bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3953: Enhanced radiation reponse in MCF-7 radioresistant cells by targeting Peroxiredoxin II
Authors: Wang Tieli , Diaz Anthony Joseph , Li Jian-Jian , Yen Yun , Tamae Daniel 
Published: May 2015

Abstract
In our previous study, we identified a protein target, Peroxiredoxin II (PrxII) to be overexpressed in radioresistant MCF+FIR3 breast cancer cells and found that its expression and function is associated with breast cancer radiation sensitivity or resistance. Small interference RNA (siRNA) targeting the PrxII gene expression was able to sensitize MCF+FIR3 radioresistant breast cancer cells to ionizing radiation. The major focus of this work was to investigate how the radiation response of MCF+FIR3 radioresistant cells was affected by siRNA that inhibits PrxII gene expression. Our results presented here show that silencing PrxII gene expression increased cellular toxicity by altering cellular thiol status, inhibiting Ca2+ efflux from the cells and perturbing the intracellular Ca2+ homeostasis. By combining radiotherapy and siRNA technology, we hope to develop new therapeutic strategies that may have potential to enhance the efficacy of chemotherapeutic agents due to its targeted property to specific cancer related genes.
Citation Format: Tieli Wang, Anthony Joseph Diaz, Jian-Jian Li, Yun Yen, Daniel Tamae. Enhanced radiation reponse in MCF-7 radioresistant cells by targeting Peroxiredoxin II. [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 3953. doi:10.1158/1538-7445.AM2014-3953
Abstract 3955: 53BP1 facilitates the ATM-dependent phosphorylation of APLF in the DNA damage response
Authors: Fenton Amanda L. , Tran Diana , Koch Christine Anne 
Published: May 2015

Abstract
Aprataxin and polynucleotide kinase-like factor (APLF) is a DNA repair factor which facilitates DNA repair in part through interactions with its forkhead-associated (FHA) domain. The APLF FHA domain mediates interactions with specific threonine phosphorylated epitopes via a functionally conserved and essential arginine residue (Arg-27). In the context of DNA double-strand break (DSB) repair, substitution of APLF amino acid residue Arg-27 to alanine abolishes interactions with the DSB repair scaffold protein XRCC4, and impairs DSB repair. APLF is also a component of the ATM-dependent DNA damage response (DDR), which also includes 53BP1, and undergoes ionizing-radiation induced phosphorylation at Ser-116 facilitating its role in DSB repair. Here we demonstrate that the APLF FHA domain is essential for Ser-116 phosphorylation and for the association with 53BP1, which collectively enhance the accumulation of APLF at sites of DNA damage. The level of 53BP1 expression, but not XRCC4, was found to correlate with the phosphorylation of APLF by ATM, and disruption of the APLF-53BP1 interaction was associated with impaired cell survival following DNA damage. These results suggest that the APLF FHA domain directs interactions with multiple partners in the DNA damage response, and that 53BP1 facilitates the ATM-dependent phosphorylation of APLF.
Citation Format: Amanda L. Fenton, Diana Tran, Christine Anne Koch. 53BP1 facilitates the ATM-dependent phosphorylation of APLF in the DNA damage response. [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 3955. doi:10.1158/1538-7445.AM2014-3955
Abstract 3966: PLK1 regulates PAX3-FOXO1 stability and its inhibition mediates regression of alveolar rhabdomyosarcoma xenograft tumors
Authors: Thalhammer Verena , Herrero-Martin David , Hecker Regina , Laubscher Dominik , Lopez-Garcia Laura , Wachtel Marco , Bode Peter , Schäfer Beat 
Published: May 2015

Abstract
Oncogenic addiction provides an opportunity to develop new treatment options, especially for childhood cancers. Pediatric tumors contain a lower number of oncogenic mutations compared to most adult cancers, suggesting stronger dependency on individual oncogenes, such as chimeric transcription factors that have the ability to control multiple oncogenic pathways. Taking advantage of this addiction, targeting of oncogenic transcription factors becomes a new powerful strategy for therapy of translocation positive pediatric tumors like alveolar rhabdomyosarcoma (aRMS), which is characterized by a very dismal prognosis.
As transcription factors are considered to be difficult to target, we developed an approach to screen for druggable upstream regulators like kinases. In two parallel activity reporter assays, using a kinome siRNA library and a small molecule library, we identified PLK1 to contribute to the activity of PAX3-FOXO1, the oncogenic transcription factor specific to aRMS. Mechanistically, we were able to demonstrate a direct interaction of the two proteins by co-immunoprecipitation. PLK1 silencing or inhibition increased degradation of PAX3-FOXO1, which suggests a stabilization of PAX3-FOXO1 due to phosphorylation by PLK1. Candidate phosphorylation sites were identified by in vitro kinase assays and mass spectrometric analysis and site-specific mutagenesis is currently utilized to validate the impact of these sites on fusion protein turnover. To highlight PLK1 as therapeutic target in aRMS, in vivo treatment studies using the PLK1 inhibitor BI 2536 resulted in complete tumor regression in two aRMS xenograft mouse models. Finally, tissue microarray analysis of human aRMS tumor biopsies showed PLK1 to be overexpressed and predictive of overall survival.
Hence, our preclinical studies validate PLK1 as highly relevant drug target in alveolar rhabdomyosarcoma, similar to recent findings in other pediatric tumors. Our data suggests that PLK1 inhibitors warrant further investigations to evaluate the potential to be translated into a clinical setting.
Citation Format: Verena Thalhammer, David Herrero-Martin, Regina Hecker, Dominik Laubscher, Laura Lopez-Garcia, Marco Wachtel, Peter Bode, Beat Schäfer. PLK1 regulates PAX3-FOXO1 stability and its inhibition mediates regression of alveolar rhabdomyosarcoma xenograft tumors. [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 3966. doi:10.1158/1538-7445.AM2014-3966
Abstract 3980: Pre-clinical evaluation of a novel DNA crosslinking agent, Ureidomustin (BO-1055) in pediatric sarcomas
Authors: Ambati Srikanth R. , Wong Elissa W. , Pera Benet , Peguero Elizabeth , Lopes Eloisi Caldas , Chen Jin-Jer , Shieh Jae-Hung , Su Tsann-Long , Moore Malcolm A. 
Published: May 2015

Abstract
DNA crosslinking agents continue to be an important part of chemotherapy for pediatric sarcomas. We tested potent analogues of phenyl N-mustard-benzene conjugates in several tumor models. In this work, we compared the efficacy of a novel water-soluble DNA alkylating agent, Ureidomustin (BO-1055) in Ewing sarcoma, rhabdomyosarcoma, osteosarcoma, desmoplastic small round cell tumor (DSRCT) cell lines and early cultures derived from primary patient samples. We tested its toxicity in normal human cells in vitro including the proliferation of mesenchymal stromal cells, bone marrow-derived endothelial cells and purified cord blood CD34+ cells in colony-forming assay (for hematopoietic progenitor cells) and in cobblestone area forming assay (for hematopoietic stem cells). We performed cell viability, cytotoxicity and caspase activation assays in a dose-dependent and time-dependent manner. We also performed apoptosis, cell cycle analyses using flow cytometry, immunoblot analysis and in vivo experiments in nude mice using Ewing sarcoma (A673) cell line transduced with GFP/luciferase for bioimaging. We evaluated cardiotoxicity in the HL-1 cardiomyocyte line in vitro and noted a 227 fold less cytotoxicity using BO-1055 compared to Doxorubicin. Based on MTD testing in nude mice, we used 30mg/kg q2d for 5 doses after tumors reached 75-100mm3 and were detected on luciferase bioimaging. Our results indicated that BO-1055 has a significant therapeutic window in its activity (mean IC50±SD μM) for rhabdomyosarcoma (0.16±0.11), Ewing sarcoma (0.48±0.29) and DSRCT (3.07±0.94) but not for osteosarcoma (IC50&gt;10μM). The mean IC50 in benign cells was &gt;10μM. Treatment with BO-1055 resulted in G2 arrest and activation of caspases 3 and 7 in a dose dependent manner. A673 xenografts were significantly inhibited by BO-1055 compared to the control mice injected with vehicle, based on mean fluorescence intensity and size of the tumors. Our results suggest that BO-1055 has potent activity against Ewing sarcoma and rhabdomyosarcoma and presents a strong rationale for further development as a therapeutic agent.
Citation Format: Srikanth R. Ambati, Elissa WP Wong, Benet Pera, Elizabeth Peguero, Eloisi Caldas Lopes, Jin-Jer Chen, Jae-Hung Shieh, Tsann-Long Su, Malcolm AS Moore. Pre-clinical evaluation of a novel DNA crosslinking agent, Ureidomustin (BO-1055) in pediatric sarcomas. [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 3980. doi:10.1158/1538-7445.AM2014-3980
Abstract 399: Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13)
Authors: Choi Dae R. , Hur Eun-Hye , Moon Ju Hyun , Goo Bon-Kwan , Choi Yunsuk , Lee Do Young , Ro Seonggu , Cho Joong Myung , Lee Je-Hwan 
Published: May 2015

Abstract
Myelodysplastic syndrome (MDS) is a clonal disorder of the hematopoietic cells occurring in elderly patients in a majority of instances. They are defined by ineffective hematopoiesis with peripheral blood cytopenias and by the risk of evolution to acute myeloid leukemia (AML). Hypomethylating agents (HMA), 5-azacytidine (AZA) and 2-deoxy-5-azacytidine (DAC), have demonstrated clinical activities with cytologic and cytogenetic responses in patients with MDS, but potential problems of both agents include the development of intrinsic and acquired resistance.
HMA-resistant patients have very poor prognosis, and this cohort of patients constitutes an important area of research. To understand mechanisms of HMA-resistance and overcome the resistance, we tried to establish HMA-resistant cells using MOLM-13, which is a cell line from a patient with AML evolved from MDS.
Original MOLM-13 cell line was sensitive to both AZA and DAC in vitro. MOLM-13 cells were exposed continuously to increasing concetrations of AZA or DAC and we could establish an AZA-resistant cell line (MOLM/AZA-1) and a DAC-resistant cell line (MOLM/DAC-5). The IC50 of AZA in MOLM/AZA-1 was 96.26 µM compared to 0.11 µM of the parent cell line; 800-fold increase in resistance to AZA. The IC50 of DAC in MOLM/DAC-5 was 207.7 µM compared to 0.07 µM of the parent cell line; 2000-fold increase in resistance to DAC. We treated th AZA- and DAC-resistant cells with vorinostat (SAHA) and a novel agent, CG200745 to test whether the histone deacetylase (HDAC) inhibitors could overcome the HMA-resistance. Cell viability assays showed that HMA-resistant cells were sensitive to both HDAC inhibitors, which dramatically decreased anti-apoptotic proteins (XIAP, MCL-1 and BCL-2) and increased PARP cleavages in the HMA-resistant cell lines. In conclusion, we successfully established established AZA- and DAC-resistant cell lines from an AML/MDS cell line, MOLM-13, and found that HDAC inhibitors might be promising in overcoming HMA-resistance. Further studies with the HMA-resistant cell lines are ongoing for elucidation of resistance mechanisms and possible role of other novel agents to overcome the HMA-resistance.
Citation Format: Dae Ro Choi, Eun-Hye Hur, Ju Hyun Moon, Bon-Kwan Goo, Yunsuk Choi, Do Young Lee, Seonggu Ro, Joong Myung Cho, Je-Hwan Lee. Establishment of hypomethylating agent-resistant cell lines using a cell line from a patient with acute myeloid leukemia evolved from myelodysplastic syndrome (MOLM-13). [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 399. doi:10.1158/1538-7445.AM2014-399
Abstract 3993: A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary cancer
Authors: Fujita Yoshihiko , Kurahashi Issei , Kurata Takayasu , Koh Yasuhiro , Sakai Kazuko , Nakagawa Kazuhiko , Nishio Kazuto 
Published: May 2015

Abstract
Background: Patients with cancer of unknown primary (CUP) present with metastatic disease for which the primary site cannot be found. Clinically, CUPs exhibit common characteristics, such as rapid progression and early dissemination, with a silent primary tumor that may become involuted and undetectable. Existence of such common properties prompts us to hypothesize that there may be potential biological markers that elucidate CUP as a whole.
Methods: Tumor mRNA samples from 60 patients with CUP were measured for the expression of ∼22,000 genes using the Affymetrix U133A Plus 2.0 GeneChip and analyzed by applying normalization and classification algorithms to the gene expression data. The similarity of each tumor specimen's gene expression pattern is then compared to the gene-expression profiles specific to non-CUP groups (containing tumors from 24 known primary sites) that were constructed using publicly available raw microarray datasets. The t-tests were performed to compare the CUP with non-CUP groups and the top 59 CUP specific genes with the highest fold change were selected (p-value &lt; 0.001).
Results: This study enabled the identification of genes that exhibited a unique expression pattern in CUP. As a high metastasis potential and vulnerability to apoptosis would explain the properties of CUP well, we first searched for genes related to metastasis and apoptosis and found 14 genes among 44 that were up-regulated by more than 2.5-fold in the CUP samples. Some of these genes were associated with the epithelial-to-mesenchymal transition (EMT), a function that has been increasingly recognized as a key step in cancer metastasis. We also identified 6 genes for ribosomal proteins among 44 up-regulated genes, two of which (RPS7 and RPL11) were known to be involved in the Mdm2 - p53 pathway.
Conclusions: The protein products of the up-regulated and down-regulated genes identified in this study suggest a biological attribute of CUP and, therefore, may become clinically useful biomarkers for CUP.
Citation Format: Yoshihiko Fujita, Issei Kurahashi, Takayasu Kurata, Yasuhiro Koh, Kazuko Sakai, Kazuhiko Nakagawa, Kazuto Nishio. A microarray-based gene expression analysis identified diagnostic biomarkers for unknown primary 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 3993. doi:10.1158/1538-7445.AM2014-3993
Abstract 3999: Characterization of the limiting steps in the melanoma metastatic cascade
Authors: Piskounova Elena , Morrison Sean 
Published: May 2015

Abstract
Metastasis is a complex multistep process: cancer cells have to detach from the bulk of the primary tumor, intravasate into the blood, survive anoikis and high shear forces in the blood stream while existing as single cells, extravasate into a distal site, and finally proliferate to form metastatic nodules. Each of these steps requires distinctive capabilities, which must either be intrinsic or gained.
We have used a melanoma xenograft model to define three major limiting steps of the metastatic cascade: intravasation into the blood, survival in circulation/extravasation into organs, and proliferation at distal sites. In our model, melanoma tumors that have previously been shown to efficiently metastasize to distal organs when grown subcutaneously (efficient metastasizers), are also capable of overcoming each of these three bottlenecks of metastasis. On the contrary, cells that are not able to metastasize when grown subcutaneously (inefficient metastasizers), are also inefficient at each of these limiting steps. This suggests that there are significant intrinsic differences between these two classes of tumors that determine the capacity of melanoma cells to grow at each step of the metastatic cascade.
To gain mechanistic insight into these differences, we have analyzed genomic mutations, gene expression and metabolomic profiles, comparing human melanomas with varying metastatic potential. Using our xenograft model we are currently investigating the role of select pathways in driving melanoma metastasis, which will ultimately lead to improved therapeutic options for patients with aggressive cancers.
Citation Format: Elena Piskounova, Sean Morrison. Characterization of the limiting steps in the melanoma metastatic cascade. [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 3999. doi:10.1158/1538-7445.AM2014-3999
Abstract 4002: Exploring the miRNA and proteomic contents of exosomes isolated from rhabdomyosarcoma tumor cells to understand their paracrine signaling
Authors: Ghayad Sandra E. , Ghamloush Farah , Saab Raya 
Published: May 2015

Abstract
Rhabdomyosarcoma (RMS) is an aggressive childhood soft tissue tumor, with two distinct subtypes, alveolar (ARMS) and embryonal (ERMS) histologies. The alveolar subtype is characterized by a specific translocation PAX-FOXO, the protein product of which is thought to contribute to its aggressive and metastatic behaviour.
Exosomes are small membranous vesicles (30-100 nm in diameter) secreted into body fluids by multiple cell types, including tumor cells. Tumor exosomes contain intact and functional protein and microRNA that can alter the cellular environment to favor tumor growth.
We hypothesize that the PAX-FOXO fusion protein results in specific effects on exosome cargo and biology, contributing to the invasive and metastatic potential of ARMS cells. Thus proteomic and molecular profiling of their exosomes may increase our understanding of the role of exosomes in sarcoma progression and may lead to discovery of useful biomarkers.
In the present study, we used miRNA array profiling to identify interesting exosomal miRNA expressed commonly in two different ARMS cell lines. We also used proteomic analysis and discovered differentially expressed ARMS exosomal proteins. Importantly, functional studies revealed that normal fibroblasts acquired invasion and migration ability through molecules transported in ARMS cell-derived exosomes.
Our results indicate that ARMS-derived exosomes have unique gene expression signatures,miRNA and proteomics profiles which will help our understanding of sarcoma biogenesis and that could be used as biomarkers for early diagnosis of ARMS, and targets for therapeutic intervention.
Citation Format: Sandra E. Ghayad, Farah Ghamloush, Raya Saab. Exploring the miRNA and proteomic contents of exosomes isolated from rhabdomyosarcoma tumor cells to understand their paracrine signaling. [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 4002. doi:10.1158/1538-7445.AM2014-4002
Abstract 4011: Single cell transcriptomic analysis identified a potential dormant signature in prostate cancer disseminated tumor cells
Authors: Lam Hung-Ming , Chéry Lisly , Coleman Ilsa , Lakely Bryce , Larson Sandy , Coleman Roger , Aguirre-Ghiso Julio , Xia Jing , Gulati Roman , Nelson Peter S. , Montgomery Bruce , Lange Paul H. , Snyder Linda A. , Vessella Robert L. , Morrissey Colm 
Published: May 2015

Abstract
Prostate cancer (PCa) disseminates before radical prostatectomy and can remain in the bone marrow for a prolonged period of time (&gt;10 years) until lethal metastasis develops. These cells are referred to as disseminated tumor cells (DTC). Dormant DTC are resistant to current chemotherapy targeting cell division, therefore understanding the nature of DTC will allow the development of novel drug target to prevent overt cancer metastases.
DTC were isolated from the bone marrow aspirates of PCa patients with no evidence of disease (NED, undetectable PSA level after 7-18 years after radical prostatectomy) or advanced diseases (ADV, disease progression after treatment or existing distant metastases). Eighty-five EpCAM+/CD45- individual cells were subjected to microarray gene expression analyses and two populations of cells were identified: erythroid progenitor-like and prostate epithelial cells. We utilized a dual signature method to identify EpCAM+/CD45- cells that are of prostatic origin. Comparison among prostate DTC showed that the DTC population within each patient was heterogeneous. Importantly, comparison between DTC from NED and ADV patients revealed that DTC from NED patients were enriched in a dormancy-associated signature identified in the head and neck squamous cell carcinoma, supporting the dormant nature of DTC from NED patients. Global clustering analysis and Ingenuity Pathway Analysis further identified a potential PCa dormancy signature, and this signature is significantly suppressed in a subpopulation of DTC isolated from ADV patients.
We reported a single cell transcriptomic analysis to reveal for the first time clinically heterogeneous DTC population in PCa patients and a dual signature method to identify cells of prostatic origin from erythroid-progenitor cells that harbored the same epithelial (EpCAM) surface marker in the bone marrow. The proposed gene signature associated with PCa dormancy may allow development of possible biomarkers to predict prognosis and therapeutic targets to promote PCa dormancy or prevent dormancy escape.
Citation Format: Hung-Ming Lam, Lisly Chéry, Ilsa Coleman, Bryce Lakely, Sandy Larson, Roger Coleman, Julio Aguirre-Ghiso, Jing Xia, Roman Gulati, Peter S. Nelson, Bruce Montgomery, Paul H. Lange, Linda A. Snyder, Robert L. Vessella, Colm Morrissey. Single cell transcriptomic analysis identified a potential dormant signature in prostate cancer disseminated tumor 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 4011. doi:10.1158/1538-7445.AM2014-4011