bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 710: The efficacy of tumor-targeting Salmonella typhimurium A1-R on bone metastasis
Authors: Miwa Shinji , Zhao Ming , Yano Shuya , Zhang Yong , Uehara Fuminari , Matsumoto Yasunori , Hiroshima Yukihiko , Yamamoto Mako , Kimura Hiroaki , Hayashi Katsuhiro , Tsuchiya Hiroyuki , Hoffman Robert M. 
Published: May 2015

Abstract
We have previously developed a genetically-modified bacterial strain of Salmonella typhimurium (A1-R), which expresses GFP. In this study, we measured the efficacy of A1-R on breast cancer bone metastasis. We established an early-stage bone-metastasis model in nude mice by cardiac injection and a late-stage model by injection into the intramedullary cavity of the tibia using MDA-MB-435 human breast cancer cells (Human breast cancer cell lines co-express neuronal, epithelial, and melanocytic differentiation markers in vitro and in vivo. PLoS One 5, e9712, 2010). Both mouse models of bone metastasis were treated with A1-R. Fluorescence imaging of the mice was performed to visualize the metastatic bone lesions. In a first set of experiments, we showed that A1-R invaded and replicated intracellularly in MDA-MB-435-GFP cells in vitro. A1-R dose-dependently inhibited proliferation of MDA-MB-435-GFP cells. In the early-stage bone-metastasis model, A1-R significantly improved metastasis-free survival. In the advanced-stage bone-metastasis model, A1-R significantly inhibited the growth of the metastatic lesions. These data indicated that A1-R is useful to prevent and inhibit the growth of metastatic breast cancer bone tumors.
Citation Format: Shinji Miwa, Ming Zhao, Shuya Yano, Yong Zhang, Fuminari Uehara, Yasunori Matsumoto, Yukihiko Hiroshima, Mako Yamamoto, Hiroaki Kimura, Katsuhiro Hayashi, Hiroyuki Tsuchiya, Robert M. Hoffman. The efficacy of tumor-targeting Salmonella typhimurium A1-R on bone metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 710. doi:10.1158/1538-7445.AM2014-710
Abstract 716: ASPH_0047: a potent and selective antisense oligonucleotide-targeting transforming growth factor beta 2 (TGF-β2)
Authors: Wosikowski Katja , Jaschinski Frank , Kohonen Hanna , Braun Stephan , Leo Eugen , Janicot Michel 
Published: May 2015

Abstract
Transforming growth factor beta (TGF-β) is a key member of a large family of cytokines, including bone morphogenetic protein (BMP), nodals, activins and others, which play critical, pleiotropic roles in the pathophysiology of various human diseases, such as cancer, inflammation, autoimmune disease, and cirrhosis/fibrosis. In particular, the different TGF-β isoforms (TGF-β1, -β2, and -β3, encoded by different genes but sharing high sequence and structure homology) are overexpressed in many human tumors. Correlations between TGF-β expression, cancer stage and clinical parameters have been reported and linked to poor clinical outcome. TGF-β has been associated with a wide range of tumor-promoting processes, including tumor cell invasion and migration, angiogenesis, immunosuppression, as well as tumor stem cell maintenance and protection. Therefore, blocking the TGF-β signaling pathway via inhibition of TGF-β expression appears as an attractive therapeutic intervention in Oncology.
We have previously reported the rational design and preliminary outcome of an extensive discovery program for identification of antisense oligodeoxynucleotides targeting the various TGF-β isoforms. We present here ASPH_0047, a 17-mer LNA-modified gapmer based on the sequence of the human TGF-β2 mRNA, as novel preclinical development candidate. ASPH_0047 shows potent and selective target downregulation (mRNA and protein) in various cell-based assays. Preliminary preclinical biodistribution studies in rodent point at tissue penetration in expected target organs (e.g., liver, kidney, spleen) and accumulation in tumor tissue consistent with observed target downregulation and efficacy in relevant in vivo experimental antitumor models. Key pharmacology properties and preclinical features of ASPH_0047 supporting rapid advancement to clinical development will be presented.
Citation Format: Katja Wosikowski, Frank Jaschinski, Hanna Kohonen, Stephan Braun, Eugen Leo, Michel Janicot. ASPH_0047: a potent and selective antisense oligonucleotide-targeting transforming growth factor beta 2 (TGF-β2). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 716. doi:10.1158/1538-7445.AM2014-716
Abstract 727: Does gene transfer of gulono-lactone oxidase into human hepatocellular carcinoma cells restore ascorbate biosynthesis
Authors: Flett Teresa , Campbell Elizabeth , Phillips Elisabeth , Vissers Margreet CM , Dachs Gabi U. 
Published: May 2015

Abstract
Humans are unable to synthesise ascorbate (vitamin C) due to a mutation in the gene for gulono-lactone oxidase (Gulo), the terminal enzyme in the synthesis pathway. Ascorbate is a vital micronutrient required for many biological functions, including its action as a vital cofactor for Cu- and Fe-containing enzymes. As enzyme cofactor for HIF-hydroxylases, it is important for the regulation of hypoxia-inducible factor-1 (HIF-1), which governs cancer growth and spread. A lack of ascorbate increases both the level and activity of HIF-1 in cell culture.
This study aimed to restore ascorbate synthesis to human cells and to determine the effect of intracellular ascorbate biosynthesis on HIF-1 levels. HepG2 cells were gene modified using Lipofectamine LTX with a plasmid encoding the mouse Gulo cDNA and a control plasmid encoding the green fluorescent protein (GFP). Modified HepG2 cells were tested for genomic incorporation by PCR, for Gulo enzyme production by Western blotting, and ascorbate synthesis by high performance liquid chromatography with electrochemical detection (HPLC-ECD). Protein levels of HIF-1alpha in hypoxic cells were measured by Western blot analysis.
Parental HepG2 cells accumulated a mean of 120 nmol ascorbate per 1 million cells when loaded for 24h with 0.5 mM ascorbate. Gene-modified HepG2Gulo cells demonstrated a change in morphology and an increase in adherence, compared to HepG2GFP and parental HepG2 cells. A PCR-positive stable clone was able to synthesise ascorbate but only when the Gulo substrate, L-gulono-1,4-lactone, was supplied. Intracellular ascorbate levels then reached 5% of saturation levels. Hypoxic HIF-1 accumulation was reduced by addition of gulonolactone to this clone. However, gulonolactone also reduced HIF-1 levels in parental HepG2 cells, suggesting that it may similarly act as cofactor for the HIF-hydroxlases.
This study indicated that the ascorbate biosynthesis pathway in human cells is significantly modified and may contain numerous non-functional members besides gulono-lactone oxidase. Future biochemical studies will determine which other enzymes are non-functional.
Citation Format: Teresa Flett, Elizabeth Campbell, Elisabeth Phillips, Margreet CM Vissers, Gabi U. Dachs. Does gene transfer of gulono-lactone oxidase into human hepatocellular carcinoma cells restore ascorbate biosynthesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 727. doi:10.1158/1538-7445.AM2014-727
Abstract 742: Antitumor activity of Trametinib, a MEK1/2 inhibitor, in malignant pleural mesothelioma cells in vitro
Authors: Cho Hiroyuki , Matsumoto Seiji , Fujita Yoshiko , Kuroda Ayumi , Hashimoto Masaki , Takuwa Teruhisa , Menju Toshi , Sonobe Makoto , Kondo Nobuyuki , Date Hiroshi , Hasegawa Seiki 
Published: May 2015

Abstract
Introducion: Malignant pleural mesothelioma (MPM) is a highly aggressive malignancy and there is no approved targeted therapy. The MAPK pathway plays critical roles in the regulation of cell proliferation, growth, differentiation, and survival in multiple solid tumors, including MPM. Trametinib, a selective MEK inhibitor, have a survival benefit in patients with V600 BRAF-mutant metastatic melanoma. FDA approved Trametinib for these patients in May 2013. The effect of Trametinib in MPM cells has not been well studied.
Purpose: We examined the effects of Trametinib in MPM cells in vitro.
Methods: To examine the effect of Trametinib on the proliferation of MPM cells, we performed cell proliferation assay using four MPM cell lines, NCI-H2452, NCI-H226, NCI-H2052 and MSTO-211H. To examine the effect of Trametinib on intracellular signaling, we performed Western blot analysis in NCI-H226 cell line.
Results: Trametinib exhibited potent antiproliferative activity in all four MPM cell lines with IC50 values ranging from 0.5 μM to 44 μM. Trametinib blocked the phosphorylation of ERK until 72 hours and decreased the expression of CD44 in a dose-dependent manner. In addition, the expression of CD44 was inhibited (48-72 hours) after the suppression of ERK phosphorylation by Trametinib.
Conclusions: Our results suggest that Trametinib is a promising therapeutic agent for MPM.
Citation Format: Hiroyuki Cho, Seiji Matsumoto, Yoshiko Fujita, Ayumi Kuroda, Masaki Hashimoto, Teruhisa Takuwa, Toshi Menju, Makoto Sonobe, Nobuyuki Kondo, Hiroshi Date, Seiki Hasegawa. Antitumor activity of Trametinib, a MEK1/2 inhibitor, in malignant pleural mesothelioma cells in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 742. doi:10.1158/1538-7445.AM2014-742
Abstract 745: A non-redox reactive allosteric inhibitor of MAPK phosphatases with selective toxicity to human cancer cells
Authors: Vollmer Laura , Vernetti Lawrence , Bakan Ahmet , Korotchenko Vasiliy , Bahar Ivet , Day Billy , Tsang Michael , Vogt Andreas 
Published: May 2015

Abstract
Mitogen-activated protein kinase phosphatases (MKPs) are members of a family of dual specificity phosphatases (DUSPs) that regulate cellular signaling homeostasis by dephosphorylating mitogen-activated kinases, key mediators of cell death and survival. The archetype MKP, DUSP1 (also termed MKP-1/CL100), is overexpressed in ovarian, breast, and prostate cancers and found elevated in the “oncogenic signature” of RAS mutant tumor cells. DUSP1 mediates cancer cell migration and invasion, and protects cells from apoptosis by clinically used antineoplastic agents and gamma-irradiation. Despite the evidence that DUSP1 is a promising anticancer target, efforts to discover small molecule inhibitors have been largely unsuccessful. The MKP active site is shallow and contains a catalytic cysteine that is sensitive to oxidation. Hence, prior discovery screens have mostly identified redox-reactive structures with promiscuous biological activities. Using a zebrafish chemical screen, we recently discovered a new DUSP inhibitory chemotype that has no redox-reactive structural features and that is thought to bind to an allosteric site adjacent to the catalytic cavity. Structure-activity relationship studies in transgenic zebrafish identified an analog (VNK-215) that retained DUSP1 and DUSP6 inhibitory activity but was well tolerated by the developing embryo. Here we hypothesized that VNK-215 could be selectively cytotoxic to cancer cells due to its ability to inhibit DUSP1 and lack of redox-reactive features. We found that in MDA-MB-231 human breast cancer cells, VNK-215 had apoptotic and antimigratory activity at concentrations that inhibited DUSP1 in mammalian cells, and induced phosphorylation of the DUSP1 substrates ERK, p38, and JNK. Studies in primary rat hepatocytes and live zebrafish embryos revealed that VNK-215, unlike previously described DUSP inhibitors, did not induce reactive oxygen species, mitochondrial damage, or toxicity. Our data suggest that the promiscuous activities of existing DUSP inhibitors are the cause of redox reactivity rather than target inhibition, and posit that DUSP1 is a druggable anticancer target for small molecule allosteric inhibitors.
Citation Format: Laura Vollmer, Lawrence Vernetti, Ahmet Bakan, Vasiliy Korotchenko, Ivet Bahar, Billy Day, Michael Tsang, Andreas Vogt. A non-redox reactive allosteric inhibitor of MAPK phosphatases with selective toxicity to human cancer cells. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 745. doi:10.1158/1538-7445.AM2014-745
Abstract 755: Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in glioblastoma and colorectal cancer
Authors: Rzymski Tomasz , Szajewska-Skuta Malgorzata , Zarebski Adrian , Sitarz Kamil , Sapala Lukasz , Zurawska Malgorzata , Salwinska Magdalena , Windak Renata , Trebacz Ewa , Daniel-Wojcik Joanna , Obuchowicz Radoslaw , Winnik Bozena , Wincza Ewelina , Kulesza Urszula , Kucwaj-Borysz Katarzyna , Milik Mariusz , Dreas Agnieszka , Brzozka Krzysztof 
Published: May 2015

Abstract
Herewith, we report development of small molecule inhibitors of MNK1 and MNK2 kinases and their cellular activity. MNK1 and 2 are MAP kinase-interacting kinases that are activated by RAS and MAPK signaling pathways and are involved in regulation of translation. Both kinases phosphorylate translation initiation factor eIF4e on a conserved serine 209 residue. eIF4E can contribute to the oncogenic transformation both in vitro and in vivo and is highly expressed in various tumor types. Interestingly, mice that lack both MNK1 and MNK2 do not have any apparent phenotype, which is promising for the therapeutic window of MNK1/2 inhibitors. SEL201 is a series of small molecule inhibitors which inhibit activity of both MNK1 and MNK2 in a low nM range. Selected compounds were tested on the kinome panels and indicated MNK1 and MNK2 as primary kinase targets. SEL201 compounds caused dose dependent inhibition of phosphorylation of eIF4e at Ser209 in various cancer cell lines at concentrations &lt;100nM, which were lower when compared with other reported MNK1/2 inhibitors such as Cercosporamid and CGP57380. Consistently, potent inhibition of eIF4e Ser209 was observed also in vivo after oral administration of the inhibitors in xenograft models. High potency, selectivity and favorable ADME/PK profile indicates that SEL201 inhibitors would be useful tools in probing molecular consequences of eIF4e Ser209 inhibition in cancer cells alone and in combination with other inhibitors targeting PI3K/mTOR or RAS/MEK pathway. SEL201 in vitro and in vivo activities on viability and metastasis will be presented in cellular and in vivo models of colorectal cancer and glioblastoma. SEL201 series is further developed as a promising anticancer therapy with potentially wide therapeutic window.
Citation Format: Tomasz Rzymski, Malgorzata Szajewska-Skuta, Adrian Zarebski, Kamil Sitarz, Lukasz Sapala, Malgorzata Zurawska, Magdalena Salwinska, Renata Windak, Ewa Trebacz, Joanna Daniel-Wojcik, Radoslaw Obuchowicz, Bozena Winnik, Ewelina Wincza, Urszula Kulesza, Katarzyna Kucwaj-Borysz, Mariusz Milik, Agnieszka Dreas, Krzysztof Brzozka. Repression of tumor survival pathways by novel and selective inhibitors of MNK1 and MNK2 kinases in glioblastoma and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 755. doi:10.1158/1538-7445.AM2014-755
Abstract 762: Prevention and reversion of multidrug resistance (MDR) in cancer by NSC23925
Authors: Yang Xiaoqian , Hornicek Francis , Duan Zhenfeng 
Published: May 2015

Abstract
The major limitation to the success of chemotherapy in cancer is the development of multidrug resistance (MDR). Preventing the emergence of MDR during chemotherapy treatment has been a high priority of clinical and investigational oncology, but remains an elusive goal. NSC23925 has recently been identified as a novel and potent MDR reversal agent. However, whether NSC23925 can prevent the development of MDR in cancer is unknown. Therefore, this study was to evaluate the effects of NSC23925 on prevention and reversion of MDR. Human osteosarcoma cell line U-2OS and Saos were exposed to increasing concentrations of taxol alone or in combination with NSC23925 for 6 months. The results showed that cells selected with increasing concentrations of taxol alone developed MDR with resistance to taxol and other Pgp substrates, while cells cultured with taxol-NSC23925 simultaneously prevented the development of MDR and cells remained sensitive to chemotherapeutic agents. Taxol selected resistant cells showed high expression and activity of drug transporter P-glycoprotein (Pgp), whereas taxol-NSC23925 combination treatment prevented the expression of Pgp. Our findings suggest that NSC23925 may prevent the development of MDR by specifically preventing the overexpression of Pgp. Moreover, NSC23925 can reverse MDR in drug resistant cells by modulating Pgp activity. Given the significant incidence of MDR in cancer and the lack of effective agents for prevention and revision of MDR, NSC23925 and derivatives hold the potential to improve the outcome of cancer patients with poor prognosis due to drug resistance.
Citation Format: Xiaoqian Yang, Francis Hornicek, Zhenfeng Duan. Prevention and reversion of multidrug resistance (MDR) in cancer by NSC23925. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 762. doi:10.1158/1538-7445.AM2014-762
Abstract 768: CB-PIC sensitizes chemoresistant cancer cells to drugs via suppression of MDR1 and its upstream signal molecules, AKT and p38-MAPK
Authors: Lee Duckgue , Yun Miyong 
Published: May 2015

Abstract
ATP-binding cassette (ABC) transporters including MDR1-/P-gp have been majorly targeted for drug resistant tumor therapies. In this study, we screened the compound that negatively affects MDR-1 expression in chomoresistant cancer cell lines. We found that CB-PIC, the novel synthetic compound, could decrease P-glycoprotein expression via disrupt AKT/p-38 signal pathway in paclitaxel resistant lung cancer cell, H460/PR and doxorubicin resistant breast cancer cell, MCF7/Adr with highly expressed P-glycoprotein. However, CB-PIC did not regulate enzyme activity of P-glycoprotein, while EGCG and tannic acid accumulated Rhodamine 123 intracellular region of cell via short time efflux assay. CB-PIC treatment resulted in disruption of proliferation of drug resistant cells. In addition, CB-PIC dramatically induced apoptosis in time and dose dependent manner in both paclitaxel and doxorubicin resistant cancer cells. Furthermore, CB-PIC sensitizes drug-resistant cancer cells to paclitaxel and doxorubicin by decrease of survival proteins, survivin, Mcl-1 and Bcl-2, as well as MDR1 suppression leading to accumulate the treated drug intracellular region. Taken together, CB-PIC suppresses the P-glycoprotein expression through inhibition of AKT/p-38 MAPK signaling resulting in the increase of drug sensitivity in chemoresistant cancer cells.
Citation Format: Duckgue Lee, Miyong Yun. CB-PIC sensitizes chemoresistant cancer cells to drugs via suppression of MDR1 and its upstream signal molecules, AKT and p38-MAPK. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 768. doi:10.1158/1538-7445.AM2014-768
Abstract 81: Deregulated expression of HDAC9 in B cells leads to the development of lymphoproliferative disease and lymphoma
Authors: Gil Veronica S. 
Published: May 2015

Abstract
Aberrant epigenetics leading to changes in chromatin structure and patterns of gene expression is an important factor in cancer pathogenesis. Histone Deacetylase 9 (HDAC9) is a class IIa chromatin-modifying enzyme that, within the haematopoietic system, is preferentially expressed in the B-cell lineage. Furthermore, HDAC9 expression is deregulated in B-lymphoid malignancies. To examine the role of HDAC9 in malignant B-cell transformation, we generated an in vivo mouse model that constitutively expresses human HDAC9 from early stages of B-cell development under the control of the immunoglobulin heavy chain (IgH) enhancer (Eµ). In this study, we demonstrate that from an average of six months of age, Eµ-HDAC9 transgenic mice displayed splenomegaly and immunophenotypic features that resemble lymphoproliferative disease (LPD) in spleen. Later on in life, up to twenty-three months of age, 24% (19 out of 78) of Eµ-HDAC9 mice developed mature B-cell neoplasms such as splenic marginal zone lymphoma (SMZL) and aggressive diffuse large B-cell lymphoma (DLBCL) that could represent a progression stage of the observed lymphoproliferative disease (LPD) and monoclonal B-cell lymphocytosis (MBL). In contrast, a low background incidence of these malignancies was observed in control mice, 2% (1 out of 46) (p = 0.0008). The molecular pathogenesis of the Eµ-HDAC9 B-cell tumors seems to involve activation-deactivation of the BCL6-p53 axis by HDAC9 influenced deacetylation thus affecting DNA repair and cell cyle progression in germinal centre (GC) during immune response. Consistently, ZFN-mediated HDAC9-knockout results in cell cycle changes leading to strong inhibition of cell growth in vitro. In summary, aberrant expression of HDAC9 leads to the development of lymphoproliferative disorders, including GC and post-GC lymphomas, demonstrating an oncogenic role for HDAC9 in B-cells and highlighting its importance as a therapeutic target.
Citation Format: Veronica S. Gil. Deregulated expression of HDAC9 in B cells leads to the development of lymphoproliferative disease and lymphoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 81. doi:10.1158/1538-7445.AM2014-81