tbuckley/cabot-search huggingface dataset:
Abstract 113: Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast cancer
Authors: Emily Ginn, Hongye Zou, Maryam M. Fallatah, Shengquan Liu, Maggie C. Louie
Journal: Cancer Research (2017)

Abstract Flexible heteroarotiniods (flex-hets) are compounds derived from retinoic acid and recent studies have indicated that these compounds exhibit anti-cancer activity. Amongst the flexible heteroarotinoids, SHetA2 has been to shown block the growth of cervical, head and neck, kidney, lung, and ovarian cancers, and most recently, prostate and breast cancers. However, due to SHetA2’s limitations— a high degree of hydrophobicity, non-selectivity, and potential liver toxicity— a second generation of analogs was developed. Results from our recent study suggest that one of the second-generation analogs, 1-(1-(naphthalen-1-yl)ethyl)-3-(4-nitrophenyl)thiourea (SL-1-09) exhibits anti-cancer activities against both ERα+ and ER- breast cancer cells at micromolar concentrations. Since SL-1-09 is a racemic mixture, the R (SL-1-29) and S (SL-1-30) enantiomers were purified and investigated for their anti-cancer properties. Our results suggest that SL-1-30 has greater growth inhibitory effects on T47D, MCF7, MDA-MB-453, MDA-MB-468 cells in comparison to SL1-29, suggesting that the activity observed in SL-1-09 is likely associated with the S enantiomer. Consistent with this data, breast cancer cells treated with SL-1-09 and SL-1-30 express lower levels of proteins that regulate the cell cycle (i.e, cyclin A, cyclin B, cyclin D1, cyclin E and cdk2). These results demonstrate that SL-1-30 and SL-1-09 inhibit breast cancer cell growth, potentially by blocking cell cycle progression, however further studies are necessary for determining the mechanisms of action. Citation Format: Emily Ginn, Hongye Zou, Maryam M. Fallatah, Shengquan Liu, Maggie C. Louie. Evaluating the anticancer activity of two flexible heteroarotinoid analogs on breast cancer [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 113. doi:10.1158/1538-7445.AM2017-113
Abstract 841: UTR analysis identifies Musashi1 as a translational regulator of radiation-induced Golgi-related gene expression
Authors: Stacey L. Lehman, John W. O'Neill, Kevin Camphausen, Philip J. Tofilon
Journal: Cancer Research (2017)

Abstract The cellular radioresponse is regulated by post-translational modification of constitutively expressed proteins and by changes in gene expression. Although the role of constitutively expressed proteins, such as those involved in the DNA damage response and cell cycle checkpoints, is well-understood in the context of the radioresponse, radiation-induced changes in gene expression are not as clearly defined. We have previously demonstrated that glioblastoma stem-like cells (GSCs) alter their gene expression at the translational level in response to ionizing radiation (IR). In particular, the NSC11 GSC line demonstrated thousands of genes differentially translated at one hour after a dose of 2 Gy, while considerably fewer were modified at the transcriptome level. Furthermore, there was little overlap between the transcriptome and the translatome. Genes undergoing translational regulation in response to IR fell into distinct functional categories, including mitochondrial structure and function, Golgi function, and translational regulation. Here, we aimed to elucidate the mechanism by which IR induces translational changes in the NSC11 GSC line. NSC11 cells were either exposed to 2 Gy or mock irradiated, and polysomes were isolated by sucrose gradient fractionation one hour later. Polysome-bound mRNA was purified and analyzed by microarray. The 5’ and 3’ untranslated regions (UTRs) of the top 75 up- and down-regulated genes were analyzed for the presence of regulatory elements. The most frequently occurring element in the UTRs of both the top up- and down-regulated genes was the Musashi1 binding site. Musashi1 is an RNA binding protein that typically binds to 3’ UTRs to regulate mRNA translation. It is a neural stem cell marker, and its expression is correlated with the grade of malignancy in glioma. GO term analysis of known Musashi1 target genes that were translationally regulated in response to IR revealed an enrichment of genes involved in Golgi function and vesicular trafficking. Knockdown of Musashi1 prevented IR-induced Golgi dispersal in NSC11 cells. Musashi1 knockdown also radiosensitized NSC11 cells, indicating a role for the protein in the cellular radioresponse. Together, these data demonstrate that in the NSC11 GSC line, Musashi1 contributes to radiation-induced translational regulation, specifically in the context of Golgi-related genes, and suggests that Musashi1 is a novel target for radiosensitization. Citation Format: Stacey L. Lehman, John W. O'Neill, Kevin Camphausen, Philip J. Tofilon. UTR analysis identifies Musashi1 as a translational regulator of radiation-induced Golgi-related gene expression [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 841. doi:10.1158/1538-7445.AM2017-841
RESPONSE: Re: Association Between Nonrandom X-Chromosome Inactivation and BRCA1 Mutation in Germline DNA of Patients With Ovarian Cancer
Authors: RE Buller, AK Sood, T Lallas, T Buekers, JS Skilling
Journal: JNCI Journal of the National Cancer Institute (1999)

Buller et al.(1) suggest a novel mechanism for genetic susceptibility to ovarian cancer.In our view, the data presented are puzzling and do not support a new model for susceptibility to ovarian cancer.There are two models under which germline mutation of an Xchromosome tumor suppressor may contribute to cancer predisposition through nonrandom X-chromosome inactivation (NXCI).In one model, approximately 30% of females (authors' data) undergo NXCI for reasons unrelated to a cancer predisposing allele, and some fraction of these carry a mutant tumor suppressor allele that manifests when the normal allele undergoes NXCI.In the second model, cells with the mutant allele present on the active X chromosome have a proliferative advantage over cells with a normal active allele during tissue morphogenesis, resulting in apparent increased rates of NXCI.This model implies that the mutant cancer susceptibility allele occurs fre-
PADDED HEADGEAR IN CONTACT FOOTBALL – INERTIA OR MOMENTUM?
Authors: Andrew McIntosh, Declan Patton
Journal: British Journal of Sports Medicine (2017)

Background Regarding padded headgear worn in contact football (excluding American football), little has changed in terms of game laws, technical specifications or market supplied models over the last 15 years. Objective Assess the impact performance and potential for padded headgear to protect the head. Design Biomechanical. Impact energy attenuation drop tests with ISO “M” headform onto a rigid flat anvil and linear impactor tests on a Hybrid III head and neck. Setting Australian rules football, rugby union and rugby league. Patients None. Interventions Laboratory testing of eight padded headgear models – six commercial and two prototypes. Main Outcome Measurements The primary study outcome measures include peak headform linear (PLA) and peak angular (PAA) accelerations and the Head Injury Criterion (HIC). Results In centre-front 0.2 m drop tests, PLA values ranged from 367 to 592 g and HIC ranged from 780 to 2064 in commercial models. In contrast a prototype “Hexlid” model produced PLA of 53 g in the same tests and 172 in 0.3 m drop tests. In 4 m/s lateral linear impacts the bare headform PLA was 107 g and PAA 7.1 krad/s 2 . Commercial headgear PLA's ranged from 91 to 100 g and PAA 6.0 to 6.8 krad/s 2 for the same tests. In contrast the “Hexlid” model produced PLA of 65 g and PAA of 4.8 krad/s 2 . PLA in 0.2 m drop tests on commercially available headgear ranged from 251 to 538 g compared to 64 to 483 g in eight models tested under equivalent conditions and available in the late 1990s. Conclusions There is no indication that the commercially available headgear would be effective in reducing concussion risk. The performance of commercially available headgear has not improved since the 1990s. Prototype headgear show how impact performance can be improved. The test methods provide the basis for technical specifications.
Abstract 1901: DNMT1 is involved in esophageal squamous cell carcinoma (ESCC) and self-renewal ability of ESCC-cancer stem cells
Authors: Ying Teng, Xiying Yu, Hui Yuan, Liping Guo, Wei Jiang, Shih-Hsin Lu
Journal: Cancer Research (2017)

Abstract DNA methylation mediated by DNA methyltransferase 1 (DNMT1) plays an important role in carcinogenesis and self-renewal ability of cancer stem cells (CSCs). However, the function of DNMT1 in esophageal squamous cell carcinoma (ESCC) carcinogenesis, especially self-renewal ability of ESCC-CSCs remains unclear. In this study, we found a high expression of DNMT1 in both side population (SP) cells and sphere formation cells that represented as substitutes for CSCs in KYSE150 and EC109 ESCC cell lines. In addition, the expression of DNMT1 was decreased during the differentiation from SP to None-SP (NSP) in these ESCC cells. These results suggested that DNMT1 might have a role in regulating self-renewal and/or differentiation of ESCC-CSCs. To further investigate DNMT1 in ESCC carcinogenesis and self-renewal ability of ESCC-CSCs, we silenced the expression of DNMT1 in KYSE150 and EC109 ESCC cells using lentivirus-mediated RNA interference (RNAi). Our results showed that ablation of DNMT1 expression in KYSE150 and EC109 ESCC cells resulted in decreased their CSCs by SP analysis and sphere formation assay. Meanwhile, ablation of DNMT1 expression inhibited malignant phenotypes in KYSE150 and EC109 cells, including cell proliferation, colony formation, migration and drug resistance abilities. Treatment of 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor that led to the degradation of DNMT1 protein by proteasome, revealed that numbers of CSCs and the malignant phenotypes of KYSE150 and EC109 ESCC cells were refrained significantly, including a dramatic inhibition of self-renewal ability of these ESCC-CSCs. Thus, our results indicated that DNMT1 was involved in ESCC carcinogenesis, especially in the maintenance of ESCC-CSCs, suggesting that DNMT1 could be a potential target for ESCC, especially ESCC-CSCs, therapy. Citation Format: Ying Teng, Xiying Yu, Hui Yuan, Liping Guo, Wei Jiang, Shih-Hsin Lu. DNMT1 is involved in esophageal squamous cell carcinoma (ESCC) and self-renewal ability of ESCC-cancer stem 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 1901. doi:10.1158/1538-7445.AM2017-1901
Abstract 3044: Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition
Authors: Joséphine Zangari, Marius Ilie, Florian Rouaud, Laurie Signetti, Mickaël Ohanna, Robin Didier, Barnabé Roméo, Dana Goldoni, Nicolas Nottet, Cathy Staedel, Jocelyn Gal, Bernard Mari, Baharia Mograbi, Paul Hofman, Patrick Brest
Journal: Cancer Research (2017)

Abstract Background: Extracellular vesicles (EVs) have been shown to play an important role in intercellular communication as carriers of DNA, RNA and proteins. While the intercellular transfer of miRNA thorough EVs has been widely studied, the stability of extracellular miRNA (ex-miRNA) once engulfed by recipient cell remains to be determined. Materials and Methods: Lung cancer cells (A549 cell line) were incubated with neutrophils or their supernatant or isolated EVs from these supernatant. Kinetics of expression of miR-223-3p were followed by RT-qPCR. FOXO1 expression and EMT expression markers were used as endpoints to follow effective effect or miR-223-3p in recipient cells. Results: We identified the ex-miRNA-directed phenotype to be transient due to the rapid decay of the ex-miRNA. We demonstrated that the ex-miR-223-3p transferred from neutrophils to cancer cells was functional as demonstrated by the decreased expression of its target, FOXO1, and the occurrence of epithelial-mesenchymal transition reprogramming. We showed that the engulfed ex-miRNA, unlike endogenous miRNA, was unstable, enabling dynamic regulation and a return to a non-invasive phenotype within less than 8 hours. This transient phenotype could be modulated by targeting XRN1/PACMAN exonuclease. Indeed, its silencing was associated with slower decay of ex-miR-223-3p and subsequently prolonged the invasive properties. Conclusion: We showed that the “steady step” level of engulfed miRNA (ex-miR-223-3p) and its subsequent activity was dependent on the presence of a donor cell in the surroundings to constantly fuel the recipient cell with ex-miRNAs and of XRN1 exonuclease, which is involved in the decay of these imported miRNAs. Citation Format: Joséphine Zangari, Marius Ilie, Florian Rouaud, Laurie Signetti, Mickaël Ohanna, Robin Didier, Barnabé Roméo, Dana Goldoni, Nicolas Nottet, Cathy Staedel, Jocelyn Gal, Bernard Mari, Baharia Mograbi, Paul Hofman, Patrick Brest. Rapid decay of engulfed extracellular miRNA by XRN1 exonuclease promotes transient epithelial-mesenchymal transition [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 3044. doi:10.1158/1538-7445.AM2017-3044
Role of radiotherapy fractionation in head and neck cancers (MARCH): an updated meta-analysis
Authors: Benjamin Lacas, Jean Bourhis, Jens Overgaard, Qiang Zhang, Vincent Grégoire, Matthew Nankivell, Björn Zackrisson, Zbigniew Szutkowski, Rafał Suwiński, Michael Poulsen, Brian O'Sullivan, Renzo Corvò, Sarbani Ghosh Laskar, Carlo Fallai, Hideya Yamazaki, Werner Dobrowsky, Kwan Ho Cho, Beth Beadle, Johannes A Langendijk, Celia Maria Pais Viegas, John Hay, Mohamed Lotayef, Mahesh K B Parmar, Anne Aupérin, Carla van Herpen, Philippe Maingon, Andy M Trotti, Cai Grau, Jean-Pierre Pignon, Pierre Blanchard, Pierre Blanchard, Jean Bourhis, Benjamin Lacas, Jean Pierre Pignon, Jacques Bernier, Quynh-Thu Le, Jens Overgaard, Masheh KB Parmar, Andy Trotti, Jai Prakash Agarwal, Anne Aupérin, Kian K Ang, Hassan K Awwad, Almalina Bacigalupo, Harry Bartelink, Ellen Benhamou, Jacques Bernier, Pierre Blanchard, Jean Bourhis, Wilfried Budach, Imjai Chitapanarux, Kwan Ho Cho, Laurence Collette, Renzo Corvò, Carla Dani, Stanley Dische, Werner Dobrowsky, James W Denham, Chantal ML Driessen, Carlo Fallai, Beth Beadle, Sarbani Ghosh Laskar, Sushmita Ghoshal, Cai Grau, Vincent Gregoire, John H Hay, Carla van Herpen, Andrzej Hliniak, Jørgen Johansen, Claus Andrup Kristiansen, Valentina Krstevska, Benjamin Lacas, Johannes A. Langendijk, Michel Lapeyre, Quynh-Thu Le, Mohamed Lotayef, Boguslaw Maciejewski, Philippe Maingon, Wojciech Michalski, Sung Ho Moon, Per Nilsson, Patrizia Olmi, Matthew Nankivell, Kinji Nishiyama, Brian O'Sullivan, Jens Overgaard, Mahesh KB Parmar, Jean-Pierre Pignon, Michael G Poulsen, Kunnambath Ramadas, Anupam Rishi, David I. Rosenthal, Giuseppe Sanguineti, Michele I Saunders, Christian Sire, Krzysztof Skladowski, Luis Souhami, Rafal Suwinski, Zbigniew Szutkowski, Nitin Tandon, Harm van Tinteren, Valter Torri, Lee Tripcony, Andy Trotti, Celia Maria Pais Viegas, John Waldron, Joachim Widder, Stuart Wong, Jonn S Wu, Hideya Yamazaki, Björn Zackrisson, Qiang Zhang
Journal: The Lancet Oncology (2017)
Abstract 4163: Blockade of the interleukin-1 signaling pathway overcomes erlotinib resistance in head and neck cancer cells
Authors: Andrean L. Simons, Aditya Stanam, Katherine N. Gibson-Corley
Journal: Cancer Research (2017)

Abstract The EGFR tyrosine kinase inhibitor erlotinib has demonstrated poor clinical response rates for head and neck squamous cell carcinoma (HNSCC) to date and the majority of respondents acquire resistance to erlotinib relatively quickly. Our previous data has shown that erlotinib activated interleukin-1 (IL-1) expression and signaling in HNSCC cells in vitro. We therefore investigated if upregulation of IL-1 signaling is involved in erlotinib resistance in HNSCC cells. We compared gene expression profiles of erlotinib-resistant (ER) and the parental erlotinib-sensitive (ES) HNSCC cell lines and observed a deregulation of the IL-1 signaling pathway in ER versus ES-HNSCC cells using microarray enrichment analysis. Secretion of IL-1 alpha (IL-1α) and IL-1 beta (IL-1β) were not significantly different in ER-SQ20B and ER-CAL 27 cells compared to their respective ES-cells, however secretion of the IL-1 receptor antagonist (IL-1RA) was significantly reduced in ER-cells compared to ES-cells. Blockade of IL-1 signaling using a recombinant IL-1R antagonist (anakinra) was able to significantly suppress the growth of ER-SQ20B but not ES-SQ20B xenografts as a single agent and in combination with erlotinib. ER-SQ20B xenografts treated with anakinra with or without erlotinib were found to be less vascularized (as determined by CD31 staining) than ER-SQ20B xenografts treated with water or erlotinib. Altogether, blockade of the IL-1 pathway using anakinra overcame erlotinib resistance in HNSCC xenografts and may represent a novel strategy to overcome EGFR inhibitor resistance for the treatment of HNSCC patients. Citation Format: Andrean L. Simons, Aditya Stanam, Katherine N. Gibson-Corley. Blockade of the interleukin-1 signaling pathway overcomes erlotinib resistance in head and neck 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 4163. doi:10.1158/1538-7445.AM2017-4163
Abstract 392: Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer
Authors: Frederick S. Varn, Yue Wang, Chao Cheng
Journal: Cancer Research (2017)

Abstract Somatic mutations have been heavily implicated in initiating and driving cancer growth and metastasis. These alterations serve as upstream events that have broad transcriptional effects by altering protein structure and function and interfering with signaling pathways. Here, we apply an iterative approach that utilizes patient gene expression profiles to define mutation-associated transcriptomic signatures. We use these signatures to quantify the level at which a given somatic mutation affects its gene’s downstream activities. Using TP53 in breast cancer as an example, we show that while TP53 mutations are the primary predictor of altered p53 activity, events such as copy number alterations and methylation changes may represent alternative routes to high p53 disruption. Conversely, we identify a class of TP53 mutations that have minimal downstream transcriptomic effects. By expanding this approach to other genes and tumor types, we show that mutation signatures derived from different tissue types exhibit varying levels of conservation, suggesting a degree of tissue-specificity in the downstream effects of somatic mutations. To provide functional context to our results, we examine the associations between different mutation signatures and various cancer-related features, including patient survival, immune infiltration, and pathway activity. Together, our results indicate the utility of using patient gene expression profiles to study mutation function. Going forward, these results may be useful in functionally annotating variants of unknown significance and broadening the potential of precision medicine-based therapeutic approaches. Citation Format: Frederick S. Varn, Yue Wang, Chao Cheng. Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer [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 392. doi:10.1158/1538-7445.AM2017-392
WHY DO PATIENTS AND CAREGIVERS SEARCH THE INTERNET FOR INFORMATION AND ASK QUESTIONS TO ONLINE LUNG SPECIALISTS? A QUALITATIVE STUDY
Authors: Romane M. Schook, Cilia Linssen, Marjan J. Westerman, Franz M. N. H. Schramel, Jan Festen, Ernst Lammers, Pieter E. Postmus
Journal: Journal of Thoracic Oncology (2011)
Abstract 2728: Frequency and prognostic value of PI3KCA mutations in early stage of colorectal cancer in Mexican patients
Authors: Erika Ruiz-Garcia, Alette Ortega, Antonio Bahena, Edith Fernandez, German Calderillo, Cesar Lopez Camarillo, Laurence Marchat, Jorge Guadarrama, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega
Journal: Cancer Research (2017)

Abstract Background: There are molecular associations between mutated profiles and microsatelital instability, both related with tumor growth and oncogenic development by activating tyrosine receptors families in colorectal cancer (CRC). It is known that exon 9 and exon 20 (H1047R) mutations in PIK3CA increased PI3K activity. Moreover, PIK3CA mutations are significantly associated with tumor recurrence and poor overall survival. The frequency of PIK3CA mutations in CCR occurs in 15-20%, being the catalytic subunit more frequently affected. The aim of our study was to investigate the frequencies and clinical implications of these genetic alterations in advanced CRC. Methods: Retrospectively, we analyzed the initial paraffin embedded tissue block of 71 Mexican patients with CCR stage II. We evaluated mutations frequency of PIK3CA exon 9 (E542K, E545K) and exon 20 (H1047R) using qBiomarker Somatic Mutation PCR for real-time PCR-based. These methodology increases specificity, multiplex PCR and allelic discrimination. The data analysis was done using Ct values and Analysis Webportal. Results: We found in our population a frequency of PIK3CA mutations of 26%. Of those, double mutants were present in 7% with a higher frequency for E545K/H1047R. Clinical implication that we found is that any active mutation of PIK3CA is associated to an increase of recurrence risk (HR 1.86;CI 95% =0.46-7.5), but most important is for E545K mutation (HR 4.17; CI 95% 0.85-20.39), meanwhile comparing no mutated with H1074R mutated samples there were no differences in HR (0.53 vs. 0.60, respectively). Conclusions: We found a higher number of PI3KCA mutations that literature reports and that E545K mutation have a worst prognostic implication but we need to increase our sample looking for statistical significance results. Data from H1047R mutation raise de hypothesis that it could exist a compensatory mechanism related to structural interactions between both helicoidal and catalitic domains. Citation Format: Erika Ruiz-Garcia, Alette Ortega, Antonio Bahena, Edith Fernandez, German Calderillo, Cesar Lopez Camarillo, Laurence Marchat, Jorge Guadarrama, Abelardo Meneses-Garcia, Horacio Astudillo-de la Vega. Frequency and prognostic value of PI3KCA mutations in early stage of colorectal cancer in Mexican patients [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 2728. doi:10.1158/1538-7445.AM2017-2728