tbuckley/cabot-search huggingface dataset:
Abstract 2547: Discovery and characterization of late-stage breast cancer estrogen receptor alpha 1 bound long non-coding RNAs
Authors: Jessica Monique Silva-Fisher, Abdallah M. Eteleeb, Torsten Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher
Journal: Cancer Research (2017)

Abstract Breast cancer (BC) is the second most common newly diagnosed cancer and the second leading cause of cancer death among women in the United States. Despite the proven benefits of adjuvant endocrine therapy in women with hormone receptor positive BC, relapses still occur even after initial treatment with endocrine therapy for 5 years, referred to as late-stage relapse. Long non-coding RNAs (lncRNAs) have been shown to be dysregulated in breast cancer. Recent studies have also shown lncRNAs to function by interfacing with corresponding RNA binding proteins to play critical regulatory roles of diverse cellular processes. Therefore, we hypothesize that lncRNAs may interact with ER to regulate genes promoting late-stage relapse. To address this, we aimed to identify lncRNAs bound to the estrogen receptor alpha 1 protein (ESR1) that promote late-stage relapse breast cancer. We first used transcriptome sequencing to identify altered expression levels of lncRNAs between 72 primary tumors and 24 late-stage relapse breast cancer patients. We detected 1192 altered lncRNAs when comparing the metastatic to the primary samples (FDR &amp;lt;0.05). Next, to identify ESR1 bound lncRNAs associated with late-stage BC, we conducted RNA Immunoprecipitation Sequencing of all transcripts bound to ESR1 as compared to an IgG control in the ER+ T47D cell line. We identified 217 lncRNAs bound to ESR1 of which 50 were up-regulated in late-stage BC, termed Late-Stage Relapse BC ESR1-bound lncRNAs (LASERs). Next, we focused on characterizing the most up-regulated differentially expressed lncRNA, LASER1. We found that LASER1 has increased expression in ER+ breast cancer cell lines. Further, elevated expression of LASER1 was also detected in MCF7 long-term estrogen deprived cells lines that have amplified ER+, suggesting an ER dependent mechanism. Preliminary functional studies indicate LASER1 to promote proliferation and invasion in BC cell lines. Ongoing studies will decipher how LASERs interact with ESR1 to promote late-stage relapse. Overall, this is the first study to discover ESR1 bound lncRNAs that may be contributing to late-stage relapse in BC patients. Citation Format: Jessica Monique Silva-Fisher, Abdallah M. Eteleeb, Torsten Nielsen, Charles M. Perou, Jorge S. Reis-Filho, Mathew J. Ellis, Elaine R. Mardis, Christopher A. Maher. Discovery and characterization of late-stage breast cancer estrogen receptor alpha 1 bound long non-coding RNAs [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 2547. doi:10.1158/1538-7445.AM2017-2547
TGFβ1 Promotes Gemcitabine Resistance through Regulating the LncRNA-LET/NF90/miR-145 Signaling Axis in Bladder Cancer
Authors: Junlong Zhuang, Lan Shen, Lin Yang, Xiaojing Huang, Qun Lu, Yangyan Cui, Xi Zheng, Xiaozhi Zhao, Dianzheng Zhang, Ruimin Huang, Hongqian Guo, Jun Yan
Journal: Theranostics (2017)

High tumor recurrence is frequently observed in patients with urinary bladder cancers (UBCs), with the need for biomarkers of prognosis and drug response.Chemoresistance and subsequent recurrence of cancers are driven by a subpopulation of tumor initiating cells, namely cancer stem-like cells (CSCs).However, the underlying molecular mechanism in chemotherapy-induced CSCs enrichment remains largely unclear.In this study, we found that during gemcitabine treatment lncRNA-Low Expression in Tumor (lncRNA-LET) was downregulated in chemoresistant UBC, accompanied with the enrichment of CSC population.Knockdown of lncRNA-LET increased UBC cell stemness, whereas forced expression of lncRNA-LET delayed gemcitabine-induced tumor recurrence.Furthermore, lncRNA-LET was directly repressed by gemcitabine treatment-induced overactivation of TGFβ/SMAD signaling through SMAD binding element (SBE) in the lncRNA-LET promoter.Consequently, reduced lncRNA-LET increased the NF90 protein stability, which in turn repressed biogenesis of miR-145 and subsequently resulted in accumulation of CSCs evidenced by the elevated levels of stemness markers HMGA2 and KLF4.Treatment of gemcitabine resistant xenografts with LY2157299, a clinically relevant specific inhibitor of TGFβRI, sensitized them to gemcitabine and significantly reduced tumorigenecity in vivo.Notably, overexpression of TGFβ1, combined with decreased levels of lncRNA-LET and miR-145 predicted poor prognosis in UBC patients.Collectively, we proved that the dysregulated lncRNA-LET/NF90/miR-145 axis by gemcitabine-induced TGFβ1 promotes UBC chemoresistance through enhancing cancer cell stemness.The combined changes in TGFβ1/lncRNA-LET/miR-145 provide novel molecular prognostic markers in UBC outcome.Therefore, targeting this axis could be a promising therapeutic approach in treating UBC patients.
Abstract 527: Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in prostate cancer
Authors: Shidong Jia
Journal: Cancer Research (2017)

Abstract The growth and survival of prostate cancer tumors relies primarily on the functioning of the androgen receptor (AR) signaling pathway. Recent studies suggested that the presence of AR-V7, a c-terminal truncated form of AR, in circulating tumor cells (CTCs) of patients with castration-resistant prostate cancer (CRPC) is associated with inherent and/or acquired resistance to enzalutamide and abiraterone, the stand of care androgen deprivation therapies in prostate cancer. A series of data also indicate that AR-Vs (eg, including AR-V7, ARv567es, AR-T878A, AR-F876L etc) may drive resistance in CRPC. Expression of AR-V7 has been shown to correlate with disease progression and shortened survival. Considering that truncated AR splicing variants with C-terminal loss lack a functional ligand-bingding domain (LBD) and are constitutively active, C-terminal AR-directed therapies may not be effective for patients with AR splicing variants. Circulating tumor cell (CTC)-based AR-V7 tests are currently being tested in the clinic. However, nearly half of the CRPC patients do not have enough CTCs for AR-V7 test, raising the request for a complementary, non-CTC platform to detect AR variants as well as other resistance markers in circulation. Here we report the development, validation and clinical application of PrediSeq-Prostate, a non-invasive next generation sequencing-based diagnostics platform that offers integrated genomic cell-free DNA (cfDNA) and cell-free RNA (cfRNA) profiling of prostate cancer, identifying known (such as AR-V7, AR-V9, AR-V2, etc) and novel AR splicing variants, point mutation, copy number, and translocation (such as TMPRSS2-ERG) using a single tube of blood. Using plasma samples from mCRPC patients that developed resistance to enzalutamide and/or abiraterone, PrediSeq-Prostate NGS test identified AR-V7, AR-V2, AR-V3, AR-V4 and other splicing variants that impact diagnosis and therapeutic selection. We also developed a Bio-Rad digital PCR assay measuring AR-V7 and AR-FL (full length) simultaneously. Collectively, PrediSeq NGS and ddPCR assays offer comprehensive genomic profiling of both cfDNA and cfRNA in all patients with prostate cancer, regardless of their status of CTC enumeration. The successful development and clinical validation of these tests has potential to enable precision medicine in prostate cancer. Citation Format: Shidong Jia. Integrated genomic cfDNA/cfRNA profiling for AR-V7 liquid biopsy test in prostate 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 527. doi:10.1158/1538-7445.AM2017-527
Abstract 5515: Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2
Authors: Lina Sun, Jianming Li
Journal: Cancer Research (2017)

Abstract Emerging evidence indicates that microRNAs, a class of small and well-conserved noncoding RNAs, participate in many physiological and pathological processes. RNase III endonuclease DICER is one of the key enzymes for microRNA (miRNA) biogenesis. However, the role of Dicer and its downstream miRNAs in colorectal cancer (CRC) remain largely unclear. Here, we found that Dicer was downregulated in tumour samples of CRC patients at both mRNA and protein levels. Importantly, more tumours were developed in mice with intestinal epithelial cells specific deletion of Dicer (Dicerloxp/+&amp;VillinCre mice) after azoxymethane (AOM) and dextran sulfate sodium (DSS) administration. Interestingly, deletion of Dicer in intestinal epithelial cells led to severe chronic inflammation and cytoskeleton remodeling of intestinal epithelium layer in mice with or without DSS administration. Microarray analysis of 3 paired Dicer deletion CRC cell lines (RKO-WT/RKO-DICER-/-, HCT116-WT/ HCT116-DICER-/- and DLD-WT/DLD-DICER-/-) showed that miR-324-5p was one of the most significant decreased miRNAs. In the intestinal epithelium of Dicerloxp/loxp&amp;VillinCre mice, miR-324-5p was also found to be markedly downregulated. Mechanistically, miR-324-5p directly bound to the 3'untranslated regions (3'UTRs) of HMGXB3 and WASF-2, two key proteins participated in cytoskeleton remodeling, to suppress their expression. Intraperitoneal injection of miR-324-5p AgomiR curtailed chronic inflammation and cytoskeleton remodeling of colorectal epithelium and restored intestinal barrier function in Dicerloxp/+&amp;VillinCre mice induced by DSS. Therefore, our study reveals a key role of a DICER/miR-324-5p/HMGXB3/WASF-2 axis in cytoskeleton remodeling and maintaining integrity of intestinal barriers and as such alludes to the possibility of screening for small-molecule compounds that boost Dicer activity as a potential strategy in the treatment of colorectal cancer. Citation Format: Lina Sun, Jianming Li. Dicer suppresses cytoskeleton remodeling and tumorigenesis of colorectal epithelium by miR-324-5p mediated suppression of HMGXB3 and WASF-2 [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 5515. doi:10.1158/1538-7445.AM2017-5515
Recombinant covalently closed circular DNA of hepatitis B virus induces long‐term viral persistence with chronic hepatitis in a mouse model
Authors: Gaiyun Li, Yuanfei Zhu, Dianhui Shao, Hao Chang, Xiaoming Zhang, Dongming Zhou, Yueqiu Gao, Ke Lan, Qiang Deng
Journal: Hepatology (2017)

Covalently closed circular DNA of hepatitis B virus (HBV) is critical for viral persistence in vivo. We recently reported a technique involving recombinant covalently closed circular DNA (rcccDNA) of HBV by site-specific DNA recombination. Using hydrodynamic injection, rcccDNA induces a temporarily prolonged HBV antigenemia in immunocompetent mice, similar to acute resolving HBV infection. In this study, we simulated the pathophysiological impact of chronic hepatitis to reproduce rcccDNA persistence in mouse models. We showed that rcccDNA achieved long-lasting persistence in the presence of a compromised immune response or when transcriptional activity was repressed. To closely mimic chronic hepatitis, we used a replication-defective recombinant adenoviral vector to deliver rcccDNA to the liver, which led to prominent HBV persistence throughout the experiment duration (>62 weeks) in transgenic mice expressing Cre recombinase under the albumin promoter. A sustained necroinflammatory response and fibrosis were identified in mouse livers, with dysplastic lesions commonly seen during the late stage of viral persistence, analogous to the progressive pathology of clinical chronic hepatitis.rcccDNA was intrinsically stable in vivo, enabling long-term persistence in the context of chronic hepatitis, and viral persistence, in turn, may promote progression of chronic liver disease; our study also presented a surrogate model of HBV cccDNA persistence in mice that could advance our understanding of the pathogenesis of chronic hepatitis B. (Hepatology 2018;67:56-70).
Mortality and Self-Harm in Association With Clozapine in Treatment-Resistant Schizophrenia
Authors: Theresa Wimberley, James H. MacCabe, Thomas M. Laursen, Holger J. Sørensen, Aske Astrup, Henriette T. Horsdal, Christiane Gasse, Henrik Støvring
Journal: American Journal of Psychiatry (2017)

This study evaluated rates of all-cause mortality and self-harm in association with clozapine treatment in individuals with treatment-resistant schizophrenia.A population-based cohort of 2,370 individuals with treatment-resistant schizophrenia after Jan. 1, 1996, was followed until death, first episode of self-harm, emigration, or June 1, 2013. Time to all-cause death and time to first episode of self-harm were analyzed in Cox regression models with time-varying treatment, adjusted for clinical and sociodemographic covariates.The rate of all-cause mortality was higher for patients not receiving clozapine than for those given clozapine (hazard ratio: 1.88, 95% confidence interval [CI]: 1.16-3.05). This was driven mainly by periods of no antipsychotic treatment (hazard ratio: 2.50, 95% CI: 1.50-4.17), with nonsignificantly higher mortality during treatment with other antipsychotics (hazard ratio: 1.45, 95% CI: 0.86-2.45). Excess mortality was observed in the year after clozapine discontinuation (hazard ratio: 2.65, 95% CI: 1.47-4.78). The rate of self-harm was higher for nonclozapine antipsychotics than for clozapine (hazard ratio: 1.36, 95% CI: 1.04-1.78).The results demonstrate a nearly twofold higher mortality rate among individuals with treatment-resistant schizophrenia not treated with clozapine compared with clozapine-treated individuals. Furthermore, the results suggest a harmful effect of other antipsychotics regarding self-harm compared with clozapine. It remains to be investigated to what extent the observed excess mortality after clozapine discontinuation is confounded by nonadherence and other unobserved factors and to what extent it is mediated by adverse effects from recent clozapine exposure or deterioration in physical or mental health precipitated by clozapine discontinuation.
Abstract P089: Estradiol Impairs Cardiac Contractile Function in Male Rodents
Authors: Georgios Kararigas, Virginie Bito, Hanna Tinel, Barbara Albrecht, Karin R Sipido, Vera Regitz-Zagrosek
Journal: Circulation Research (2011)

Several clinical and animal studies have challenged the notion that 17beta-estradiol (E2) is cardioprotective. Recently, we identified that in E2-treated male human cardiac tissues there was an increased expression level of the myosin regulatory light chain (Mrlc) interacting protein (Mylip) gene compared to controls. Mylip has been shown to bind and target Mrlc for proteasomal degradation in neuronal cells. Modulation of contraction by Mrlc in the heart has been well documented. Mutant mice for Mrlc phosphorylation show defects in heart contraction. Here, we tested the hypothesis that the induction of Mylip by E2 is associated with reduced Mrlc protein levels and impaired contractile function. Eleven-month old male C57BL/6J mice were injected intraperitonealy with E2 (n = 6) or vehicle (Ctrl; n = 4). Five hours after injection, cardiomyocytes (CMs) were isolated and were either frozen in TRIzol reagent for RNA isolation or used for cell shortening measurements. Quantitative real-time PCR revealed that E2-treated CMs had higher Mylip levels than Ctrl CMs (49% induction, P &lt; 0.05). In addition, there was a decreased abundance of Mrlc protein in E2-treated CMs compared to Ctrl CMs (74% reduction, P &lt; 0.05). Recordings of unloaded cell shortening at 1, 2 and 4 Hz demonstrated that the treatment with E2 impaired CM contractile function compared to Ctrl CMs (1 Hz: 31%, adjusted P &lt; 0.001; 2 Hz: 30%, adjusted P &lt; 0.01; 4 Hz: 25%, adjusted P &lt; 0.01). Similarly, there was a significant decrease in the rate of contraction of E2-treated CMs compared to controls. Next, we assessed the effect of E2 on cardiac contractility ex vivo using Langendorff-perfused rat hearts. Although at baseline there were no significant changes, the response to isoprenaline was blunted in E2-treated hearts. E2 levels in elderly and/or obese men might increase considerably and they have been associated with an increased risk and incidence of cardiovascular disease. However, explanations for causal pathways and putative mechanisms for this association have not been identified. Based on our present findings, we suggest that MYLIP could contribute to this association and we propose that MYLIP could become a pharmacological target in this high-risk group.
Abstract 4125: Comparison between knockdown of Pim-1, Pim-2 and Pim-3 identifies Pim-2 as the most relevant Pim oncogene in hepatocellular carcinoma
Authors: Ulrike Weirauch, Pia Kürz, Achim M. Aigner
Journal: Cancer Research (2017)

Abstract Introduction Pim-Kinases (Pim - proviral integration site for moloney murine leukemia virus; Pim-1, -2, -3) are a family of serine/threonine kinases with oncogenic potential. They are overexpressed in various solid tumors including hepatocellular carcinoma (HCC) and have been found responsible for malignant transformation, induction of cell proliferation and inhibition of apoptosis. While the main focus has been on Pim-1 so far, the other Pim kinases, esp. Pim-2, have not been explored in detail. Objectives The aim of this study was to compare the tumor-inhibitory effects of the single and combined of Pim family members in HCC, for evaluating their individual contributions and potential as therapeutic target. To this end, RNA interference (RNAi) for specific gene knockdown was employed. Materials and methods Different HCC cell lines were transfected with small interfering RNAs (siRNAs) for inducing RNAi and transient target gene downregulation. Various cellular and molecular effects were analysed. Results Transient siRNA transfection led to robust and specific knockdown of the selected Pim kinase(s) on mRNA and protein level. This resulted in anti-proliferative and pro-apoptotic effects. Most profound consequences on cell growth, cell cycle and apoptosis were observed upon Pim-2 knockdown, with little additive effects upon combined inhibition. These cellular changes were paralleled by alterations of various genes involved in cell cycle, cell survival, EMT and other important cellular processes. Conclusion In hepatocellular carcinoma, Pim-2 represents a functionally relevant oncogene. We demonstrate its higher potential as compared to the other Pim family members, and analyze various consequences of its inhibition or knockdown on the cellular and molecular level. Taken together, this identifies Pim-2 as a potentially relevant target gene for therapeutic intervention. Citation Format: Ulrike Weirauch, Pia Kürz, Achim M. Aigner. Comparison between knockdown of Pim-1, Pim-2 and Pim-3 identifies Pim-2 as the most relevant Pim oncogene 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 4125. doi:10.1158/1538-7445.AM2017-4125
Abstract 2427: Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben
Authors: Christine Strelchuk, Holly Jones Taggart
Journal: Cancer Research (2017)

Abstract Parabens are a group of chemical compounds extensively used as preservatives in consumer products such as cosmetics, pharmaceuticals and processed food. Parabens have been shown to have endocrine disrupting properties, to accumulate in breast tissue and to increase the proliferation of hormone receptor positive breast cancer cell lines through competitive binding to the estrogen receptor. Studies have shown that isobutylparaben has the highest binding affinity for the aryl hydrocarbon receptor (AhR), reported to bind environmental toxins. This study examined the alterations in gene expression correlated to exposure of the hormone receptor negative breast cancer cell line MDA-MB-231 to isobutylparaben over a 72 hour time frame. Exposure of the cells to concentrations of isobutylparabens commonly found in consumer products alters the genetic expression profile of the cells. In our study, detectable expression levels of AhR mRNA decreased, while cytochrome P450 (CYP1A1) and receptor activator of NFκB ligand (RANKL) mRNA levels increased, as analyzed by qPCR. The downregulation of AhR and altered expression levels of invasion related genes is suggestive of an increased metastatic phenotype with exposure to isobutylparaben. Citation Format: Christine Strelchuk, Holly Jones Taggart. Alterations in gene expression after exposure of MDA-MB-231 cells to isobutylparaben [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 2427. doi:10.1158/1538-7445.AM2017-2427
Abstract 5555: Integrative network variomics reveals complex genotype to phenotype relationships in cancer
Authors: Nidhi Sahni, Song Yi
Journal: Cancer Research (2017)

Abstract Proteins interact with other macromolecules in complex cellular networks for signal transduction and biological functions. Recently a deluge of genomic information becomes available from patients stricken by a variety of cancer types. In cancer, genetic aberrations have been traditionally thought to abolish the entire gene function. It has been increasing appreciated that each genomic mutation of a gene could have a subtle but unique effect on protein function or network rewiring, contributing to diverse phenotypic consequences across cancer patient populations. In this study, we designed an integrative multi-omics platform using systems biology approaches to functionally assess the effects of cancer genetic variants. We compared a broad spectrum of mutation classes for a wide range of mechanistic effects on gene function in the context of signaling networks. Our results reveal a functional landscape of context-specific signaling network perturbations underlying cancer genetic heterogeneity at the base-pair resolution. Such information is critical for understanding the complex pleiotropic effect of cancer genes, and provides a possible link between genotype and phenotype in cancer. Furthermore, this study suggests new perspectives in targeted therapy and precision medicine. Citation Format: Nidhi Sahni, Song Yi. Integrative network variomics reveals complex genotype to phenotype relationships 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 5555. doi:10.1158/1538-7445.AM2017-5555