tbuckley/cabot-search huggingface dataset:
Abstract 4462: Cytotoxic effects of a novel BRD4 inhibitor in uveal melanoma cells with Gnaq/11 mutations
Authors: Grazia Ambrosini, Gary K. Schwartz
Journal: Cancer Research (2016)

Abstract Uveal melanoma (UM) is an aggressive intraocular malignancy with high tendency to metastasize to the liver. The majority of UM harbor activating mutations in the G proteins Gnaq/11, and amplification of the oncogene c-Myc. Currently available drugs have shown limited response in patients with UM and there is an urgent need for new effective therapies. Recent findings from our laboratory demonstrated that UM cells with Gnaq/11 mutations are dependent on BRD4 activity. BET proteins are epigenetic readers involved in chromatin remodeling and transcriptional regulation. BRD4 inhibitors consist of small molecules that competitively displace BRD4 from acetylated histones, resulting in the suppression of the MYC transcriptome and other BRD4-dependent genes. Here, we report that a novel clinical BRD4 inhibitor from Plexxikon (Berkeley, CA), PLX51107, induces high cytotoxic activity in UM cell lines at nanomolar concentrations. In cells with Gnaq/11 mutations, PLX51107 showed an IC50 of 250nM, similar to the pre-clinical compound JQ1. In contrast, PLX51107 did not have a significant effect (IC50&amp;gt;3000nM) in cells without the mutations. PLX51107 induced marked apoptosis in Gnaq/11 mutant cells, as detected by Annexin V staining and induction of cleaved PARP. It also suppressed the expression of BRD4 targets, i.e c-Myc, Rad51, and induced the pro-apoptotic protein Bim. In mouse xenograft models of UM PLX51107 significantly inhibited tumor growth. Since the MAPK pathway plays a major role in UM, we explored the combination of PLX51107 with a MEK inhibitor, and found increased activity in vitro and in vivo. All together, these observations support the idea that this clinical BRD4 inhibitor represents a novel therapeutic intervention against UM with Gnaq/11 mutations, and clinical development is planned. Citation Format: Grazia Ambrosini, Gary K. Schwartz. Cytotoxic effects of a novel BRD4 inhibitor in uveal melanoma cells with Gnaq/11 mutations. [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 4462.
A new 3p25 locus is associated with liver fibrosis progression in human immunodeficiency virus/hepatitis C virus‐coinfected patients
Authors: Damien Ulveling, Sigrid Le Clerc, Aurélie Cobat, Taoufik Labib, Josselin Noirel, Vincent Laville, Cédric Coulonges, Wassila Carpentier, Bertrand Nalpas, Markus H. Heim, Thierry Poynard, Andreas Cerny, Stanislas Pol, Pierre‐Yves Bochud, François Dabis, Ioannis Theodorou, Yves Lévy, Dominique Salmon, Laurent Abel, Stéphanie Dominguez, Jean‐François Zagury
Journal: Hepatology (2016)

There is growing evidence that human genetic variants contribute to liver fibrosis in subjects with hepatitis C virus (HCV) monoinfection, but this aspect has been little investigated in patients coinfected with HCV and human immunodeficiency virus (HIV). We performed the first genome‐wide association study of liver fibrosis progression in patients coinfected with HCV and HIV, using the well‐characterized French National Agency for Research on AIDS and Viral Hepatitis CO13 HEPAVIH cohort. Liver fibrosis was assessed by elastography (FibroScan), providing a quantitative fibrosis score. After quality control, a genome‐wide association study was conducted on 289 Caucasian patients, for a total of 8,426,597 genotyped (Illumina Omni2.5 BeadChip) or reliably imputed single‐nucleotide polymorphisms. Single‐nucleotide polymorphisms with P values &lt;10 −6 were investigated in two independent replication cohorts of European patients infected with HCV alone. Two signals of genome‐wide significance ( P &lt; 5 × 10 −8 ) were obtained. The first, on chromosome 3p25 and corresponding to rs61183828 ( P = 3.8 × 10 −9 ), was replicated in the two independent cohorts of patients with HCV monoinfection. The cluster of single‐nucleotide polymorphisms in linkage disequilibrium with rs61183828 was located close to two genes involved in mechanisms affecting both cell signaling and cell structure ( CAV3 ) or HCV replication ( RAD18 ). The second signal, obtained with rs11790131 ( P = 9.3 × 10 −9 ) on chromosome region 9p22, was not replicated. Conclusion : This genome‐wide association study identified a new locus associated with liver fibrosis severity in patients with HIV/HCV coinfection, on chromosome 3p25, a finding that was replicated in patients with HCV monoinfection; these results provide new relevant hypotheses for the pathogenesis of liver fibrosis in patients with HIV/HCV coinfection that may help define new targets for drug development or new prognostic tests, to improve patient care. (H epatology 2016;64:1462‐1472)
Abstract 3562: BCR/ABL increases EZH2 levels which regulates XIAP expression via miRNA-219 in chronic myeloid leukemia cells
Authors: Takayuki Ikezoe, Chie Nishioka, Jing Yang, Akihito Yokoyama
Journal: Cancer Research (2016)

Abstract In this study, we showed that the levels of enhancer of zeste homolog 2 (EZH2) in bone marrow mononuclear cells (BMMNCs) isolated from individuals with chronic myeloid leukemia (CML) (n = 12) were greater than those in BMMNCs isolated from healthy volunteers (n = 6). Lentiviral transduction of the BCR/ABL gene in Ba/F3 cells increased EZH2 levels in parallel with phosphorylation of STAT5. Notably, chromatin immunoprecipitation assays showed that STAT5A bound to a promoter region of the EZH2 gene, resulting in an increase in the transcriptional activity of EZH2 in leukemia cells. Importantly, downregulation of EZH2 by short hairpin RNAs (shRNAs) inhibited the expression of the antiapoptotic protein XIAP and increased the miR-219 levels associated with a decrease in hypermethylation of miR-219-1 CpG islands. Moreover, overexpression of miR-219 decreased the levels of XIAP in CML cells. Since the 3′-untranslated region (3′-UTR) of XIAP contains miR219-5p-complementary binding site, miR-219 might modulate the expression of XIAP through binding of miR-219 on the 3′-UTR of XIAP. Taken together, BCR/ABL positively regulates the expression of EZH2 via STAT5 signaling. EZH2 modulates epigenetic changes at DNA methylated regions encoding miR-219 and downregulates the level of miR-219, resulting in upregulation of XIAP. Citation Format: Takayuki Ikezoe, Chie Nishioka, Jing Yang, Akihito Yokoyama. BCR/ABL increases EZH2 levels which regulates XIAP expression via miRNA-219 in chronic myeloid leukemia cells. [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 3562.
Recruiting Patients With Stroke Into Cell Therapy Trials
Authors: Vivek Misra, William J. Hicks, Farhaan Vahidy, Susan Alderman, Sean I. Savitz
Journal: JAMA Neurology (2016)

Clinical trials are under way to test the safety and efficacy of different types of cell therapies in patients with ischemic stroke. The informed consent process for recruitment of patients with stroke in cell therapy trials is complex and requires extensive discussions on multiple aspects.Various issues in approaching patients with stroke and their families and discussing participation in cell therapy studies are described, including participation in clinical trials, clarifying the perception of stem cell therapy and the risks of bone marrow harvest, and discussing risks vs benefits, cell-based therapies for chronic stroke, and consent for minority and immigrant populations.Informed consent for cell therapy studies in patients with stroke requires lengthy discussions about several issues unique to clinical trials in stroke patients. Careful thought is needed to create an informative consent process.
Abstract 2357: Therapeutic potential of the natural human IgG1k antibody pritumumab
Authors: Ivan Babic, Rajesh Mukthavaram, Natsuko Nomura, Sandeep Pingle, Mark C. Glassy, Santosh Kesari
Journal: Cancer Research (2016)

Abstract Pritumumab is a natural human IgG1 kappa antibody derived from a regional draining lymph node of a patient with cervical carcinoma. The recognized antigen is an altered form of vimentin, called ecto-domain vimentin (EDV), that is expressed on the cell surface of epithelial tumor cells. A recombinant version of the mAb was made using the GPEx® system in CHO cells. In a series of comparable studies the CHO mAb was compared with the original hybridoma. Binding specificity with both flow cytometry and immunohistochemical analysis, Western blot analysis, and Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) activity confirms the comparability of the two versions. A concentration-dependent study of pritumumab-mediated ADCC suggests an EC50 of 39.6ng/ml. Further studies include establishing a xenograft model with both SCID and athymic nude mice in which pritumumab was effective in preventing tumor growth in nude mice but not in SCID mice. Analysis of a blood brain barrier model suggests pritumumab shows minimal distribution in normal brain tissues and significant binding in tumor areas of brain tissues indicating the mAb crosses the tumor brain barrier. Overall, these data together suggest pritumumab is suitable for development as an anti-tumor therapeutic. Citation Format: Ivan Babic, Rajesh Mukthavaram, Natsuko Nomura, Sandeep Pingle, Mark C. Glassy, Santosh Kesari. Therapeutic potential of the natural human IgG1k antibody pritumumab. [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 2357.
Abstract 3083: Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis
Authors: Santanu Paul, Lisa Stehno-Bittel, Animesh Dhar
Journal: Cancer Research (2016)

Abstract Purpose: Pancreatic ductal adenocarcinoma (PDAC) or pancreatic cancer is one of the most lethal malignancies in humans. The survival rate for two years is very limited in most of cases (10%) after diagnosis of this disease. This is because current therapeutic regimens have limited effectiveness. Novel therapeutic targets are needed to treat this disease. GZ17-06.12 contains a nutraceutical for its anti-cancer properties, in several cancers. Crude extracts of the plant Arum palaestinum Boiss used in traditional Israeli and Palestinian medicine, have demonstrated cytostatic and cytotoxic activities in colon, prostrate and lung carcinoma. Therefore, we hypothesize that GZ17-06.12 will inhibit tumor progression and metastasis in PDAC. Experimental Procedure: In this study, we have determined cell proliferation, pancosphere formation and apoptosis following treatment of different doses oGZ17-06.12 for 24-72 hours using MiaPaCa-2 and S2-007 human pancreatic cancer cells. Cell cycle distribution and apoptosis were measured using flow cytometic analysis. Orthotopic pancreatic cancer model in athymic mice was developed and GZ17-06.12 was given orally for 20 days to those mice. Proliferative markers, pEGFR/pAkt and apoptotic markers, Bax/Bcl-2, were monitored following treatment with GZ17-06.12 in both in vivo and in vitro models. Metastatic markers, MMP-2 and MMP-9 were measured in metastatic tissues in orthotopic models. Results: GZ17-06.12 inhibited proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. Cell cycle analysis suggested that cells were arrested in S and G2 phase following treatment. In addition, GZ17-06.12 induced apoptosis in both in vitro and in vivo pancreatic cancer. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, GZ17-06.12 decreased the number and size of the pancospheres in S2-007 cells with concomitant inhibition of pancreatic cancer stem cell markers, DCLK1, Lgr5 and EpCam. The effect of GZ17-06.12 suppressed tumor growth and metastatic potential as indicative of MMP-2 and MMP-9 activity in primary and metastatic tumors. Conclusions: GZ17-06.12 significantly reduces tumorigenesis and metastasis in both in vitro and in vivo pancreatic cancer models, inhibiting proliferation with concomitant increase of apoptosis. Citation Format: Santanu Paul, Lisa Stehno-Bittel, Animesh Dhar. Novel inhibitor GZ17-06.12 suppresses pancreatic cancer tumorigenesis. [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 3083.
Effects of perioperative enteral EPA-enriched immunonutrition on meaningful loss of lean body mass after total gastrectomy for gastric cancer: Post hoc analysis of a phase III study.
Authors: Takaki Yoshikawa, Naoki Hiki, Kentaro Sakamaki, Seiji Ito, Kazumasa Fujitani, Nobuhiro Takiguchi, Yoshiyuki Kawashima, Kazuhiro Nishikawa, Mitsuru Sasako, Satoshi Ida, Toru Aoyama, Michitaka Honda, Tsutomu Sato, Souya Nunobe, Takashi Ogata, Haruhiko Cho
Journal: Journal of Clinical Oncology (2016)

85 Background: Total gastrectomy for gastric cancer significantly reduces body weight, especially lean body mass (LBM), through surgical stress and decrease of the calorie intake. Eicosapentaenoic acid (EPA)-enriched enteral nutrition (EPA-EN) could modulate immune function and limits catabolism. In our phase III study to compare perioperative standard diet with or without EPA-EN, additional EPA-EN did not contribute to prevent weight loss or LBM. Recently, 5% or more LBM loss after surgery was reported to impair compliance of post-operative S-1 adjuvant chemotherapy. This post hoc study explored whether additional EPA-EN prevented meaningful loss of LBM for compliance of adjuvant chemotherapy after surgery. Methods: Key entry criteria of this phase III study was (1) histologically proven adenocarcinoma of the stomach, (2) clinical T1-T4a and M0, (3) R0 resection is possible by total gastrectomy, (4) sufficient oral intake, and (5) sufficient organ function. The patients were randomized to Group A: no supplementation with oral nutrients (standard diet) or Group B: standard diet with oral supplementation of ProSure including 600 kcal with 2.2 g EPA for 7 days before surgery and for 21 days after surgery. For both groups, patients underwent total gastrectomy with Roux-en Y reconstruction. Results: A total of 127 patients (Group A: 63, Group B: 64) were enrolled in the study. All background factors were well balanced between the both groups. Median relative performance of supplement in group B was 100% before surgery and 54% after surgery. 5% or more LBM loss at 1 month after surgery was observed in 44 patients (80.0%) in group A and in 37 patients (67.3%) in group B (p = 0.194), while that at 3 months after surgery was found in 51 patients (91.1%) in group A and in 43 patients (76.8%) in group B (p = 0.070). Conclusions: Perioperative standard diet with EPA-enriched enteral nutrition tended to prevent meaningful loss of LBM after total gastrectomy. Further analysis is required whether perioperative EPA enriched EN improve compliance of S-1 adjuvant chemotherapy after total gastrectomy. Clinical trial information: UMIN000006380.
Ambient Air Pollutant Exposures and Hospitalization for Kawasaki Disease in Taiwan: A Case-Crossover Study (2000–2010)
Authors: Chau-Ren Jung, Wei-Ting Chen, Yu-Ting Lin, Bing-Fang Hwang
Journal: Environmental Health Perspectives (2016)

Kawasaki disease (KD) is an acute and multi-systemic vasculitis that occurs predominantly in infants and young children. Although the etiological agent of KD remains unclear, limited studies have reported that windborne environmental factors may trigger KD.We conducted a time-stratified case-crossover study to assess the associations between air pollutants and KD in Taiwan.We identified children < 5 years old with a diagnosis of KD from the Longitudinal Health Insurance Database 2000 (LHID2000) between 2000 and 2010. We obtained data regarding carbon monoxide (CO), nitrogen dioxide (NO2), ozone (O3), particulate matter with aerodynamic diameter < 10 μm (PM10), and sulfate dioxide (SO2) from 70 monitoring stations and used inverse distance weighting to calculate average daily exposures for the residential postal code of each case. We performed conditional logistic regression to estimate associations between KD and each air pollutant according to interquartile range (IQR) increases and quartiles of exposure on the day of hospitalization versus 3-4 reference days during the same month for each case. Additionally, we estimated associations with single-day exposures lagged 1-2 days.We identified 695 KD hospital admissions during the study period. An IQR increase (28.73 ppb) of O3 was positively associated with KD after adjusting for temperature, humidity, northward wind, and eastward wind [adjusted odds ratio = 1.21; 95% confidence interval (CI): 1.01, 1.44]. There were no significant associations between KD and CO, NO2, PM10, or SO2. The association with O3 was limited to exposure on the day of hospitalization and to exposure during the summer months (June-August).Our results provide new evidence that exposure to O3 may increase the risk of KD in children. However, further investigation is needed to confirm the association and identify a potential biological mechanism.
Abstract LB-265: IRF8 is an essential transcriptional activator of iNOS although MDSCs up-regulate iNOS expression via an IRF8-independent mechanism
Authors: Mohammed M. Ibrahim, Amy V. Paschall, Priscilla S. Redd, Kebin Liu
Journal: Cancer Research (2016)

Abstract Nitric Oxide Synthase (NOS) is a family of enzymes that catalyzes L-arginine metabolism to generate nitric oxide (NO). There are three main isoforms of NOS, named neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS or NOS2). These three distinct isoforms of NOS have different cellular localization, regulation, and catalytic properties. iNOS is the most extensively studied one among these three NOS isoforms. iNOS was originally identified in myeloid cells, and it is known that its expression is often induced after myeloid cell activation by endotoxins or cytokines to generate NO which then acts as a defense effector to suppress invading microorganisms or neoplastic cells. It is known that IFNγ signaling pathway and NF-κB synergistically regulate iNOS expression, and that IFN regulatory factor 8 (IRF8) enhances interaction between IFNγ signaling and NF-κB in regulation of iNOS expression. However, the molecular mechanism underlying iNOS expression regulation in myeloid cell lineage is still not fully understood. We report here that IRF8 is an essential transcription activator of iNOS in myeloid cells since IRF8-deficient myeloid cells lose iNOS expression. Furthermore, a key phenotype of IRF8 KO mice is the mass accumulation of CD11b+Gr1+ myeloid-derived suppressor cells (MDSCs), suggesting that IRF8 is a key suppressor of MDSC differentiation under physiological conditions. On the other hand, accumulation of MDSCs is a hallmark of cancers and iNOS expression is dramatically elevated in tumor-induced MDSCs, despite that tumor-induced MDSCs exhibit diminished IRF8 expression. Furthermore, the IFNγ signaling pathway is impaired and NF-κB subunits are undetectable in tumor-induced MDSCs. Our data therefore indicate that iNOS expression is activated by an IRF8-independent mechanism that is also IFNγ and NF-κB-independent in tumor-induced MDSCs under pathological conditions. At the functional level, we determined that iNOS-KO mice exhibit lower tumor incidence as compared to WT mice. However, the sizes of established tumors are not different between iNOS-KO mice and WT mice. Taken together, our data determine that IRF8 is an essential transcriptional activator of iNOS expression in myeloid cells under physiological conditions, although iNOS expression is activated by an IFNγ-, NF-κB-, and IRF8-independent mechanism in tumor-induced MDSCs under pathological conditions. iNOS acts as a suppressor of tumor cell colonization but not tumor growth. Citation Format: Mohammed M. Ibrahim, Amy V. Paschall, Priscilla S. Redd, Kebin Liu. IRF8 is an essential transcriptional activator of iNOS although MDSCs up-regulate iNOS expression via an IRF8-independent mechanism. [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-265.
Abstract 4318: Reversal of BRCA-1 CpG hyperthylation by genistein and (-)-epigallocatechin-3-gallate in human breast cancer cells with activated AhR
Authors: Ornella I. Selmin, Andreas J. Papoutsis, Donato F. Romagnolo
Journal: Cancer Research (2016)

Abstract Sporadic breast cancers, which represent the vast majority (∼90%) of breast tumor cases, do not have mutations in the tumor suppressor gene, BRCA-1 but have absent or markedly reduced levels of BRCA-1 similar to those observed in hereditary BRCA-1 tumors. Therefore, understanding the non-mutational mechanisms that contribute to repression of BRCA-1 has important implications for the prevention of both hereditary and sporadic breast tumors. Agonists of the aromatic hydrocarbon receptor (AhR) are ubiquitous in the environment and include dietary compounds, metabolites of fatty acids, industrial pollution, and photoproducts generated in the skin from ultraviolet radiation. In cultured estrogen-receptor (ER)α-positive MCF-7 breast cancer cells, we found that activation of the AhR with the prototype ligand 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) repressed by 50% estradiol-induced BRCA-1 expression. Conversely, the post-treatment with the soy isoflavone genistein and tea (-)-epigallocatechin-3-gallate (EGCG) at physiological doses (1 μM) rescued within 24 to 48 h BRCA-1 expression to levels ∼2.0 to 3.0-fold higher than those measured in cells treated with estradiol alone. Genistein and EGCG reversed BRCA-1 promoter hypermethylation in AhR-activated MCF-7 cells. In ERα-negative and AhR-overexpressing UACC-3199 breast cancer cells, genistein (1 μM) reactivated BRCA-1 expression. The post-treatment of AhR-activated MCF-7 cells with genistein and EGCG antagonized the recruitment of DNA-methyl transferase-1 (DNMT-1) enzyme to the BRCA-1 promoter. These results suggest the involvement of epigenetic mechanisms in the repression of BRCA-1 and reversal effects of genistein and EGCG against breast tumorigenesis associated with activation of the AhR. Citation Format: Ornella I. Selmin, Andreas J. Papoutsis, Donato F. Romagnolo. Reversal of BRCA-1 CpG hyperthylation by genistein and (-)-epigallocatechin-3-gallate in human breast cancer cells with activated AhR. [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 4318.