies suggest that cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. We previously found that cisplatin increases expression of major histocompatibility (MHC) class I and programmed death ligand 1 (PD-L1) in HNSCC cell lines in vitro. Methods: In the current study, we investigated other components of the antigen processing machinery (APM) by flow cytometry following treatment with cisplatin. Using the syngeneic mouse oral cancer 1 (MOC1) model of HNSCC, we then investigated the effects of cisplatin and anti-PD-1 antibody, alone or in combination, on tumor growth and survival. Results: Using three different HNSCC cell lines, we found that levels of the APM components LMP2, ERp57 and calreticulin increased in all cell lines treated with cisplatin, whereas TAP1/2 increased dramatically only in one cisplatin-treated cell line with wildtype TP53 (UMSCC-74A). In MOC1 tumor-bearing mice, tumor growth was partially delayed by treatment with cisplatin and anti-PD-1 antibody alone and substantially delayed when these agents were given in combination, with resultant increased survival. Comparison of different treatment schedules suggested that concurrent administration is more effective than giving cisplatin one day prior to anti-PD-1 or giving anti-PD-1 one day prior to cisplatin. Conclusions: Despite upregulating PD-L1 on tumor cells and decreasing levels of circulating immune cells, cisplatin may enhance some aspects of anti-tumor immunity in the tumor microenvironment. While no mice were cured with concurrent cisplatin and anti-PD-1 antibody, tumor growth was substantially delayed. These results suggest a rationale for combining cisplatin and anti-PD-1 monoclonal antibodies, perhaps with radiation or other therapies, in additional preclinical studies and clinical trials of HNSCC. Supported by NIDCD intramural project ZIA-DC-DC000090. Citation Format: Linda Tran, Clint T. Allen, So-Jin Park, Roy Xiao, Carter Van Waes, Nicole C. Schmitt. Anti-tumor activity of cisplatin is enhanced by PD-1 blockade in preclinical models of head and neck squamous cell 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 2637. doi:10.1158/1538-7445.AM2017-2637
Abstract 3368:Omicsdata integration analysis in high grade serous ovarian cancer: results from three studies
Authors: Yanina Natanzon, Madalene Earp, Julie M. Cunningham, Kimberly R. Kalli, Stacey J. Winham, Sebastian M. Armasu, Melissa C. Larson, Chen Wang, David D. Bowtell, Dale W. Garsed, Ellen Goode
Journal: Cancer Research (2017)

Abstract High grade serous ovarian cancer (HGSOC) is a complex disease in which initiation and progression have been associated with gene mutation, DNA methylation changes, genetic variation, and epigenetic processes. Variation in several susceptibility regions and cancer-typical global methylation patterns have been observed in HGSOC; however, this knowledge has not been compelling in understanding HGSOC intiation or progression. As ingetration of genomic, epigenomic, and transcriptomic data has increased mechanistic understanding in other cancers, we hypothesized that tumor methylation alone or in combination with germline genetic variation influences tumor gene expression in HGSOC. We examined three nested models using an Elastnic Net (ENET) penalized regression method while adjusting for somatic copy number (CNV): a) germline genotype and tumor DNA methylation (full model), b) genotype only, and c) DNA methylation only. We included 339 cases from The Cancer Genome Atlas (TCGA), 54 cases from Mayo Clinic, and 78 cases from the Australian Ovarian Cancer Study (AOCS). Genotyping and copy number calls on germline DNA, expression, methylation and copy number on somatic samples were collected and analyzed on different platforms separately at each study site. We excluded genes with low overall expression and thus analyzed a total of 11,922 genes available in three datasets ( Ensembl IDs, 500kb window up- and downstream). In general, combining genomic data in HGSOC did not reveal a role for germline genetic variation in altering gene expression. However, in methylation only models 79 genes were associated with differential expression in the TCGA cases (permutation multiple testing adjusted p-val &amp;lt;0.05), in the Mayo cases (unadjusted p-val &amp;lt;0.05) and AOCS cases (unadjusted p-val &amp;lt;0.05). A known tummor suppressor (FBXW7) was associated with differential expression in the three datasets at p-val &amp;lt;0.01. This work demonstrates the feasibility, utility, and statistical power of ENET gene-level analyses incoporating maximal genomic information. Citation Format: Yanina Natanzon, Madalene Earp, Julie M. Cunningham, Kimberly R. Kalli, Stacey J. Winham, Sebastian M. Armasu, Melissa C. Larson, Chen Wang, David D. Bowtell, Dale W. Garsed, Ellen Goode. Omics data integration analysis in high grade serous ovarian cancer: results from three studies [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 3368. doi:10.1158/1538-7445.AM2017-3368
Abstract 4421: IGF2 regulates mitochondrial cell energy phenotype and biogenesis in TNBC cells
Authors: Maria L. Pagan, Vinodh Kumar Radhakrishnan, Daisy De Leon
Journal: Cancer Research (2017)

Abstract Triple-negative breast cancer (TNBC) is very aggressive, resistant to chemotherapy and more likely to relapse, causing the worst prognosis. African American (AA) women suffer higher incidence and mortality of TNBC due to the expression of high levels of Insulin Growth Factor 2 (IGF2) which promotes tumor progression, metastasis, and chemoresistance. Also, it has been established that functional mitochondria and mitochondrial DNA (mtDNA) are essential for cancer cell growth. Mutations and/or reductions in mtDNA copy number that alter the Oxidative Phosphorylation (OXPHOS) physiology are common features of TNBC. We have demonstrated that mtDNA content is lower in CRL-2335 AA TNBC cell line when compared to the CRL-2335 IGF2 knockout cell line. Thus, we propose that IGF2 regulates the mtDNA content. This study was designed to demonstrate if IGF2 regulates mitochondrial genes to determine the cell energy phenotype. An XFp analyzer was used to study the mitochondrial function in terms of OCR (Oxygen Consumption Rate/Mitochondrial Respiration) and ECAR (Extracellular Acidification Rate/ Glycolysis) in the wild type and IGF2 stable knockout of CRL-2335 AA TNBC cells. Real Time PCR was performed to study the gene expression pattern of IGF2, PGC1α and PGC1β. PGC1α and PGC1β are critical genes in the regulation of the mitochondrial biogenesis, thus, they are important in the cellular metabolic phenotype. Utilizing the Seahorse metabolic system we assessed cell energy phenotype and alterations in terms of mitochondrial respiration rate (OCR) % and Glycolysis (ECAR) %. Our preliminary results showed that the overall OCR and ECAR of the stressed CRL-2335 AA TNBC cells was altered according to the levels of IGF-II expressed. Furthermore, the results demonstrated that there was a metabolic shift in the CRL-2335 AA TNBC cells towards the glycolytic pathway when IGF2 was knockout in comparison to the wild type CRL-2335 cells. Also, IGF2 knockout cells showed higher gene expression rate of PGC1β as compared to the wild type. The above data confirms that IGF2 plays a critical role in determining the cell energy phenotype. Citation Format: Maria L. Pagan, Vinodh Kumar Radhakrishnan, Daisy De Leon. IGF2 regulates mitochondrial cell energy phenotype and biogenesis in TNBC 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 4421. doi:10.1158/1538-7445.AM2017-4421
Abstract 3463: Mitotic regulation of the tumor suppressor phosphatase PHLPP1
Authors: Agnieszka T. Grzechnik, Alexandra C. Newton
Journal: Cancer Research (2017)

Abstract The PH domain Leucine-rich repeat Protein Phosphatases (PHLPP) are tumor suppressors originally discovered for their ability to directly dephosphorylate and inactivate the pro-survival kinase Akt, a key transducer of growth factor signaling. In the decade since this discovery, a number of other PHLPP targets have been elucidated, but still little is known about the molecular mechanisms governing the function and regulation of PHLPP itself. Here we report that PHLPP1 is hyperphosphorylated during mitosis and that, additionally, PHLPP1 suppresses the phosphorylation of the mitotic kinase CDK1. Specifically, we show that PHLPP1 undergoes an electrophoretic mobility shift in mitotic cells that is lost when lysates are treated in vitro with lambda phosphatase, suggesting that PHLPP1 is phosphorylated during mitosis. In addition to a cell cycle-dependent change in its post-translational modifications, PHLPP1 suppresses the phosphorylation of the main mitotic cyclin dependent kinase, CDK1, at Tyr15, an inhibitory phosphorylation that must be removed in order for cells to progress through mitosis. First, Tyr15 phosphorylation is increased in phlpp1-/- mouse embryonic fibroblasts (MEFs) compared to wild-type MEFs. Second, pharmacological inhibition of PHLPP1 in wild-type MEFs results in an increase in Tyr15 phosphorylation. Activation of key mitotic kinases, such as CDK1, and inactivation of phosphatases is required for the large increase in protein phosphorylation that occurs during mitosis. As such, reversible protein phosphorylation plays a role in regulating proper progression through mitosis, which is essential as errors in mitosis can result in aneuploidy, a hallmark of cancer. Our data support a previously undescribed role for PHLPP1 in regulating mitotic progression, potentially providing novel insight into how PHLPP suppresses tumorigenesis. Citation Format: Agnieszka T. Grzechnik, Alexandra C. Newton. Mitotic regulation of the tumor suppressor phosphatase PHLPP1 [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 3463. doi:10.1158/1538-7445.AM2017-3463
Combination of AAV-TRAIL with miR-221-Zip Therapeutic Strategy Overcomes the Resistance to TRAIL Induced Apoptosis in Liver Cancer
Authors: Sisi Ma, Jiazeng Sun, Yabin Guo, Peng Zhang, Yanxin Liu, Dexian Zheng, Juan Shi
Journal: Theranostics (2017)

TNF-related apoptosis-inducing ligand (TRAIL) possesses the capacity to induce apoptosis in a wide variety of tumor cells without affecting most normal cells.However, it has now emerged that many primary cancer cells are resistant to TRAIL monotherapy.Overcoming the intrinsic or acquired TRAIL resistance is desirable for TRAIL-mediated cancer therapy.In this study, we found that the miR-221/222 cluster was up-regulated in TRAIL-resistant liver cancer cells.Specific inhibitors of miR-221 and/or miR-222, called sponge, TuD and miR-Zip were constructed, and their ability to overcome TRAIL resistance was compared.Among them, AAV-mediated gene therapy using co-expression of TRAIL with miR-221-Zip showed the most synergistic activity in the induction of apoptosis in vitro.In vivo treatment of nude mice bearing human TRAIL-resistant liver cancer xenografts with AAV-TRAIL-miR-221-Zip also led to growth inhibition.This sensitizing effect of miR-221-Zip was associated with increased expression of PTEN, the miR-221 target, as well as with decreasing levels of Survivin.Moreover, miR-221 expression was concomitant with promotion of Survivin expression and suppression of PTEN expression.TRAIL sensitivity of cancer cells isolated from liver cancer tissues or from patients was significantly correlated with miR-221 expression.And miR-221 blood expression levels in liver cancer patients were correlated with TRAIL sensitivity, thus it had the potential to be a predictor of TRAIL sensitivity in liver cancer.These data suggested the potential of combining AAV-TRAIL with miR-221-Zip as a therapeutic intervention for liver cancer.