bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4963: The dynamic change of CD47 expression promotes tumor burden, metastases and resistance of breast cancer cells to radiotherapy.
Authors: Menaa Cheikh , Fan Ming , Lu Hsien-Chen , Alexandrou Aris , Juma Shuaib , Perks Julian , Li Jian Jian 
Published: August 2014

Abstract
Immune tolerance towards malignant cells is responsible for tumor progression and metastases. Despite their immunogenicity, cancer cells developed sophisticated mechanisms by which they are able to neutralize and/or evade the immune-surveillance. Recently, the overexpression of CD47 has been suggested to participate in the immune escape mechanism in several malignant diseases. However, mechanisms involved in CD47 expression, especially in response to anticancer agents are not yet known. In this study, we found that CD47 is overexpressed in breast cancer cells (MCF7, MDA-231, 4T1 cells) compared to non-transformed breast epithelial cells (MCF10A) and this expression is further enhanced in response to radiation (5Gy). The expression of CD47 was found to be regulated by NF-κB through a specific responsive element in the CD47 promoter as assessed by gene deletion and ChiP assays. Furthermore, using syngeneic orthotopic 4T1 mouse model, we found that CD47 is critical for both tumor burden and metastases, since anti-CD47 (100 μg/day/mice) was able to reduce tumor growth when the antibody was injected during 4T1 inoculation (day 0) or 15th after tumor growth. Consequently, tumor size and lesions were reduced and mouse survival was increased in the presence of anti-CD47 and this effect was further enhanced with radiation (4 Gy/day for 5 days). Taken together, these data suggest that CD47 expression is a marker for tumor aggressiveness and resistance to anti-cancer agents and therefore could be a potential target to treat metastatic and recurrent tumors.
Citation Format: Cheikh Menaa, Ming Fan, Hsien-Chen Lu, Aris Alexandrou, Shuaib Juma, Julian Perks, Jian Jian Li. The dynamic change of CD47 expression promotes tumor burden, metastases and resistance of breast cancer cells to radiotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4963. doi:10.1158/1538-7445.AM2013-4963
Abstract 5541: Therapeutic targeting of CRM1 in ovarian cancer.
Authors: Miyake Takahito M. , Pradeep Sunila , Zand Behrouz , Dalton Heather J. , Wen Yunfei , Armaitz Pena Guillermo N. , Kauffman Michael , McCauley Dilara , Shacham Sharon , Wiktorowicz John E. , Sood Anil K. 
Published: August 2014

Abstract
Background: CRM1 is a nuclear export protein which increases cell viability through nuclear export signal-dependent protein exclusion of tumor suppressor proteins. Selective Inhibitor of Nuclear Exprot (SINE) is a novel class of drugs that selectively inhibit CRM1. Here, we tested the biological effects of targeting CRM1.
Methods and results: To explore the efficacy of SINE CRM1 anatgonists in ovarian cancer, we tested the selective small molecule KPT-185(in vitro) against human ovarian cancer cell lines. KPT-185 reduced cell viability in multiple (A2780, A2780CP20, IGROV-1 and SKOV3) human ovarian cancer cell lines with IC50 levels ranging from 0.2 - 0.75μM. Nuclear localization and significantly increased expression of tumor suppressor proteins (e.g., p53, p21 and Fox03a) was noted in response to KPT-185 treatment. Moreover, synergistic reduction in cell viability was noted with topotecan, cisplatin and liposomal doxorubicin (interaction index was 0.45, 0.78 and 0.59, respectively). Using the A2780 in vivo orthotopic ovarian cancer model, oral administration of KPT-330 (in vivo) monotherapy at 20mg/kg twice a week resulted in 90% tumor reduction (p&lt;0.01). In combination with topotecan, there was 98% reduction (p&lt;0.01) in tumor growth. KPT-330 also showed significant tumor growth inhibition in combination with weekly paclitaxel or bevacizumab. Histological examination of obtained tumor samples showed 2.5-fold increase in number of caspase-3 positive cells (p&lt;0.01) and 0.4-fold decreased of Ki67 positive cells (p&lt;0.05) in KPT-330 treated group. In each experiment, KPT-330 was well tolerated and no significant changes in mouse body weight were noted.
Conclusion: CRM1 inhibitor is a potent inhibitor of ovarian cancer growth and merits additional development.
Citation Format: Takahito M. Miyake, Sunila Pradeep, Behrouz Zand, Heather J. Dalton, Yunfei Wen, Guillermo N. Armaitz Pena, Michael Kauffman, Dilara McCauley, Sharon Shacham, John E. Wiktorowicz, Anil K. Sood. Therapeutic targeting of CRM1 in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5541. doi:10.1158/1538-7445.AM2013-5541
Abstract 5647: Receptor tyrosine kinase plasticity as a mechanism of acquired resistance to cetuximab in vitro: potential for co-targeting with antibody mixtures.
Authors: Kjaer Ida , Kragh Michael , Horak Ivan D. , Pedersen Mikkel Wandahl 
Published: August 2014

Abstract
Cetuximab is an EGFR-blocking antibody that belongs to the first generation of monoclonal antibodies approved for treatment of head and neck squamous cell carcinoma and metastatic colorectal cancer. Although anti-EGFR therapy is clinically successful, development of cetuximab resistance is an increasing problem in the clinic. Thus, a better understanding of the mechanisms responsible for development of cetuximab resistance is valuable for development of the next generation of antibody therapeutics.
Here we report the establishment of a number of cetuximab-resistant clones derived from the cetuximab-sensitive head and neck squamous carcinoma cell line HN5. Initial characterization of the cetuximab-resistant cells shows that the total level of EGFR is lower compared to the parental cells, but that the cetuximab binding is unaltered. However, cetuximab resistant clones remain dependent on EGFR for growth and proliferation, as a mixture of antibodies targeting non-overlapping epitopes on EGFR is able to partially overcome the cetuximab-induced resistance. Inititial results indicate that the antibody mixture overcomes cetuximab resistances by inducing efficient EGFR internalization followed by lysosomal degradation of the receptor. Removal of EGFR from the cell surface blocks interactions of EGFR with other receptor tyrosine kinases (RTKs) and intracellular proteins as compensatory response to cetuximab inhibition.
The observed level of inhibition of the resistant clones by the anti-EGFR antibody mixture did not, however, induce as efficient growth inhibition as in the parental cells, indicating additional resistance mechanisms. Indeed we were able to show that adding antibodies to other RTKs to the anti-EGFR antibody mixture restored sensitivity of the resistant cells to a level similar to parental cells.
In conclusion, our results demonstrate that cetuximab resistant clones remain partially dependent on EGFR for growth and proliferation. Additional RTKs are activated as a compensatory response to the EGFR inhibition, demonstrating the plasticity of the RTK family. Our results provide a rationale for targeting multiple RTKs to overcome acquired resistance to currently approved mAbs or to delay the emerge of resistance if used upfront.
An update will be presented.
Citation Format: Ida Kjaer, Michael Kragh, Ivan D. Horak, Mikkel Wandahl Pedersen. Receptor tyrosine kinase plasticity as a mechanism of acquired resistance to cetuximab in vitro: potential for co-targeting with antibody mixtures. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5647. doi:10.1158/1538-7445.AM2013-5647
Abstract 5657: Polyamidoamine dendrimers induce epigenetic changes in cultured normal and malignant human lung epithelial cells.
Authors: Kohonen Pekka J. , Feliu Neus T. , Palmberg Lena , Karlsson Hanna L. , Wallberg Annika E. , Grafström Roland C. , Fadeel Bengt 
Published: August 2014

Abstract
Dendrimers constitute structurally well-defined nanomaterials that are potentially useful for a vast range of biomedical applications, including targeted cancer therapy. Polyamidoamine (PAMAM) dendrimers are a relatively unexplored material subclass from consideration of low-dose studies of toxicological and biological effects, including epigenetic changes that may link to altered cell differentiation and risk of transformation. The present study assessed cell viability, histone modifications, genome-wide DNA methylation and gene expression changes in primary human bronchial epithelial cells (PBEC) and the human alveolar epithelial cell line A549 following exposure to 4th generation PAMAM dendrimers with hydroxyl (-OH) or amino (-NH2) terminating groups. The preliminary results show that these PAMAMs can regulate DNA methylation and histone modification at micromolar levels without significant effect on cell viability (lactate dehydrogenase assay). Specific changes in DNA methylation patterns implicated inflammation-related genes, although with different results in the two model systems. The results imply epigenetic regulation of gene expression by PAMAMs, and follow up work now investigates this hypothesis. Close attention to safety issues is of paramount importance for the sustainable development of the nanotechnologies, especially for biomedical applications, and the present data may shed light on potential long-term/low-dose effects of engineered nanomaterials.
Citation Format: Pekka J. Kohonen, Neus T. Feliu, Lena Palmberg, Hanna L. Karlsson, Annika E. Wallberg, Roland C. Grafström, Bengt Fadeel. Polyamidoamine dendrimers induce epigenetic changes in cultured normal and malignant human lung epithelial cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5657. doi:10.1158/1538-7445.AM2013-5657
Abstract 658: Methylation profile of CCNA1, MGMT, HIC1, TIMP3, AIM1, DAPK and CDH1 genes in head and neck cancer.
Authors: Arantes Lidia Maria R B , de Carvalho Ana Carolina , Melendez Matias Eliseo , Tajara Eloiza Elena , Goloni-Bertollo Eny Maria , Carvalho André L. ,   Head and Neck Genome Project GENCAPO
Published: August 2014

Abstract
Head and neck carcinomas are among the most frequent tumor types worldwide, with around 500,000 new cases diagnosed per year. The most common variant is the squamous cell carcinoma from the upper aerodigestive tract (HNSCC), representing 90% of these malignancies. Activation of proto-oncogenes and inactivation of tumor suppressor genes are the major genetic alterations involved in carcinogenesis. The increase in methylation in the promoter region of a tumor suppressor gene, or the lack of methylation of a proto-oncogene promoter region, can lead to progressive reduction/enhancement of its expression, resulting in its silencing, thus selecting cells with proliferative advantage. Promoter hypermethylation is considered a tumor marker in a variety of malignant neoplasias, including HNSCC. The objective of this work was to analyze the hypermethylation profile of CCNA1, MGMT, HIC1, TIMP3, AIM1, DAPK and CDH1 genes in DNA tumor samples of HNSCC patients included in Head and Neck Genome Project (GENCAPO). In this study, DNA was extracted from 33 tumor samples from HNSCC patients. Extracted DNA was submitted to bisulfite treatment and analyzed using Quantitative Methylation-Specific PCR (Q-MSP), this real-time PCR methodology allows a more objective, robust, and rapid assessment of promoter methylation status. Criteria for positive methylation of promoter regions by Q-MSP range from 0.01 to 100%. Our results showed that at least two of these genes were found methylated in 100% of the samples analyzed. In addition, the presence of promoter hypermethylation of Cyclin A1 (CCNA1) was significantly associated to absence of tobacco consumption (P=0.042). However, methylated DNA tumors were not associated with tumor site (CCNA1, P=0.55; MGMT, P=0.29; HIC1, P=1.00; TIMP3, P=1.00; AIM1, P=1.00 and DAPK, P=1.00) nor clinical stage (CCNA1, P=0.64; MGMT, P=0.38; HIC1, P=1.00; TIMP3, P=0.57; AIM1, P=0.55 and DAPK, P=1.00). In conclusion, the results suggest that hypermethylation of the CCNA1 gene is significantly associated to tobacco consumption in head and neck squamous cell carcinoma patients.
Citation Format: Lidia Maria R B Arantes, Ana Carolina de Carvalho, Matias Eliseo Melendez, Eloiza Elena Tajara, Eny Maria Goloni-Bertollo, André L. Carvalho, Head and Neck Genome Project GENCAPO. Methylation profile of CCNA1, MGMT, HIC1, TIMP3, AIM1, DAPK and CDH1 genes in head and neck cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 658. doi:10.1158/1538-7445.AM2013-658
Abstract 978: Synergistic activity of EP-100 and chemotherapies in cancer cell lines.
Authors: Leuschner Carola , Gavini Shashi , Alila Hector W. 
Published: August 2014

Abstract
EP-100, a targeted anti-cancer drug comprised of a lytic peptide fused to Luteinizing Hormone Releasing Hormone (LHRH), is in Phase 2 clinical trial in tumors that over-express LHRH receptors in combination with paclitaxel. It kills cancer cells by membrane disruption. EP-100 was tested in combination with paclitaxel, vinorelbine, doxorubicin, cisplatinum, vincristine and 5 fluorouracil (5FU) in vitro. The sequence of adding EP-100 to the chemotherapeutics was tested in consideration of their half-lives (hours) than EP-100 (minutes). EP-100 was added to the cells before or after treatment with the chemotherapeutics to determine the order of treatment for maximum synergy. Cells were cultured in the presence of each single agent and in combination with EP-100 for 72h. Data were analyzed as IC50 values for each single drug and the combination with EP-100. Combination indices (CI) on interaction of EP-100 and each chemotherapeutic were determined. EP-100 alone was cytotoxic at low uM concentrations in LHRH receptor (+), multi-drug resistant human uterine sarcoma cell line MES-SA-Dx5 and a human breast cancer cell line MDA-MB-231 after 72 h incubation. Both cell lines were resistant to paclitaxel, vinorelbine, vincristine, 5-FU and cisplatinum. MES-SA-Dx5 cells were resistant to doxorubicin. Addition of EP-100 to each of the chemotherapeutics increased sensitivity to all of the drugs except 5-FU (Table 1). Combinations of EP-100 with paclitaxel, vincristine, vinorelbine, doxorubicin and cisplatinum resulted in potentiation of activity in a synergistic manner for both uterine sarcoma and breast cancer cell lines. The combination effects were synergistic with CIs of 0.2. The sequence of exposure was most potent when EP-100 was given first followed by incubation with paclitaxel, doxorubicin or vinorelbine.
Table 1 In vitro activities (IC50 - nM) MES-SA-Dx5 Combination Index Potentiation MDA-MB-231 Combination Index Potentiation EP-100 Alone 3044 ± 558 1400 ± 300 Paclitaxel 33.7 ± 2.2 86.2 ± 5.9 EP100+Paclitaxel 0.014 ± 0.002 0.001 6000 15.9 ± 0.8 0.22 5.7 Vincristine 124.7 ± 16.3 26.3 ± 4.1 EP-100+Vincristine 5.7 ± 0.9 0.02 21.7 1.8 ± 0.1 0.09 15 Doxorubicin 32.6 ± 4.3 1.26 ± 0.4 EP-100+Doxorubicin 3.3 ± 0.6 0.09 9.6 1.1 ± 0.04 NA 1 Vinorelbine 63.22 ± 15.9 23.7 ± 3.4 EP-100+Vinorelbine 6.0 ± 1.6 0.06 10.5 3.1 ± 0.9 0.1 7.6 CDDP 54.5 ± 5.8 19.9 ± 6.2 EP-100 + CDDP 8.0 ± 2.6 0.2 6.8 8.1 ± 1.9 0.1 2.5
These results indicate that EP-100 synergizes with paclitaxel, doxorubicin, vinorelbine, vincristine and cisplatinum but not 5-FU in drug resistant human uterine sarcoma and breast cancer cells.
Citation Format: Carola Leuschner, Shashi Gavini, Hector W. Alila. Synergistic activity of EP-100 and chemotherapies in cancer cell lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 978. doi:10.1158/1538-7445.AM2013-978
Abstract SY31-03: Genome regulation by long noncoding RNAs.
Authors: Chang Howard Y. 
Published: August 2014

Abstract
The central dogma of gene expression is that DNA is transcribed into messenger RNAs, which in turn serves as the template for protein synthesis. The discovery of extensive transcription of large RNA transcripts that do not code for proteins, termed long noncoding RNAs (lncRNAs) provide an important new perspective on the centrality of RNA in gene regulation. An emerging theme from multiple model systems is that LncRNAs form extensive networks of ribonucleoprotein (RNP) complexes with numerous chromatin regulators, and target these enzymatic activities to appropriate locations in the genome. Consistent with this notion, long noncoding RNAs can function as modular scaffolds to specify higher order organization in RNP complexes and in chromatin states. I will discuss how this mode of regulation is particularly relevant to cancer and the maintenance of genome integrity.
Citation Format: Howard Y. Chang. Genome regulation by long noncoding RNAs. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr SY31-03. doi:10.1158/1538-7445.AM2013-SY31-03
Abstract A20: IDH mutations and 2-HG selectively affect histone methylation in the endogenous setting
Authors: Lin Fallon , Saenz-Vash Veronica , Zhai Huili , Fletcher Joy , Acker Mike , Jiang David , Gounarides John , Levell Julian , Pagliarini Raymond 
Published: August 2014

Abstract
Highly recurrent somatic mutations in the isocitrate dehydrogenase (IDH) 1 and 2 enzymes have been identified in a variety of tumor types including GBM and glioma subtypes, acute myelogenous leukemia, chondrosarcoma, and cholangiocarcinoma, among others. Mutant IDH proteins gain a novel function: the production of the “oncometabolite” 2-hydroxyglutarate (2-HG), which accumulates in the tumors of affected patients. The similarity of 2-HG to a-ketoglutarate, a cofactor required for the function of a large number of cellular enzymes, has led to the hypothesis that 2-HG may alter the function of one or more of these enzymes. Current literature has shown that 2-HG is able to inhibit a number of epigenetic factors (i.e. Jmj-domain histone demethylases, and the TET family of methylcytosine oxidases) though most of these studies have been carried out using over-expression systems that can potentially force non-relevant phenotypes. To this end, we explored histone methylation changes in a variety of cells that harbor endogenous heterozygous IDH1/2 mutations. Using an LC-MS based method to detect histone modifications, we profiled IDH MUT vs. WT cells to evaluate which global histone methylation changes correlated with mutant IDH status and whether these changes were widespread or discrete. This unbiased search highlighted IDH-dependent modifications of Histone 3 on Lysine 9 (H3K9) as the histone mark of highest interest for further study. We followed up by assessing the sufficiency and necessity of IDH mutation and 2-HG to alter H3K9 methylation using immunoblotting techniques. Our results suggest that H3K9 methylation is particularly sensitive to mutant IDH and 2-HG, which may give us further insight into the mechanism of how mutant IDH drives tumorgenicity.
Citation Format: Fallon Lin, Veronica Saenz-Vash, Huili Zhai, Joy Fletcher, Mike Acker, David Jiang, John Gounarides, Julian Levell, Raymond Pagliarini. IDH mutations and 2-HG selectively affect histone methylation in the endogenous setting. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A20.
Abstract A32: Aberrant gene repression with H3K27me3 modification in human small cell lung cancer
Authors: Kaneda Atsushi , Sato Teruyuki , Tsuji Shingo , Isagawa Takayuki , Nukiwa Toshihiro , Ishikawa Yuichi , Aburatani Hiroyuki 
Published: August 2014

Abstract
Small cell lung cancer (SCLC), approximately 15% of all the lung cancer cases, is a subtype of lung cancer with poor prognosis. Expression profiling analysis of 23 SCLC cases and 42 normal tissues revealed that EZH2 and other PRC2 members were highly expressed in SCLC. ChIP-seq analysis for H3K27me3 in 3 SCLC cell lines, Lu130, H209 and DMS53, showed that genes enriched with H3K27me3 mark in SCLC were not only PRC2-target genes in ES cells, but also other genes, such as cellular adhesion-related genes. These H3K27me3(+) genes in SCLC were significantly repressed in expression, and introduction of them into SCLC cell lines lead to growth inhibition. Shorter overall survival of clinical SCLC cases correlated to repression of those H3K27me3(+) genes, including PRC target genes. Treatment with a PRC2 inhibitor resulted in growth inhibition of SCLC cell lines, indicating that high expression of PRC2 would contribute to gene repression in SCLC, and may play a role in genesis of SCLC.
Citation Format: Atsushi Kaneda, Teruyuki Sato, Shingo Tsuji, Takayuki Isagawa, Toshihiro Nukiwa, Yuichi Ishikawa, Hiroyuki Aburatani. Aberrant gene repression with H3K27me3 modification in human small cell lung cancer. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A32.
Abstract A34: Nucleosome dynamics of cell differentiation
Authors: Li Zhaoyu 
Published: August 2014

Abstract
Nucleosome occupancy is fundamental for establishing chromatin architecture. However, little is known about the relationship between nucleosome dynamics and initial cell lineage specification. Here, we determine the mechanisms that control global nucleosome dynamics during embryonic stem (ES) cell differentiation into endoderm. Both nucleosome depletion and de novo occupation occur during the differentiation process, with higher overall nucleosome density after differentiation. The variant histone H2A.Z and the winged helix transcription factor Foxa2 both act to regulate nucleosome depletion and gene activation, thus promoting ES cell differentiation, whereas DNA methylation promotes nucleosome occupation and suppresses gene expression. Nucleosome depletion during ES cell differentiation is dependent on Nap1l1-coupled SWI/SNF and INO80 chromatin remodeling complexes. Thus, both epigenetic and genetic regulators cooperate to control nucleosome dynamics during ES cell fate decisions. Currently, we determine whether chromatin remodeling complexes are involved in nucleosome occupation.
Citation Format: Zhaoyu Li. Nucleosome dynamics of cell differentiation. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Jun 19-22, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2013;73(13 Suppl):Abstract nr A34.