tbuckley/cabot-search huggingface dataset:
Benefits and Risks of Antithrombotic Therapy in Essential Thrombocythemia
Authors: Derek K. Chu, Christopher M. Hillis, Darryl P. Leong, Sonia S. Anand, Deborah M. Siegal
Journal: Annals of Internal Medicine (2017)

Patients with essential thrombocythemia (ET) are at high risk for both thrombosis and hemorrhage.To evaluate the risks and benefits of antithrombotic therapy in adults with ET.Multiple databases, including MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, through 4 March 2017.Randomized and observational studies of antiplatelet or anticoagulant therapy, published in any language and reporting thrombotic or hemorrhagic events.Two reviewers independently extracted data, assessed risk of bias, and graded certainty of evidence.No relevant randomized trials were identified. Twenty-four observational studies (18 comparative and 6 single-group) involving 6153 patients followed for 31 711 patient-years were reviewed; most were deemed to have high risk of bias. Most patients receiving antiplatelet therapy (3613 of 4527 [80%]) received low-dose aspirin (50 to 150 mg/d); 914 (20%) received high-dose aspirin (300 to 600 mg/d), dipyridamole, or other agents. Overall, findings were inconsistent and imprecise. The reported incidence rates of thrombosis, any bleeding, and major bleeding without antiplatelet therapy ranged from 5 to 110 (median, 20), from 3 to 39 (median, 8), and from 2 to 53 (median, 6) cases per 1000 patient-years, respectively. The reported relative risks for thrombosis, any bleeding, and major bleeding with antiplatelet therapy compared with none ranged from 0.26 to 3.48 (median, 0.74), from 0.48 to 11.04 (median, 1.95), and from 0.48 to 5.17 (median, 1.30), respectively. Certainty of evidence was rated low or very low for all outcomes.No randomized trials, no extractable data on anticoagulants, lack of uniform bleeding definitions, and systematic reporting of outcomes.Available evidence about the risk-benefit ratio of antiplatelet therapy in adults with ET is highly uncertain.Regional Medical Associates. (PROSPERO: CRD42015027051).
Abstract 4320: The Survivin-targeting miR-542-3p overcomes erbB3 signaling-mediated chemo-resistance and enhances the antitumor activity of paclitaxel against erbB2-positive breast cancer
Authors: Hui Lyu, Shuiliang Wang, Jingcao Huang, Bolun Wang, Bolin Liu
Journal: Cancer Research (2017)

Abstract Elevated expression of erbB3 interacts with erbB2 in breast cancer cells to confer chemo-resistance via induction of Survivin. However, the underlying mechanism of erbB3 signaling-induced upregulation of Survivin remains elusive. Ectopic expression or downregulation of erbB3 in erbB2-positive breast cancer cells did not alter Survivin mRNA levels and had no significant effect on Survivin protein stability. We thus hypothesize that the erbB3 signaling modulates certain miRNAs that target Survivin to influence its protein translation. Here we showed that overexpression of erbB3 decreased and specific knockdown of erbB3 enhanced expression of two Survivin-targeting miRNAs, miR-203 and miR-542-3p in breast cancer cells. While the specific inhibitor of either miR-203 or miR-542-3p clearly attenuated an anti-erbB3 antibody (Ab)-mediated reduction of Survivin, a more profound effect on Survivin expression was observed with inhibition of miR-542-3p than miR-203 inhibition. Consistently, miR-542-3p mimic was much more effective than miR-203 mimic not only to downregulate Survivin, but also to enhance paclitaxel-induced apoptosis in the otherwise paclitaxel-resistant breast cancer cells. Moreover, using a murine tumor xenografts model established from a human breast cancer cell line expressing both erbB2 and erbB3, we discovered that the combinations of miR-542-3p mimic and paclitaxel, as compared to either agent alone, significantly inhibited tumor growth in vivo. Collectively, these data demonstrate that the erbB3 signaling upregulates Survivin via inhibition of miR-203 and miR-542-3p in erbB2-positive breast cancer cells. Since miR-542-3p has three binding sites on the 3’UTR of erbB3 mRNA, the miR-542-3p mimic serves as an excellent replacement therapeutic agent to downregulate Survivin, and thereby significantly enhances the antitumor activity of paclitaxel against erbB2-positive breast cancer. Citation Format: Hui Lyu, Shuiliang Wang, Jingcao Huang, Bolun Wang, Bolin Liu. The Survivin-targeting miR-542-3p overcomes erbB3 signaling-mediated chemo-resistance and enhances the antitumor activity of paclitaxel against erbB2-positive 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 4320. doi:10.1158/1538-7445.AM2017-4320
Abstract 1576: UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling
Authors: Haolong Li, Ning Xie, Ruiqi Chen, Mélanie Verreault, Ladan Fazli, Martin E. Gleave, Olivier Barbier, Xuesen Dong
Journal: Cancer Research (2017)

Abstract Background: Castration resistant prostate cancer (CRPC) is characterized by a shift of androgen receptor (AR) signaling from ligand-dependent to ligand-independent. Defining mechanisms that control AR signaling transformation is important to develop therapies for disease control. UDP-glucuronosyltransferase 2B17 (UGT2B17) is a key enzyme that maintains androgen homeostasis by catabolizing AR agonists into inactive forms. Although enhanced UGT2B17 expression by antiandrogens was reported in androgen-independent prostate cancers, its role in regulating AR signaling transformation and CRPC progression remain unknown. Method and Results: We first evaluated the UGT2B17 protein expression levels by immunohistochemistry (IHC) on Vancouver Prostate Centre tissue microarrays. We show that higher UGT2B17 protein expression in prostate tumors is associated with higher Gleason score, metastasis and CRPC progression. The expression and activity of UGT2B17 are also higher in androgen-independent compared to androgen-dependent cell lines. Interestingly, enzalutamide-resistant MR49F cells expresses low UGT2B17 mRNA but strong protein expression, suggesting that posttranslational mechanisms may enhance UGT2B17 protein stability in these cells. We then constructed PCa cell lines with gain-of-function UGT2B17 by lentivirus. Functional analyses indicate that UGT2B17 stimulates cancer cell proliferation, invasion, and xenograft progression to CRPC after prolonged androgen deprivation. To further decipher the molecular mechanisms by which UGT2B17 enhance PCa cell growth independent of androgen, we performed gene microarray using LNCaP(mock) and LNCaP(UGT2B17) cells cultured under the regular serum condition or the prolonged androgen deprivation condition. Microarray analyses reveal that UGT2B17 suppresses androgen-dependent AR transcriptional activity, while enhancing androgen (ligand)-independent AR transcriptional activity. The latter targets genes associated with cell mitosis. These UGT2B17 actions in reprogramming androgen signaling are mainly mediated by activating the c-Src kinase. We confirmed that, in CRPC tumors, UGT2B17 expression is positively associated with c-Src activation. Conclusion: These results indicate that UGT2B17 expedites CRPC progression by enhancing ligand-independent AR signaling that activates predominantly cell mitosis in cancer cells. Citation Format: Haolong Li, Ning Xie, Ruiqi Chen, Mélanie Verreault, Ladan Fazli, Martin E. Gleave, Olivier Barbier, Xuesen Dong. UGT2B17 promotes castration-resistant prostate cancer progression through enhancing ligand-independent AR signaling [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 1576. doi:10.1158/1538-7445.AM2017-1576
Abstract 4287:HABP2p.G534E variant in patients with family history of thyroid and breast cancer
Authors: Maisa Pinheiro, Sandra A. Drigo, Fabio A. Marchi, Renata Tonhosolo, Sonia C. Andrade, Igor Jurisica, Luiz P. Kowalski, Maria Isabel W. Achatz, Silvia R. Rogatto
Journal: Cancer Research (2017)

Abstract Background. Familial Papillary Thyroid Carcinoma (PTC) has been recently associated with the HABP2 p.G534E mutation. In this study we evaluated the putative association of the HABP2 p.G534E mutation and familial history of PTC and Breast Carcinoma (BC) in the Brazilian population. Methods. Germline mutations of twenty unrelated individuals with personal and/or family history of PTC and/or BC were identified by whole exome sequencing (WES), using Nextera Exome Enrichment kit and HiSeq200 platform (Illumina). Two cases were positive for p.G534E. Family members from both positive cases (seven from Family 1 and three from Family 2) were recruited for segregation analysis. An additional patient and three relatives (Family 3) with history of PTC and BC were included for validation. Fifty frozen PTC tumor samples and 170 healthy Brazilian individuals were also screened for the HABP2 variant. Confirmation and validation were performed by Sanger sequencing. Results. Interestingly, Family 1 reported a consanguineous history, reflected in two homozygous cases: the proband (PTC) and his unaffected sister. Also, only one (BC) out of eight tested members was negative for p.G534E. In the Family 2, the only patient diagnosed with PTC was negative for the mutation, while three relatives were positive for the same loci. The index case (PTC) from Family 3, was wild type for HABP2 and three relatives tested were positive carriers. In PTC tumor samples the Allele Frequency (AF) was 0.04: two heterozygous and one homozygous for p.G534E. Among 170 healthy individuals, five were heterozygous for the variant, representing an AF of 0.0147. The two index patients evaluated by WES also presented interesting pathogenic variants in genes potentially associated with deregulation of the extracellular matrix organization pathway (CTSB, TNXB, COL4A3, COL16A1, COL24A1, COL5A2, NID1, LOXL2, MMP11, TRIM24 and MUSK) and DNA repair function (NBN and MSH2). Conclusion. Our findings suggest that HABP2 is not a predisposition gene involved in familial PTC and BC. Financial Support: FAPESP (2013/01867-8 and 2014/03983-8) and CNPq (481132/2012-0) Note: This abstract was not presented at the meeting. Citation Format: Maisa Pinheiro, Sandra A. Drigo, Fabio A. Marchi, Renata Tonhosolo, Sonia C. Andrade, Igor Jurisica, Luiz P. Kowalski, Maria Isabel W. Achatz, Silvia R. Rogatto. HABP2 p.G534E variant in patients with family history of thyroid and 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 4287. doi:10.1158/1538-7445.AM2017-4287
Abstract 5827: Role of Ewing sarcoma EWS/FLI1 protein in midzone formation during mitosis
Authors: Mizuki Azuma
Journal: Cancer Research (2017)

Abstract Ewing sarcoma remains the second most common form of bone and cartilage cancer in children. Although EWS/FLI1 fusion protein (derived by chromosomal translocation) is known to induce aberrant transcription in the patient cells, why and how this molecule leads to tumorigenesis specifically in skeletal cell lineage is not understood. We previously reported a novel role of EWS/FLI1, which interacts with EWS and leads to mitotic defects through an inhibition of EWS function. We further demonstrated that EWS interacts with Aurora B and relocates from inner centromere to the midzone (a midline structure that is consisted spindles called the central spindle) during anaphase of mitosis. Disruption of EWS-directed Aurora B-relocation leads to defects in cytokinesis, and to induction of chromosome instability (CIN). EWS is an abundant molecule that is localized throughout the entire cytoplasm of anaphase, but how EWS specifically regulates midzone formation is not understood. A potential candidate mechanism is post-translational modification of EWS to modulate its activity in a spatial-temporal manner. Because previous studies showed that EWS/FLI1-T79 is a potential modification site of O-GlcNAcylation and phosphorylation, we hypothesized that the O-GlcNAcylation of EWS/FLI1 contributes to the impairment of Aurora B-relocation. Our study shows that high cellular O-GlcNAc increases the level of O-GlcNAcylation of EWS/FLI1 accompanied by the impairment of the Aurora B relocation and of central spindle formation. Contrary, EWS/FLI1-T79A and EWS/FLI1-T79D (phospho-mimic mutant) does not impair the mislocation of Aurora B at the midzone, suggesting that the O-GlcNAcylation of EWS/FLI1 is responsible for mislocation of Aurora B at the midzone. The O-GlcNAc-dependent impairment of midzone formation by EWS/FLI1 may lead to the identification of therapeutic targets for Ewing sarcoma patients. Citation Format: Mizuki Azuma. Role of Ewing sarcoma EWS/FLI1 protein in midzone formation during mitosis [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 5827. doi:10.1158/1538-7445.AM2017-5827
Abstract 3033: The PRL family of tyrosine phosphatases as a novel drug targets in acute lymphoblastic leukemia
Authors: Jessica S. Blackburn
Journal: Cancer Research (2017)

Abstract The aggressive and unpredictable behavior of acute lymphoblastic leukemia (ALL) presents a major clinical challenge in both the pediatric and adult setting. The development of new and better chemotherapies for this disease requires a detailed understanding of the genes and pathways that drive ALL malignancy. Phosphatases are emerging as new drug targets with important roles in leukemia progression. To determine the extent to which phosphatases play a role in ALL malignancy, we used CRISPR/Cas9 to knock out expression of 255 individual phosphatases in human T-cell acute lymphoblastic leukemia cell lines and screened for deleterious effects on cell viability. Top hits from this screen included the protein tyrosine phosphatase type IVa family, also known as the PRLs. PRL3 is genomically amplified in a subset of human T-ALL, and more than 50% of human ALL patients have significantly higher expression of PRL2 and/or PRL3, compared to normal lymphocytes, suggesting that these PRLs may play an important role in ALL malignancy. Transgenic Myc-induced ALL models in zebrafish showed that overexpression of PRL2 and PRL3 significantly shortened latency of primary and relapse ALL, enhanced leukemia stem cell self-renewal (PRL2) and prevented apoptosis after standard chemotherapy treatment (PRL3). Finally, a specific PRL inhibitor strongly induced apoptosis of PRL-expressing ALL cells in a dose-dependent manner, in both zebrafish models in vivo and human cell lines in vitro. We have identified several FDA-approved, general phosphatase inhibitors that have potent anti-PRL activity and are capable of killing ALL cells in vitro. Current work is focused on moving these inhibitors into pre-clinical testing using patient-derived xenografts. Pull-down approaches are also being used to identify the substrates of PRL phosphatase activity that are critical to ALL survival and may represent new, tractable drug targets for the treatment of ALL. &amp;lt;!–EndFragment–&amp;gt; Citation Format: Jessica S. Blackburn. The PRL family of tyrosine phosphatases as a novel drug targets in acute lymphoblastic leukemia [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 3033. doi:10.1158/1538-7445.AM2017-3033
Abstract 3111: Validated antibody Database: A curated database of antibodies cited in formal publications
Authors: Hanqing Xie
Journal: Cancer Research (2017)

Abstract Currently research antibodies have a serious quality problem, which is one of the major contributing factors to the irreproducibility of published reports. Labome organizes antibody applications cited in formal publications and has developed Validated Antibody Database (VAD). VAD, a manually curated database, compiles commercial and non-commercial antibodies whose specificities and applications have been independently reported in published results from formal articles. Labome prioritizes the curation of articles with knockout studies and monoclonal antibodies. One of the benefits of our curation effort is the identification of cross-reactive species and novel applications for antibodies, which are often developed for human/mouse proteins and tested by suppliers for a limited number of applications. Labome registers many antibodies having cross-reactivities with model organisms such as flies, worms, zebrafish, and frogs and with novel applications from the literature. The current version released in September 2016 is based on over 50000 formal publications and is freely accessible for online browsing. Citation Format: Hanqing Xie. Validated antibody Database: A curated database of antibodies cited in formal publications [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 3111. doi:10.1158/1538-7445.AM2017-3111
Abstract 5691: <i>ESR1</i> methylation in plasma cfDNA of patients with high-grade serous ovarian cancer
Authors: Lydia Giannopoulou, Sophia Mastoraki, Areti Strati, Isaam Chebouti, Sabine Kasimir-Bauer, Evi S. Lianidou
Journal: Cancer Research (2017)

Abstract Introduction: ESR1 methylation is frequently observed in many types of solid malignancies, but few studies attempted to investigate ESR1 methylation status in ovarian cancer so far. We examined for the first time ESR1 methylation in plasma samples of high-grade serous (HGSC) ovarian cancer patients, using a novel real-time MSP assay. Materials and methods: We first developed and validated a highly specific and sensitive real-time MSP assay for ESR1 methylation. A commercially available 100% methylated standard was used as positive control in all experiments. We then evaluated ESR1 methylation in plasma (2mL) of 59 pre-surgery, mainly advanced stage HGSC patients. A control group of 51 plasma samples from healthy women was recruited for the evaluation of specificity of our assay. All cfDNA samples isolated from plasma were subjected to sodium bisulfite (SB) treatment and were then analyzed by real-time MSP for ESR1 methylation. For the normalization of the results, we used ACTB as a reference gene. The real-time PCR assay for ACTB was designed to amplify specifically SB treated DNA. Results: The real-time MSP assay is highly sensitive, as it detects down to 0.1% of ESR1 methylation in the presence of 99.9% non-methylated sequences. ESR1 methylation was detected in 18/59 (30.5%) high-grade serous ovarian patients, but only in 1/51 (2.0%) of healthy women. All results were obtained after normalization with ACTB as a reference gene. Conclusion: We report for the first time that ESR1 methylation can be detected in cfDNA of high-grade serous ovarian cancer patients, but not in healthy women. Further investigation is required to determine the clinical significance of ESR1 methylation status in cfDNA of HGSC patients. We also aim to evaluate our findings in a larger group of patients. Citation Format: Lydia Giannopoulou, Sophia Mastoraki, Areti Strati, Isaam Chebouti, Sabine Kasimir-Bauer, Evi S. Lianidou. ESR1 methylation in plasma cfDNA of patients with high-grade serous ovarian 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 5691. doi:10.1158/1538-7445.AM2017-5691
Abstract 3497: Network-based systematic inference of lncRNA activity in breast cancer
Authors: Matthew Ung, Daniel Mattox, George Wang, Chao Cheng
Journal: Cancer Research (2017)

Abstract The production of lncRNA is widespread across the human genome, yet the functions of lncRNAs and the phenotypes resulting from their activation have remained largely unstudied. In cancer, several lncRNAs have been found to associate with disease development and poor patient prognosis including HOTAIR and MALAT1. Recent studies have been performed using lncRNA microarrays or re-annotated probes from coding gene microarrays to systematically investigate their roles in cancer. However, datasets from lncRNA microarrays are typically not accompanied by comprehensive clinical information that can be used to draw associations between lncRNA expression and clinical phenotypes. Furthermore, lncRNA stability and cellular localization is highly variable suggesting that expression-based inference of lncRNA activity may not always be an accurate measure of its activity. To address this issue, we introduce an activity-based approach whereby we analyze the expression of lncRNA target genes to infer lncRNA activity. Specifically, we construct a breast cancer specific lncRNA-target gene network from RNA-seq data using a network reconstruction algorithm. We then apply this network to several breast cancer microarray datasets to systematically investigate lncRNA activity and their association with clinical phenotypes. Notably, we find that certain lncRNAs are active in specific molecular subtypes of breast cancer even though their expression levels do not reveal significant differences. Lastly, we performed survival analysis to systematically screen for novel lncRNAs whose activity associate with patient prognosis. Our results suggest that activity-based inference of lncRNAs can identify novel lncRNAs that may serve as therapeutic targets or biomarkers in breast cancer. Citation Format: Matthew Ung, Daniel Mattox, George Wang, Chao Cheng. Network-based systematic inference of lncRNA activity in 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 3497. doi:10.1158/1538-7445.AM2017-3497