tbuckley/cabot-search huggingface dataset:
Abstract 3355: Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating cells
Authors: Lovisa Lundholm, Petra Hååg, Mina Eriksson, Beata Brzozowska, Rolf Lewensohn, Andrzej Wojcik, Kristina Viktorsson
Journal: Cancer Research (2016)

Abstract Tumors are suggested to be highly responsive to epigenetic alterations such as histone modifications and DNA methylation. We have previously reported a resistant phenotype of sphere-forming non-small cell lung cancer (NSCLC) tumor initiating cells (TICs) with an impaired activation of DNA-damage response proteins. Here we set out to analyze chromatin compactness since a heterochromatic structure has been postulated to constitute a barrier to DNA damage and repair. We show that certain NSCLC and small cell lung cancer (SCLC) TICs have elevated levels of the heterochromatin markers heterochromatin protein 1γ (HP1γ) and trimethylated lysine 9 of histone 3 (H3K9me3). Chromatin modulators were tested and histone deacetylase inhibitors (HDACi) vorinostat, panobinostat and trichostatin A reduced the cell viability of NSCLC TICs compared to bulk cells after 72 h. We could also demonstrate that TICs are more responsive to HDAC inhibitors since the euchromatin marker acetylated lysine 8 of histone H4 (H4K8ac) was increased after vorinostat and trichostatin A in NSCLC TICs but not in bulk cells. Pretreatment with HDACi inhibitors sensitized NSCLC TICs to cisplatin and ionizing irradiation. Accordingly, pretreatment with vorinostat increased the phosphorylation of the DNA-damage response proteins ataxia telangiectasia mutated (ATM) and DNA-dependent protein kinase (DNA-PK) upon irradiation in NSCLC TICs, whereas bulk cells already had a higher level with radiation only. In conclusion, we demonstrate that lung cancer TICs display a heterochromatic structure compared to bulk cells and that NSCLC TICs have an enhanced sensitization upon DNA damage inflicted by cisplatin or radiation after HDACi pretreatment. Citation Format: Lovisa Lundholm, Petra Hååg, Mina Eriksson, Beata Brzozowska, Rolf Lewensohn, Andrzej Wojcik, Kristina Viktorsson. Opening up heterochromatin by histone deacetylase inhibition improves response to DNA damage in lung cancer tumor initiating 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 3355.
Abstract 547: Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer
Authors: Sven H. Petersen
Journal: Cancer Research (2016)

Abstract Apart from the cytotoxic effect of radiation- or chemotherapy it has become evident that these treatments are able to induce an immune response which can play an additional and pivotal role in clearing tumours. This treatment-induced immunogenic tumour cell death (ICD) enables the host's immune system to recruit to the tumour and recognise and kill tumour cells which can even extend to yet untreated metastases, a phenomenon called “abscopal effect”. For the first time, we found evidence that radiation and/or chemo-treatment stimulates a pronounced up-regulation of both, PD-L1 and Galectin-9 on pre-apoptotic and apoptotic gastric tumour cells. Both these proteins exert immuno-modulatory signals which in turn may dampen the aimed immunogenicity of the treatment. PD-L1, which is the ligand to programmed cell death protein 1 (PD1) on T cells, and its upregulation is commonly used by cancer cells to evade immunity. PD-L1 causes T cell apoptosis and hence an inhibition of T cell driven anti-tumour immunity. Galectin-9 exerts immunoinhibitory functions and is, together with the immunostimulatory molecule HMGB1, a competitive binding partner for the receptor T-cell immunoglobulin domain and mucin domain 3 (Tim-3). Once engaged by its ligand, Tim-3 either exerts stimulatory or inhibitory effects, depending on ligand, cell type, maturation state and Tim-3 expression rate. Together with PD-L1, Galectin-9 enables a complex interplay between cancer cells and cells of the adaptive immune response expressing PD1 and Tim-3. Based on these results, we are investigating the mechanism responsible for PD-L1 and Galectin-9 upregulation and the effect on the efficacy of radio- as well as chemotherapy on tumour eradication. Additionally, due to their potentially enhancing effect on anti-tumour immunity, we are studying the therapeutic value of blocking Abs specific for human PD1 and/or Tim-3 in cancer immunotherapy. Citation Format: Sven H. Petersen. Radio- and chemotherapy causes up-regulation of immunoinhibitory ligands pd-l1 and galectin-9 in gastric cancer. [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 547.
Paired Exome Analysis Reveals Clonal Evolution and Potential Therapeutic Targets in Urothelial Carcinoma
Authors: Philippe Lamy, Iver Nordentoft, Karin Birkenkamp-Demtröder, Mathilde Borg Houlberg Thomsen, Palle Villesen, Søren Vang, Jakob Hedegaard, Michael Borre, Jørgen Bjerggaard Jensen, Søren Høyer, Jakob Skou Pedersen, Torben F. Ørntoft, Lars Dyrskjøt
Journal: Cancer Research (2016)

Greater knowledge concerning tumor heterogeneity and clonality is needed to determine the impact of targeted treatment in the setting of bladder cancer. In this study, we performed whole-exome, transcriptome, and deep-focused sequencing of metachronous tumors from 29 patients initially diagnosed with early-stage bladder tumors (14 with nonprogressive disease and 15 with progressive disease). Tumors from patients with progressive disease showed a higher variance of the intrapatient mutational spectrum and a higher frequency of APOBEC-related mutations. Allele-specific expression was also higher in these patients, particularly in tumor suppressor genes. Phylogenetic analysis revealed a common origin of the metachronous tumors, with a higher proportion of clonal mutations in the ancestral branch; however, 19 potential therapeutic targets were identified as both ancestral and tumor-specific alterations. Few subclones were present based on PyClone analysis. Our results illuminate tumor evolution and identify candidate therapeutic targets in bladder cancer. Cancer Res; 76(19); 5894-906. ©2016 AACR.
Abstract 4461: Epigenetics in doxorubicin and docetaxel-resistant triple negative breast cancer
Authors: Terra Sztain, Helena Chang
Journal: Cancer Research (2016)

Abstract Triple negative breast cancers (TNBC) do not express estrogen receptor, progesterone receptor, or Her2/neu hence there are no targeted therapies for this type of breast cancer. Chemotherapy is the systemic treatment option with doxorubicin and docetaxel being the two most commonly used drugs. It is well known drug resistance can lead to treatment failure in these patients. It is therefore essential to uncover information on the mechanism of these resistance pathways, and identify novel molecular markers for developing potential pathway driven treatment. Our previous studies have shown that genes, ataxia telangiectasia mutated (ATM), TGF-β, Bcl-2, NDRG1 and NDRG2 are closely related to cancer stem cell marker CD24 expression, and drug resistance toward doxorubicin and docetaxel in TNBC. In this study, two TNBC cell lines HCC1806 and HCC1937 were epigenetically examined by ChIP-qPCR. The gene promoters of the above five genes, within a 1kb range were analyzed. Results showed that both drugs significantly decreased total Histone 3 quantity, which is representative of total nucleosome density, at ATM and TGFB1 promoters, and additionally doxorubicin at NDRG1 promoter. Doxorubicin also decreased histone acetylation and methylation of H3K9 significantly at NDRG1 and consistently at the other gene promoters, while docetaxel showed consistent increase of methylation at H3K9. Results suggest that treatment with the two drugs affects an epigenetic pathway involving one or several epigenetic cofactors (methyltransferases, acetyltransferases, nucleosome remodeling complexes, etc.). Elucidating this pathway may provide valuable information for the treatment of TNBC. Citation Format: Terra Sztain, Helena Chang. Epigenetics in doxorubicin and docetaxel-resistant triple negative breast cancer. [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 4461.
The awareness of depression and anxiety in cancer patients.
Authors: Yu-qing Wang, Yu Jiang, Di Luo, Ying Wang, Ke Xu, Yao-tiao Deng, Jie Zhang, Hui-ping Chen, Bo Zheng, Boyan Huang, Xiang-yu Xia
Journal: Journal of Clinical Oncology (2016)

e21550 Background: Depression and anxiety is prevalent among cancer patients and show serious impact. This study was conducted to investigate the knowledge of and attitude to depression and anxiety in cancer patients, and to explore demographic characteristics associated with it. Methods: In the cross-sectional study, 226 cancer patients completed the hoc designed questionnaire including demographic characteristics and two vignette describing DSM-V major depression and generalized anxiety. Seven questions were attached to each vignette. Results: 73.01% of patients recognized depression as mental disorder, influenced by residence (P= 0.019, country vs city) and educational level (P= 0.014, primary vs advanced, P= 0.019, middle vs advanced) in multivariate logistic regression, while 82.30% for anxiety. 34.55% of patients specifically indentified depression vignette as depression, influenced by age (P= 0.02, middle vs older), residence (P= 0.014, country vs city, P= 0.020, town vs city), educational level (P= 0.018, middle vs advanced) and existence of religious (P= 0.022), while 49.23% for anxiety influenced by educational level (P= 0.04, middle vs advanced) only. The percentage of patients who see the necessity to seek treatment from the doctor was 38.74% for depression and 32.31% for anxiety. Educational level (P= 0.039, middle vs advanced) influenced the result for depression while none for anxiety. 4.19% of patients held discrimination for depression influenced by sex (P= 0.007) and source of medical costs (P= 0.013), while 2.05% for anxiety influenced only by sex (P= 0.001). 77.98 % of patients thought that patients with depression could receive chemotherapy and 76.45% for anxiety being influence by residence (P= 0.024, town vs city).78.7% patients thought they would be influenced by their ward-mate with depression while 74.4% for anxiety.62.1% of the patients thought they would tell the doctor about the depression of their ward-mate, influence by existence of religious faith (P= 0.043) while 67.91% for anxiety, influenced by residence (P= 0.024, town vs city). Conclusions: Lack of correct knowledge about depression and anxiety is highly prevalent among cancer patients. Measures should be taken to improve the current situation.
Abstract 2881: Deubiquitinase Usp9x controls tumorigenicity through regulation of the Ets-1 transcription factor in melanoma
Authors: Harish Potu, Luke F. Peterson Peterson, Malathi Kandarpa Kandarpa, Anupama Pal Pal, Hanshi Sun Sun, Paul W. Harms Harms, Peter C. Hollenhorst Hollenhorst, Ugur Eskiocak Eskiocak, Moshe Talpaz Talpaz, Nicholas J. Donato Donato
Journal: Cancer Research (2016)

Abstract Transcription factors are frequently deregulated in cancer cells and may be good therapeutic targets, but few successful targeting strategies have been reported. Deubiquitinases (DUBs) are specialized enzymes that regulate the ubiquitin (Ub) content on many proteins and DUB expression and activity are elevated in a number of cancers where they can act to alter tumor suppressor and/or oncoprotein levels. We previously described Usp9x activity and expression in melanoma; here we sought to investigate its role in primary melanoma and metastatic disease. Usp9x was upregulated in tumor cells compared to normal melanocytes and Usp9x expression and activity were found to be essential for 3D growth and melanoma tumor expansion in vivo. We defined the Usp9x ubiquitinated protein landscape and demonstrate that Usp9x regulates Ets-1, a cancer-promoting transcription factor. Usp9x binds, deubiquitinates and thereby stabilizes Ets-1 protein, and primary tissue and tumor analysis demonstrated elevated and coincident Usp9x/Ets-1 protein expression in melanoma compared to normal skin or benign nevi. Usp9x knockdown or Usp9x inhibition with small molecule G9 reduced Ets-1 protein levels and blocked tumor growth in vitro and in vivo. Conversely, Usp9x overexpression in melanoma cells increased Ets-1 protein levels and enhanced 3D tumor growth in vitro and in vivo, which were all reversible by treatment with G9. We conclude that Usp9x is essential for Ets-1 protein stability and may be therapeutically exploited with small molecule Usp9x inhibitors to reduce Ets-1-dependent gene expression and tumorigenicity. Citation Format: Harish Potu, Luke F. Peterson Peterson, Malathi Kandarpa Kandarpa, Anupama Pal Pal, Hanshi Sun Sun, Paul W. Harms Harms, Peter C. Hollenhorst Hollenhorst, Ugur Eskiocak Eskiocak, Moshe Talpaz Talpaz, Nicholas J. Donato Donato. Deubiquitinase Usp9x controls tumorigenicity through regulation of the Ets-1 transcription factor in melanoma. [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 2881.
Abstract 2652: Pan-cancer analysis of programmed death-ligand 1 (PD-L1) amplifications
Authors: Jan Budczies, Michael Bockmayr, Frederick Klauschen, Wilko Weichert, Carsten Denkert, Albrecht Stenzinger
Journal: Cancer Research (2016)

Abstract PD-L1, located in the chromosomal region 9p28, is a ligand of programmed cell death protein 1 (PD-1) and has been described as immune checkpoint regulator that allows cancers to evade the host immune system. To stratify patients for treatment with PD-1 inhibitors, PD-L1 expression is currently intensively studied on RNA and protein levels. However, no comprehensive study of PD-L1 amplifications including many cancer types has been performed so far. We investigated PD-L1 amplifications in eighteen cancer types that were copy number profiled, gene expression profiled and clinically characterized by the TCGA consortium: Acute Myeloid Leukemia (LAML), Bladder Urothelial Carcinoma (BLCA), Brain Lower Grade Glioma (LGG), Breast invasive carcinoma (BRCA), Cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), Colorectal adenocarcinoma (COADREAD), Glioblastoma multiforme (GBM), Head and Neck squamous cell carcinoma (HNSC), Kidney renal clear cell carcinoma (KIRC), Liver hepatocellular carcinoma (LIHC), Lung adenocarcinoma (LUAD), Lung squamous cell carcinoma (LUSC), Ovarian serous cystadenocarcinoma (OV), pancreatic adenocarcinoma (PAAD), Sarcoma (SARC), Skin Cutaneous Melanoma (SKCM), Stomach adenocarcinoma (STAD) and Uterine Corpus Endometrial Carcinoma (UCEC). We found a diverse landscape of focal PD-L1 amplification, 9p chromosome arm amplifications and polysomy 9. Focal amplifications had the highest incidence in OV (10.7%), LUSC (9.8%), HNSC (8.6%), BLCA (8.3%), SARC (8.2%), CESC (7.1%), STAD (6.8%) and BRCA (5.3%). 9p amplifications were most frequently found in OV (12.6%), BLCA (7.4%), BRCA (6.8%) and LUAD (5.2%). Polysomy 9 had the highest incidence in COADREAD (14.0%), HNSC (13.6%), CESC (11.2%), SARC (9.4%) and STAD (7.2%), BLCA (5.9%) and GBM (5.5%). In a pooled analysis of focal and non-focal alterations, PD-L1 amplifications positively correlated with gene expression in nine cancer types and significantly (p &amp;lt; 0.05) shortened overall survival in five cancer types. In summary, PD-L1 amplifications represent a frequent genetic alteration that occurs in many cancer types and could potentially be exploited for patient stratification and immune therapy. Citation Format: Jan Budczies, Michael Bockmayr, Frederick Klauschen, Wilko Weichert, Carsten Denkert, Albrecht Stenzinger. Pan-cancer analysis of programmed death-ligand 1 (PD-L1) amplifications. [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 2652.
Abstract 2657: Target specificity of epigenetic therapy in cancer
Authors: Takahiro Sato, Matteo Cesaroni, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J. Issa
Journal: Cancer Research (2016)

Abstract A major question facing the use of epigenetic therapies in cancer is specificity in modulating gene expression. In addition, combined targeting of DNA and histone methylation remains largely unexplored despite the promising synergistic effects observed from combining DNA methyltransferase inhibitors with HDAC inhibitors. To address these questions, we performed RNA-seq, DNA methylation analysis and ChIP-seq (H3K4me2, H3K9me2, and H3K27me3) to study the effects of inhibitors of DNA methyltransferases (DAC), histone deacetylases (Depsi), histone demethylases (KDM1A inhibitor S2101), and histone methylases (EHMT2 inhibitor UNC0638 and EZH2 inhibitor GSK343) in three different cancer models (colon cancer, breast cancer, and leukemia). In colon cancer cells (YB5), DAC affected 3% of the transcriptome and 93% of the effect was gene upregulation. DAC had a greater effect on genes expressed in normal tissues and silenced in cancer (443 genes) compared to genes that do not change in cancer (194 genes). 90% of DAC targets genes showed no promoter DNA methylation in normal colon but gained methylation in cancer. Depsi changed the expression of 35% of the transcriptome and showed little specificity for gene upregulation or silenced genes. S2101, UNC0638, and GSK343 had limited effects on their own (&amp;lt;1.5% of the transcriptome), but UNC0638 and GSK343 preferentially targeted genes with H3K9me2 or H3K27me3, respectively. DAC combined with histone methylation inhibitors led to synergistic gene upregulation while still maintaining specificity for DNA methylated and silenced genes. These synergistic genes had limited overlap, indicating the possibility to target distinct sets of genes based on different epigenetic therapy combinations. IPA analysis demonstrated that these genes are enriched in cancer pathways, and consistent with this analysis, the combination therapies were able to decrease cancer cell proliferation more effectively than monotherapy. Broadly similar results were seen with genome wide studies in both breast cancer (MCF7) and leukemia (HL-60) cells. These results demonstrate that DNA methyltransferase inhibitors preferentially target cancer relevant genes, and can be combined with inhibitors targeting histone methylation for synergistic effects while still maintaining specificity. Citation Format: Takahiro Sato, Matteo Cesaroni, Shoghag Panjarian, Anthony Tran, Jozef Madzo, Yasuyuki Okamoto, Hanghang Zhang, Xiaowei Chen, Jaroslav Jelinek, Jean-Pierre J. Issa. Target specificity of epigenetic therapy in cancer. [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 2657.
Abstract 570: Long-term efficacy and downstream mechanism of anti-Annexin A2 monoclonal antibody in a pre-clinical model of aggressive human breast cancer
Authors: Mahesh C. Sharma, George P. Tuszynski, Marc R. Blackman, Meena Sharma
Journal: Cancer Research (2016)

Abstract Abstract: There are considerable direct evidences to support that calcium binding protein ANX A2 is a potential target for aggressive breast cancer. The most compelling evidence is based on the fact that ANX A2 overexpress specifically in aggressive triple negative human breast cancer (TNBC) cell lines as well as in human breast cancer tissues. Previously, we and others have demonstrated a unique role of ANX A2 in cancer invasion including breast cancer. Moreover we demonstrated that anti-ANX A2 monoclonal antibody (anti-ANX A2mAb)-mediated immunoneutralization of ANX A2 inhibited invasive human breast growth in a xenograft model. We further evaluated long-term effect of multiple treatments of anti-ANX A2mAb and its mechanism of inhibition of human breast tumor growth. We now show that three treatments of anti-ANX A2mAb showed significant inhibition of breast tumor growth in immunodeficient mice and anti-tumor response was started from day 94. After treatments, we followed tumor growth for 172 days and our results demonstrated 67% inhibition of tumor growth without detectable adverse effects. Biochemical analysis demonstrated anti-ANX A2mAb treatment caused significant inhibition of tissue plasminogen activator (tPA) synthesis in the tumor microenvironment. This led to disruption of plasmin generation that consequently inhibited activation of MMP-9 and MMP-2. These results suggest that ANX A2 plays an important role in aggressive breast tumor growth by regulating proteolytic pathway in the tumor microenvironment. ANX A2 may represent a new target for the development of therapeutics for the treatment of aggressive breast cancer. Citation Format: Mahesh C. Sharma, George P. Tuszynski, Marc R. Blackman, Meena Sharma. Long-term efficacy and downstream mechanism of anti-Annexin A2 monoclonal antibody in a pre-clinical model of aggressive human breast cancer. [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 570.
Abstract 1370: A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application
Authors: Chi-Kuan Chen.
Journal: Cancer Research (2016)

Abstract Background: Determining RAS mutation status is considered as prognostic factor for colorectal cancer patients in anti-epidermal growth factor receptor (EGFR) antibody therapy. Because genetic testing remains costly and time-consuming, it is necessary to develop mutation specific antibody for immunological analysis. However RAS G12D mutation antibody for immunohistochemical (IHC) staining is not available. Results: Here we report a novel RAS G12D rabbit polyclonal antibody (GTX132407) for immunochemistry (IHC) testing, which was developed by cooperating with GeneTex In. Based on analyzing 15 clinical colorectal cancer specimens, the result of IHC staining using RAS G12D mutation specific antibody (GTX132407) was correlated with genetic testing of RAS G12D mutation using ultra-sensitive total RAS mutation screen kit [Hong Jing Biotechnology Inc. (FemtoPath)]. Conclusion: In summary, the result showed that IHC testing with RAS G12D specific mutation antibody could be a reliable tool for predicting RAS genetic mutation status. Citation Format: Chi-Kuan Chen. A new RAS G12D specific rabbit polyclonal antibody for immunohistochemical FFPE application. [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 1370.
TRANSFUSION OF LEUKOCYTE-DEPLETED RED BLOOD CELLS IS INDEPENDENTLY ASSOCIATED WITH INCREASED MORBIDITY AFTER PAEDIATRIC CARDIAC SURGERY
Authors: F. Grotenhuis, R. Berger, T. Ebels, H. Burgerhof, M. Albers, M.C.J. Kneyber, Johannes Burgerhof
Journal: Intensive Care Medicine (2011)