tbuckley/cabot-search huggingface dataset:
Abstract 997: Hotair promotes glioma cell cycle through a b-catenin mediated mRNA network
Authors: Qixue Wang, Kai Huang, Yu Ren, Yunfei Wang, Bingcong Zhou, Yanli Tan, Chuan Fang, Jie Li, Chunsheng Kang
Journal: Cancer Research (2016)

Abstract Background: LncRNA hotair is an oncogene that involves in the progression of several cancers. Previously we and others have reported that hotair promotes glioblastoma progression by regulating cell cycle. However, further mechanism still needs to be explored. The wnt/b-catenin signaling pathway is a crucial factor in the development of many cancers. B-catenin is a nuclear transcription factor that regulates multiple genes involved in cell proliferation, survival and EMT that contribute to glioma development. Methods: Positive correlation genes of hotair were picked up from CGGA (Chinese Glioma Genome Atlas) database by bioinformatics analysis. Real Time PCR is used to test the mRNA expression levels in U87 cells and astrocytes. Western blot is emplored to determine PKM2 expression after knocking down hotair. Further more, and nude mouse glioma intracranial model is employed to examine in vivo impact of hotair on GBM. Results: Hotair is a cell cycle related lncRNA as previously reported. Bioinformatics analysis indicated that various genes play important roles on cell cycle are positively correlated with hotair. Theses genes might be the executors of hotair on cell cycle regulating. We constructed a top 18 hotair-related genes network by connectivity. To test the hypothesis, we knock down hotair expression in U87 cells, and found out that FOXM1, CCNA2, CEP55, CENEP, CCNB2, HMMR, NCAPG, NUSAP were down-regulated significantly. In addition, overexpression of hotair in astrocytes could upregulate the mRNA of those genes. To further explore the regulatory mechanism, we analyed the promoter of these hotair-regulated genes and found out b-catenin/TCF4 binding site on all of them. This indicated that hotair might upregulate cell cycle associated genes through b-catenin/TCF4 pathway. FH535 is an inhibitor of wnt/b-catenin. The mRNA expression of these genes could be suppressed by FH535 treatment, which confirms the promoter analysis. It is reported that PKM2 could promote b-catenin nuclear translocation. Interestingly, we found out that binding site of miR-330 exists on both of hotair and PKM2 mRNA. Knocking-down of hotair inhibited PKM2 mRNA and protein expression in U87, U87vIII, U251 and LN229 cells. Further more, hotair siRNA could inhibit glioma growth in vivo. Conclusion: Our data indicated that hotair promotes glioma cell cycle through a b-catenin mediated mRNA network, and hotair could be a a biomarker and therapeutic target in glioblastoma. Meanwhile, there are still a lot of work to be done. Citation Format: Qixue Wang, Kai Huang, Yu Ren, Yunfei Wang, Bingcong Zhou, Yanli Tan, Chuan Fang, Jie Li, Chunsheng Kang. Hotair promotes glioma cell cycle through a b-catenin mediated mRNA network. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 997.
Abstract 1644: NF-κB inhibitor DMAPT blocks non-homologous end-joining repair of radiation-induced DSBs in NSCLC
Authors: Peter V. Deraska, Colin O’Leary, Jean-Bernard Lazaro, Christopher J. Sweeney, Alan D. D’Andrea, David Kozono
Journal: Cancer Research (2016)

Abstract Background: Despite optimal multimodality therapy, non-small cell lung carcinoma (NSCLC) remains the leading cause of cancer-related death in the United States. A common limitation is our inability to provide sufficient radiotherapy (RT) to eradicate tumor due to risk of toxicities in surrounding tissues. There is thus an unmet need for radiosensitizers that can improve the therapeutic index. Dimethylaminoparthenolide (DMAPT), an orally bioavailable small molecule NF-κB inhibitor, inhibits repair of ionizing radiation (IR)-induced DNA double strand breaks (DSBs) and increases control of subcutaneous mouse NSCLC xenografts. While our prior work focused on inhibition of homologous recombination as a mechanism for radiosensitization, we sought to characterize the effect of DMAPT on a second major DSB repair pathway, non-homologous end-joining (NHEJ). Methods: NHEJ was assessed in NSCLC lines using the pEJ reporter and flow cytometry. The NF-κB super repressor (IκBαS32A,S36A) was used as a control. Immunofluorescence and Western blotting were used to assess NHEJ biomarkers including 53BP1, DNA-PKS2056, Ku70/80 and XRCC4. Cell fractionation was performed to assess Ku chromatin binding. Quantitative RT-PCR was performed to assess gene transcription. Ku complexes were purified to identify binding partners. Results: NSCLC cells treated with IR-sensitizing doses of DMAPT (5-15 μM) or the NF-κB super repressor showed significant decreases in NHEJ. DMAPT increased the persistence of 53BP1 foci, indicating a failure to complete NHEJ. Regardless of exogenous DNA damage, there was reduced Ku70 chromatin binding following DMAPT treatment. DMAPT-treated cells produced fewer distinct IR-induced DNA-PKS2056 foci. Further, there was decreased IR-induced XRCC4 chromatin recruitment, suggesting that repair was impaired prior to ligation. There was no change in Ku70/80 transcription following DMAPT and/or IR. However, Western blotting of purified Ku complexes showed that DMAPT treatment decreased Ku association with RNA binding partners including RPL19. We also observed decreased recruitment of DNA-PKcs to the Ku complex, suggesting decreased Ku affinity for DSBs. Conclusions: These results indicate that DMAPT radiosensitizes NSCLC by perturbing the binding affinity of Ku to RNA, DNA and its complex binding partners, thus blocking NHEJ. Further mechanistic investigation and analysis of NHEJ biomarkers in vivo is needed to identify the precise mechanism. Citation Format: Peter V. Deraska, Colin O’Leary, Jean-Bernard Lazaro, Christopher J. Sweeney, Alan D. D’Andrea, David Kozono. NF-κB inhibitor DMAPT blocks non-homologous end-joining repair of radiation-induced DSBs in NSCLC. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1644.
Abstract 4631: SCFFbxo7 ubiquitin ligase targets cereblon to limit the anti-myeloma activity of IMiDs
Authors: Jiye Liu, Wenrong Zhou, Yan Feng, Tianyu Song, Shaobing Gao, Junfeng Wu, Zhenggang Peng, Yong Cang
Journal: Cancer Research (2016)

Abstract Multiple myeloma (MM) patients have witnessed significantly improved survival after the approved treatment with the proteasome inhibitor bortezomib and immunomodulatory drugs (IMiDs) including thalidomide and its derivatives lenalidomide and pomalidomide. IMiDs directly bind cereblon (CRBN), an adaptor of the Cul4-DDB1 (CRL4) ubiquitin ligase, and activate CRL4CRBN to target B cell-specific transcription factors IKZF1 and IKZF3 for ubiquitination. IKZF1 and IKZF3 are essential for MM cell survival and their proteasomal degradation induced by IMiDs provides insights into how these drugs work. Paradoxically, IMiDs achieve better clinical response in MM patients when combined with bortezomib, which blocks IKZF1 and IKZF3 turnover and would in principle counteract IMiDs therapy. We performed a CRISPR-based genome-wide knockout screening for regulators of pomalidomide sensitivity in MM cells, and found that CRBN is inherently unstable and its level is controlled by the COP9 signalosome (CSN) to sustain IMiDs cytotoxicity. When unbound to CRL4, CRBN is recruited by the F-box protein Fbxo7 to the Cul1-Skp1 (SCF) ubiquitin ligase for ubiquitination and degradation, a process suppressed by CSN-mediated de-neddylation of Cul1. Deletion of SCFFbxo7 components, or treatment with bortezomib or neddylation inhibitor MLN4924 stabilizes CRBN, and IMiDs further promote the loading of CRBN to CRL4 by inhibiting SCFFbxo7-targeted CRBN degradation, leading to enhanced turnover of IKZF1 and IKZF3 in MM cells and synergistic inhibition of MM cell proliferation. Our findings unravel a dual role of IMiDs in activating CRL4CRBN E3 ligase in MM cells and provide a framework to select patients most susceptible to bortezomib and IMiDs combination therapy. Citation Format: Jiye Liu, Wenrong Zhou, Yan Feng, Tianyu Song, Shaobing Gao, Junfeng Wu, Zhenggang Peng, Yong Cang. SCFFbxo7 ubiquitin ligase targets cereblon to limit the anti-myeloma activity of IMiDs. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4631.
Five-year survival and durability results of brentuximab vedotin in patients with relapsed or refractory Hodgkin lymphoma
Authors: Robert Chen, Ajay K. Gopal, Scott E. Smith, Stephen M. Ansell, Joseph D. Rosenblatt, Kerry J. Savage, Joseph M. Connors, Andreas Engert, Emily K. Larsen, Dirk Huebner, Abraham Fong, Anas Younes
Journal: Blood (2016)
Immunohistochemical Profile and Prognostic Significance in Chinese Primary Central Nervous System Lymphoma: Analysis of 132 Cases
Authors: Jing Liu, Yaming Wang, Xiaoyan Li, Zhe Liu, Xueyan Bai, Jun Qian, Hong Zhu, Bingxu Wang, Yifeng Du, Qiaoyun Tang, Zhenkun Yu, Yajie Wang, Shengjun Sun, Nan Ji, Yilong Wang, Xuefei Sun, Yuanbo Liu
Journal: Blood (2015)
Abstract 3678: The tumor suppressive small GTPase DiRas3 (ARHI) inhibits proliferation and activation of NF-κB in glioblastoma
Authors: Amy Rymaszewski, Michael Straza, Anne Frei, Carmen Bergom
Journal: Cancer Research (2016)

Abstract Glioblastoma (GB) is the most aggressive malignancy affecting the central nervous system (CNS) with a median survival of 12 to 15 months even with surgery, radiation and chemotherapy. Previous research demonstrates that increased activation of NF-κB is critical for GB growth, proliferation and the up regulation of genes involved in cytokine production, cell cycle regulation, apoptosis and cell adhesion. Understanding the molecular targets that regulate NF-κB may provide more effective therapeutic targets for GB. DiRas family small GTPases, which are homologous to pro-oncogenic Ras GTPases, are tumor suppressive rather than tumor promoting and include DiRas1, DiRas2 and DiRas3 (ARHI). DiRas1 and DiRas2 have been suggested to be tumor suppressive in CNS malignancies, but the role of DiRas3 in CNS malignancies remains unknown. Here we demonstrate that expression of DiRas3 protein in GB cell lines is absent, although DiRas3 is expressed in non-malignant glial cells. Re-expression of DiRas3 in U-87 cells reduces cell proliferation by 20%. Using a NF-κB transcriptional activity luciferase reporter assay demonstrates that DiRas3 expression reduces NF-κB transcriptional activity by 70% compared to vector control. Further experiments demonstrate that decreased NF- κB activity occurs via reduced phosphorylation of the NF-κB inhibitor IκBα. The reduced phosphorylation of IκBα could be a result of decreased AKT and ERK activity, as increased ERK and AKT activity can stimulate NF-κB pathways. Our lab has previously demonstrated that the most common binding partner for DiRas1 and DiRas2 was the small GTPase binding protein SmgGDS, and DiRas1 and DiRas2 also reduce NF- κB activation. However, DiRas3 does not interact with SmgGDS, suggesting that DiRas3 can reduce NF-κB in a SmgGDS-independent manner. Understanding the role of DiRas3 and its binding partners in mediating NF- κB activation may lead to novel therapeutics for glioblastoma. Citation Format: Amy Rymaszewski, Michael Straza, Anne Frei, Carmen Bergom. The tumor suppressive small GTPase DiRas3 (ARHI) inhibits proliferation and activation of NF-κB in glioblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3678.
Abstract 4899: The regulation by kinases of the expression of human major histocompatibility class I molecules
Authors: Elliott J. Brea, Claire Oh, Eusebio Manchado, Ron Gejman, George Mo, Patrizia Mondello, Ralph Garippa, Neal Rosen, David A. Scheinberg
Journal: Cancer Research (2016)

Abstract The major histocompatability complex (MHC) is a central receptor in the adaptive immune response and is the underlying target of several effective therapies for cancer. Druggable kinases may provide the opportunity to modulate the immune response toward MHC. However, the regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. The entire human kinome was screened using a pooled shRNA interference-based approach in a human mesothelioma cell line to uncover kinase regulators of MHC-I. Negative and positive regulators of cell surface HLA levels were discovered. A subset of highly scoring positive and negative kinase hits were subsequently validated by additional RNAi, and pharmacologic inhibitors when available. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of HLA expression in multiple cancer types. We mapped the pathways responsible for increased HLA upon kinase inhibition. Interestingly, inhibition of the MAP Kinase pathway broadly influenced expression of other components of the antigen presentation machinery. Moreover, DDR2 and MINK1 were shown to positively regulate HLA-A*02:01. This had therapeutic relevance, as shown with a therapeutic TCR mimic antibody to a MHC/peptide complex. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Citation Format: Elliott J. Brea, Claire Oh, Eusebio Manchado, Ron Gejman, George Mo, Patrizia Mondello, Ralph Garippa, Neal Rosen, David A. Scheinberg. The regulation by kinases of the expression of human major histocompatibility class I molecules. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4899.
Co-targeting androgen receptor (AR) and DNA repair: A randomized ETS gene fusion-stratified trial of abiraterone + prednisone (Abi) +/- the PARP1 inhibitor veliparib for metastatic castration-resistant prostate cancer (mCRPC) patients (pts) (NCI9012)—A University of Chicago phase II consortium trial.
Authors: Maha Hussain, Stephanie Daignault, Przemyslaw Twardowski, Costantine Albany, Mark N. Stein, Lakshmi Priya Kunju, Javed Siddiqui, Dan Robinson, Rohit Mehra, Kathleen A. Cooney, Robert B. Montgomery, Emmanuel S. Antonarakis, Daniel H. Shevrin, Paul Gettys Corn, Young E. Whang, David C. Smith, Megan Veresh Caram, Walter Michael Stadler, Felix Yi-Chung Feng, Arul M. Chinnaiyan
Journal: Journal of Clinical Oncology (2016)

5010 Background: In preclinical CRPC models, PARP1 inhibition synergizes with AR targeted therapy and induces DNA damage, especially in ETS fusion-positive tumors. We hypothesized: co-targeting PARP-1 + AR is superior to AR inhibition and ETS is a response predictor. Methods: Eligible mCRPC pts underwent metastatic (mets) disease biopsy (bx), were stratified by ETS status and randomized to Abi (Arm A) or Abi + Veliparib (Arm B). The primary endpoint was confirmed PSA response rate (RR, ≥ 50% decline). Secondary endpoints included safety, objective RR (ORR), progression free survival (PFS), and if DNA repair gene deficiency (DRD; homozygous deletions or deleterious mutations: BRCA 1, BRCA 2, ATM, FANCA, PALB2, RAD51B, RAD51C) predicts response. 148 pts stratified by ETS status to be randomized to detect a 20% PSA RR improvement assuming a 5% 1-sided type I error and 80% power. Primary analysis: PSA RR logistic model to test the interaction of ETS status and treatment with a significance threshold of 0.15. Results: 185 eligible pts underwent mets bx (89 soft tissue, 96 bone); 159 (86 %) had adequate tissue, 35% were ETS +ve (IHC). 153 pts (88% white, 8% black, median age 68 years, median PSA 35.4 ng/ml) were randomized: Arms A/B: 74/79. Hyperglycemia was the most common G3/4 AE (≥ 5% in both arms). PSA RR: Arm A 63%, Arm B 67%. ORR: Arm A 36%, Arm B 49%. Median PFS: Arm A 8.5 months (m) (95% CI: 8.1 – 13.5), Arm B 11m (95% CI: 8.1 – 13.8). More Arm B pts were on therapy for 12 (34% vs 30%) and 18 + cycles (20% vs 16%). There were no differences by ETS status. Exploratory analysis from sequencing mets tissue (N=66) was performed. 18 pts (27%) had DRD; >80% in both arms had PSA response. Median PFS (95% Cl) by DRD status: no DRD: 5.8 ms (4.2 - 8.2) vs DRD 13.5 ms (8.2 - NR). Conclusions: This first mets biomarker-based trial was feasible. The trend is in favor of Abi + Veliparib with regard to PSA RR, ORR, therapy duration and mPFS. Exploratory analysis suggest that DRD is associated with better response. Updated clinical and sequencing data will be reported. Clinical trial information: NCT01576172.
P0480 : Role of the immune microenvironment during hepatocellular carcinoma
Authors: A. L’Hermitte, S. Pham, M. Anson, A.-M. Denoyelle, G. Couchy, C. Perret, J. Zucman-Rossi, C. Desdouets, J.-P. Couty
Journal: Journal of Hepatology (2015)
Oxygen Tension in the Bone Marrow (BM) of Patients with Malignant and Indolent Monoclonal Gammopathy: Role of Hypoxia and Hypoxia-Inducible Factor (HIF)-1α in the Regulation of Gene Expression and Pro-Angiogenic Profiles of CD138+ Cells.
Authors: Nicola Giuliani, Simona Colla, Paola Storti, Valentina Sgobba, Katia Todoerti, Gaetano Donofrio, Marina Bolzoni, Manuela Abeltino, Mirca Lazzaretti, Sabrina Bonomini, Monica Crugnola, Antonino Neri, Vittorio Rizzoli
Journal: Blood (2009)
Abstract LB-195: The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity
Authors: Shikshya Shrestha, Steven M. Offer, Robert B. Diasio
Journal: Cancer Research (2016)

Abstract Nearly one-third of cancer patients that receive the commonly prescribed chemotherapy drug 5-fluorouracil (5-FU) experience severe (grade 3+) adverse toxicity related to treatment. Approximately 1,300 deaths are directly attributed to 5-FU toxicity annually in the U.S. While three deleterious genetic variations in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) are well-established predictors of severe toxicity (i.e., *2A, p.I560S, p.D949V), they only explain 30-35% of adverse cases of 5-FU toxicity. Recently, an intronic variant (rs75017182) has been suggested to contribute to 5-FU toxicity risk by promoting the alternative splicing of DPYD. However, recent clinical studies are conflicting as to the degree to which rs75017182 affects DPD enzyme function, and it remains unclear as to the extent to which DPYD splicing is affected in carriers. The primary aim of this study was to directly determine correlations between rs75017182, DPD enzyme function, and DPYD splicing. Genotyping for rs75017182, *2A, p.I560S, and p.D949V was performed on DNA obtained from 3950 healthy participants in the Mayo Clinic Biobank. Individuals carrying one or more of the genotyped variants, as well as matched non-carriers, were asked to provide an additional blood sample that was used to measure DPYD expression, DPYD splicing relevant to rs75017182, and DPD enzyme activity (n = 204). A moderate, but significant, reduction was noted in the expression of canonically spliced DPYD in rs75017182 carriers compared to non-carriers. DPD enzyme activity in peripheral blood mononuclear cells was similarly reduced in rs75017182 carriers. The degree to which DPD activity was reduced in rs75017182 carriers was not as severe as was noted for carriers of the toxicity-associated variants *2A, p.I560S, or p.D949V. Collectively, our data support a model in which rs75017182 leads to alternative splicing of a fraction of primary transcripts that harbor the variant, which in turn causes a modest reduction in the levels of functional DPD enzyme. The modest phenotypes noted may partially explain some of the discrepant results noted between various clinical studies that have attempted to evaluate the variant. Citation Format: Shikshya Shrestha, Steven M. Offer, Robert B. Diasio. The intronic DPYD variant rs75017182 correlates with a modest reduction in DPD enzyme activity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-195.
Abstract 98: The somatic mutational landscape of the mitochondrial genome in prostate cancer: evaluation of clinical impact
Authors: Julia F. Hopkins, Veronica Y. Sabelnykova, John Watson, Lawrence E. Heisler, Junyan Zhang, Michael Fraser, Theodorus van der Kwast, Robert G. Bristow, Paul C. Boutros
Journal: Cancer Research (2016)

Abstract Prostate cancer remains the most prevalent and second most lethal non-skin cancer in men. Whole genome studies have provided important insights into specific driver genes, however most of these studies have not assessed one key portion of the genome: the mitochondrial genome. To gain a complete understanding of the most commonly-diagnosed sub-groups of prostate cancer: low- and intermediate-risk localized disease, we surveyed the mitochondrial genomes from next-generation sequencing (NGS) data of over 300 tumour samples from prostate cancer patients. These samples were mainly from prostate cancer patients with clinical Gleason Scores of 3+3, 3+4 and 4+3. All had at least 5 years of follow-up data (median &amp;gt; 8 years), allowing identification of clinical associations with identified somatic mutations via Cox Proportional Hazards modeling and machine-learning. Recurrent somatic mutations in mtDNA were identified, and these were associated with clinical outcomes. One third of patients were found to have a somatic mtDNA mutation. These mutations appear to be associated with age of patient. The mtDNA region with the majority of mutations was the regulatory D-loop region, although certain proteins had high numbers of mutations. Those somatic mutations occurring within the coding regions in general were nonsynonymous. Specific identified candidate somatic mutations were validated via Sanger sequencing. Clinical associations between somatic were also integrated with existing copy-number alteration (CNA) biomarkers using machine learning methods to evaluate performance. mtDNA mutations were also compared to identified aberrations (CNA, PGA, SNVs) within the nuclear genome to determine correlations between the two genomes, in addition to other somatic mutations or altered-expression in nuclear-encoded mitochondrial proteins. Taken together, these data demonstrate a key role for mitochondrial mutations in driving prostate cancer. Citation Format: Julia F. Hopkins, Veronica Y. Sabelnykova, John Watson, Lawrence E. Heisler, Junyan Zhang, Michael Fraser, Theodorus van der Kwast, Robert G. Bristow, Paul C. Boutros. The somatic mutational landscape of the mitochondrial genome in prostate cancer: evaluation of clinical impact. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 98.