bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 804: Disseminated tumor cell heterogeneity and dormancy in prostate cancer.
Authors: Lam Hung-Ming , Chéry Lisly , Coleman Ilsa , Lakely Bryce , Larson Sandy , Coleman Roger , Brown Lisha , Doan Kathy , Noteboom Jennifer , Zhang Xiaotun , True Lawrence , Nelson Peter , Montgomery Bruce , Lange Paul , Snyder Linda , Vessella Robert , Morrissey Colm 
Published: August 2014

Abstract
Prostate cancer (PCa) can remain in the bone marrow for a prolonged period of time (&gt;5 years) while the patient shows no evidence of disease before the cancer eventually recurs. Dormant cancer cells can be detected in bone, the principal metastatic site of PCa, and these bone-homing cancer cells are known as disseminated tumor cells (DTC). Little information is available on the heterogeneity and dormancy of DTC in PCa. In this study, we isolated and compared the gene expression profile of individual DTC (n=45) from the bone marrow of 4 PCa patients with no evidence of disease and 5 patients with advanced disease. Using principle component analysis and cluster analysis of the 1000 most variable genes, we determined the heterogeneity of the DTC population within each patient. To identify a dormancy signature from DTC in the bone marrow and primary PCa cells, we carried out two gene expression analyses: DTC in patients with no evidence of disease vs. those with advanced disease, and primary PCa tissues from patients with a short vs. long dormancy period post radical prostatectomy (8-86 months). Genes associated in other cancers with cellular senescence, cell-cycle inhibition, and dormancy were analyzed. Candidate genes from both gene expression arrays were validated at the protein level by a tissue microarray consisting of 64 primary PCa cases that recurred after either a short or long dormancy period post radical prostatectomy (6-121 months).
The identification of heterogeneous gene signatures in DTC and novel proteins that promote dormancy will guide the development of possible biomarkers and therapeutic targets to prevent PCa recurrence, possibly by either eliminating DTC or inhibiting their escape from dormancy.
Citation Format: Hung-Ming Lam, Lisly Chéry, Ilsa Coleman, Bryce Lakely, Sandy Larson, Roger Coleman, Lisha Brown, Kathy Doan, Jennifer Noteboom, Xiaotun Zhang, Lawrence True, Peter Nelson, Bruce Montgomery, Paul Lange, Linda Snyder, Robert Vessella, Colm Morrissey. Disseminated tumor cell heterogeneity and dormancy in prostate 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 804. doi:10.1158/1538-7445.AM2013-804
Abstract 805: Simultaneous copy number gains of NUPR1 and ERBB2 predicting poor prognosis in early-stage breast cancer.
Authors: Chung Yeun-Jun , Jung Seung-Hyun , Lee Ahwon , Yim Seon-Hee 
Published: August 2014

Abstract
The full extent of chromosomal alterations and their biological implications in early breast carcinogenesis has not been well examined. In this study, we aimed to identify chromosomal alterations associated with poor prognosis in early-stage breast cancers (EBC). A total of 145 EBCs (stage I and II) were examined in this study. We analyzed copy number alterations in a discovery set of 48 EBCs using oligoarray-comparative genomic hybridization. In addition, the recurrently altered regions (RARs) associated with poor prognosis were validated using an independent set of 97 EBCs. A total of 23 RARs were defined in the discovery set. Six were commonly detected in both stage I and II groups (&gt; 50%), suggesting their connection with early breast tumorigenesis. There were gains on 1q21.2-q21.3, 8q24.13, 8q24.13-21, 8q24.3, and 8q24.3 and a loss on 8p23.1-p22. Among the 23 RARs, copy number gains on 16p11.2 (NUPR1) and 17q12 (ERBB2) showed a significant association with poor survival (P=0.0186 and P=0.0186, respectively). The patients simultaneously positive for both gains had a significantly worse prognosis (P=0.0001). In the independent replication, the patients who were double-positive for NUPR1-ERBB2 gains also had a significantly poorer prognosis on multivariate analysis (HR=7.31, 95% CI 2.65-20.15, P=0.0001). The simultaneous gain of NUPR1 and ERBB2 can be a significant predictor of poor prognosis in EBC. Our study will help to elucidate the molecular mechanisms underlying early-stage breast cancer tumorigenesis. This study also highlights the potential for using combinations of copy number alterations as prognosis predictors for EBC.
Citation Format: Yeun-Jun Chung, Seung-Hyun Jung, Ahwon Lee, Seon-Hee Yim. Simultaneous copy number gains of NUPR1 and ERBB2 predicting poor prognosis in early-stage breast 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 805. doi:10.1158/1538-7445.AM2013-805
Abstract 821: Subgroups of urothelial carcinoma of the bladder defined by genomic analysis.
Authors: Hurst Carolyn D. , Platt Fiona M. , Taylor Claire F. , Knowles Margaret A. 
Published: August 2014

Abstract
Urothelial carcinoma (UC) of the bladder is a heterogeneous disease and presents a significant challenge in disease management. The divergence in clinical behaviour of tumors of similar stage and grade indicates the presence of molecular subgroups. In this study we aimed to identify novel genomic subgroups of UC to provide improved subclassification at diagnosis. We assessed 160 bladder tumors comprising all stages and grades and including 49 high-stage T1 (T1G3) tumors for genome-wide copy number alterations and mutations in 8 key genes (AKT1, FGFR3, HRAS, KRAS, NRAS, PIK3CA, TP53, TSC1) implicated in UC. This revealed the existence of potential genomic subclasses of the “gold-standard” stage/grade groups of UC. The clinical management of patients with T1G3 tumors is particularly challenging as this subset of tumors exhibit highly divergent behaviour. Three major subgroups of T1G3 tumors were identified that differed with respect to copy number alterations and to FGFR3 and TP53 mutation status. One of these, which showed a prevalence of copy number losses, had the highest rate of stage progression/metastasis. We also identified novel regions of copy number alteration, concomitant molecular events, and relationships between molecular events and clinico-pathological features. Tumors harbouring FGFR3 mutations were found to be more chromosomally stable than their wild-type counterparts and FGFR3 mutation was mutually exclusive with overrepresentation of 8q in non-muscle-invasive tumors. In muscle-invasive (MI) tumors, losses of regions on 10q (including PTEN), 16q and 22q and gains on 10q, 11p, 12p, 19p and 19q were positively associated with metastasis. TP53 mutation in MI tumors was positively associated with losses on 16p, 2q, 4q, 11p, 10q, 13q, 14q, 16q and 19p and gains on 1p, 8q, 10q and 12q. Molecular alterations involving chromosome 9 were highly complex and copy number loss in the CDKN2A region was positively associated with deletions on 6p, 6q, 9p, 9q, 11p, 13q and 17p, and gains on 1q, 4q, 7p, 7q, 8p, 17q and 20q in MI tumors. Our findings add information to conventional histopathological classification and may lead to improved biological understanding and the development of robust prognostic biomarkers. Studies of larger numbers of tumors are underway to confirm the subgroups and relate findings to clinico-pathological data.
Citation Format: Carolyn D. Hurst, Fiona M. Platt, Claire F. Taylor, Margaret A. Knowles. Subgroups of urothelial carcinoma of the bladder defined by genomic analysis. [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 821. doi:10.1158/1538-7445.AM2013-821
Abstract 831: Elucidating the roles of differentially expressed microRNAs in glioblastoma multiform.
Authors: Liu Yi Shiuan 
Published: August 2014

Abstract
To understand the roles of miRNA in the pathogenesis of glioblastoma multiform (GBM), we used the quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay to profile 29 pairs of GBM core and peripheral tissue samples. We also employed deep sequencing technology to determine the expression levels of human miRNAs in one pair of GBM samples. These studies revealed that human miRNA miR-196b was over-expressed in GBM samples. Expression levels of miR-196b in cell lines derived from GBM tumors also exhibit a grade-dependent increase.
To explore the function of miR-196b in GBM, we constructed lentiviral vectors and overexpressed miR-196b in GBM cell lines. Over-expression of miR-196b enhanced cell growth and survival, promoted anchorage-independent growth and enhanced migration. To understand the targets and pathways underlying the tumor promoting activity of miR-196b, we compared gene expression patterns in control and miR-196b over-expressing cells. The cDNA microarray data were analyzed using the online GSEA Bioinformatics tools to indentify pathways altered by miR-196b. We also performed an in-house TargetScan analysis to predict and score putative miR-196b targets. Finally, results from GSEA analyses were combined with the target list which contained 700 high efficacy human miR-196b targets to identify targets of miR-196 with significant biological impact.
Through these studies, we will explore the potential roles of miR-196b in the regulation of tumor suppressor genes in brain cancer by elucidating the mechanisms of direct or indirect targets and downstream related genes.
Citation Format: Yi Shiuan Liu. Elucidating the roles of differentially expressed microRNAs in glioblastoma multiform. [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 831. doi:10.1158/1538-7445.AM2013-831
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 834: NRH:quinone oxidoreductase 2 (NQO2) stabilization of C/EBPα against 20S proteasomal degradation leads to protection against radiation-induced myeloproliferative diseases.
Authors: Xu Junkang , Jaiswal Anil 
Published: August 2014

Abstract
NRH:quinone oxidoreductase 2 (NQO2) is a flavoprotein that protects cells against radiation and chemical induced oxidative stress. Disruption of NQO2 gene in mice leads to γ-radiation-induced myeloproliferative diseases. In this report, we found that NQO2 in presence of its cofactor NRH protected C/EBPα against 20S degradation. Coimmunoprecipitation studies showed that 20S proteasome and NQO2 both interact with myeloid differentiation factor C/EBPα. 20S proteasome interaction with C/EBPα led to the degradation of C/EBPα. Deletion and site-directed mutagenesis demonstrated that NQO2 and 20S competed for the same binding region of S(268)GAGAGKAKKSV(279) in C/EBPα. Exposure of mice and HL-60 cells to γ-radiation enhanced the levels of NQO2, which led to increased NQO2 interaction with C/EBPα and decreased 20S interaction with C/EBPα. This resulted in the stabilization of C/EBPα and protection against γ-radiation-induced myeloproliferative diseases. NQO2-/- mice deficient in NQO2 failed to stabilize C/EBPα. This contributed to the development of γ-radiation-induced myeoproliferative disease in NQO2-/- mice.
Citation Format: Junkang Xu, Anil Jaiswal. NRH:quinone oxidoreductase 2 (NQO2) stabilization of C/EBPα against 20S proteasomal degradation leads to protection against radiation-induced myeloproliferative diseases. [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 834. doi:10.1158/1538-7445.AM2013-834
Abstract 836: Decursin and doxorubicin are in synergy for the induction of apoptosis via STAT3 and/or mTOR pathways in human multiple myeloma cells.
Authors: Jung Duck-Beom , Jeong Soo-Jin , Kwon Hee-Young , Jung Ji Hoon , sohn Eunjung , Sin Eun Ah , Kim Ji-Hyun , Cho Sun-Mi , Yun Miyong , Lee Hyo-jung , Kim Sung Hoon 
Published: August 2014

Abstract
Drug resistance causes a serious limitation for the chemotherapy of multiple myeloma. Combination cancer therapy is one of attractive approaches to overcome drug resistance of cancer cells. In the present study, we investigated the synergistic effect of decursin (a major compound in Angelica gigas) and doxorubicin on the induction of apoptosis in three human multiple myeloma cells. Concurrent treatment of decursin and doxorubicin significantly exerted significant cytotoxicity, while doxorubicin or decursin alone had no cytotoxic effect at physiologically relevant concentrations in signal transducer and activator of transcription 3 (STAT3) positive cell lines such as U266 and RPMI8226 cells and also STAT3 negative cell line MM.1S cells. We further demonstrated that the loss of the viability of the cells co-treated with decursin and doxorubicin was due to the induction of apoptosis. Combination treatment of doxorubicin and decursin enhanced the activation of caspapse-9 and 3, the cleavage of poly (ADP-ribose) polymerase (PARP) and sub G1 population compared to either drug alone in three multiple myeloma cells. In addition, the combined treatment of doxorubicin and decursin downregulated the phosphorylation of the mammalian target of rapamycin (mTOR) and its downstream S6K1 and activated the phosphorylation of extracellular signal regulated kinase (ERK) in three multiple myeloma cells. Furthermore, the combined treatment of doxorubicin and decursin reduced mitochondrial membrane potential, suppressed the phosphorylation of JAK2, STAT3 and Src, activated SHP-2 and attenuated the expression of cyclind-D and survivin in STAT3 positive U266 cells. Conversely, the broadly-acting tyrosine phosphatases inhibitor pervanadate reversed STAT3 inactivation and also PARP cleavage and caspase-3 activatio induced by combine treatment of doxorubicin and decursin in U266 cells.
Citation Format: Duck-Beom Jung, Soo-Jin Jeong, Hee-Young Kwon, Ji Hoon Jung, Eunjung sohn, Eun Ah Sin, Ji-Hyun Kim, Sun-Mi Cho, Miyong Yun, Hyo-jung Lee, Sung Hoon Kim. Decursin and doxorubicin are in synergy for the induction of apoptosis via STAT3 and/or mTOR pathways in human multiple myeloma 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 836. doi:10.1158/1538-7445.AM2013-836
Abstract 842: Role of Galectin-3 in invasive and apoptotic properties of neuroblastoma cells.
Authors: Wesley Umadevi V. , Resad Esat , Dempsey Robert J. 
Published: August 2014

Abstract
Background: Neuroblastoma (NB) is a childhood cancer derived from the neural crest stem cells. It generally progresses to an aggressive therapy resistant, fatal metastatic tumor. MYCN over-expression and amplification, and increased BDNF/TrkB signaling are used as signatures of high-risk NB. However, only about 25% of malignant tumors display these features. Thus, the identification of additional biomarkers and therapeutic targets is essential. Up-regulation of Galectin 3 (Gal-3), a multifunctional, carbohydrate binding cytokine has been extensively correlated with highly malignant behavior and poor prognosis of many cancers. However, the role of Gal-3 in NB is largely unknown. In this study, we investigated the expression pattern of Gal-3 in a panel of NB cell lines and examined whether silencing of Gal-3 expression by means of a siRNA approach decreases their invasive properties, and increases their sensitivity to pro-apoptotic chemotherapeutic drug, fenretinide (4-HPR), a synthetic retinoid derivative.
Materials and Methods: We utilized RT-PCR gene expression analysis, RNA interference approaches, western blot and immunofluorescence analysis, scratch technique, transwell Boyden chamber migration assay, colony forming assay, and cytokine antibody array screening to address these studies.
Results: Gal-3 expression is differentially regulated in TrkB-positive, MYCN-amplified (SMS-KCNR and SK-N-BE) and TrkB-negative, non-MYCN-amplified (SK-N-AS, SK-N-SH, and SH-SY5Y) NB cell lines. Gal-3 expression was significantly higher in SK-N-AS cells that are of glial sub-lineage. Gal-3 was expressed both in cytoplasm and membrane. On the other hand, Gal-3 expression was relatively lower in less invasive, non-tumorigenic SK-N-SH cells. Silencing of Gal-3 by a small-interfering RNA against Gal-3 (Gal-3-SiRNA) decreased the colony forming potential, in vitro migratory and angiogenic abilities of SK-N-AS cells. Pre-treatment with Gal-3 SiRNA increased the sensitivity of SK-N-AS cells to 4-HPR induced apoptosis. Furthermore, exogenous Gal-3 treatment in neuroblast like Neuro-2a cells resulted in the up-regulation of IL-6 and phosphorylation of the pro-survival molecule AKT.
Discussion: Our data suggest that Gal-3 mediates migratory and invasive phenotype of non-MYCN amplified NB derived cells possibly via regulating the IL-6 signaling and Akt phosphorylation. Silencing of Gal-3 may be potentially useful to suppress the resistance of NB cells to apoptosis.
Citation Format: Umadevi V. Wesley, Esat Resad, Robert J. Dempsey. Role of Galectin-3 in invasive and apoptotic properties of neuroblastoma 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 842. doi:10.1158/1538-7445.AM2013-842
Abstract 843: Inhibition of AKT signaling promotes FOXO3a-dependent apoptosis in castration-resistant prostate cancer cells.
Authors: Das Trinath P. , Damodaran Chendil 
Published: August 2014

Abstract
Treatment for aggressive prostate cancers involves hormonal ablation therapy, radical prostatectomy, radiation therapy, chemotherapy or in combination. Despite their initial sensitivity to these treatments, prostate cancer eventually progresses to castration -resistant prostate cancer (CRPC), which is both aggressive and refractory to current therapeutic modalities. Hence, CRPC demands the identification of novel targeted therapies with minimal side effects. We identified Withaferin-A (WA) a major bioactive compound derived from the medicinal plant, Withania somnifera, is extensively used in Asian herbal medicines to treat a variety of ailments, including cancer. Earlier, we reported that WA induced the pro-apoptotic gene, prostate apoptosis response-4 (Par-4) and apoptosis in CRPC cells. These results encouraged us to determine the mechanism of action of WA on CRPC cells. It is known that activated AKT negatively regulates forkhead transcription factor class O family protein (FOXO3a) that regulates genes involved with tumorigenesis, cell cycle arrest or apoptosis.
In the present study, we found that FOXO3a is an upstream of Par-4 signaling which transactivates Par-4 function in CRPC cells. Inhibition of AKT activation by WA facilitates nuclear translocation of FOXO3a which in turn activates Par-4 mediated apoptosis in CRPC cells. Our confocal and immuno-precipitation studies confirmed that upon activation. FOXO3a and Par-4 were co-localized in the nucleus. Similar results were found with overexpression of FOXO3a showing transactivation of Par-4 and growth arrest in CRPC cells. Treatment of actinomycin-D or cyclohexmide along with WA, confirmed that FOXO3a regulation on Par-4 function in CRPC cells. On contrary, inhibition of FOXO3a by siRNA resulted in down regulation of Par-4 and apoptosis by WA in CRPC cells suggesting FOXO3a activation is necessary for the induction of Par-4 mediated apoptosis. Promoter bashing studies suggest a direct interaction of FOXO3a with Par-4 promoter; a sequential deletion of FOXO3a DNA binding sites in Par-4 promoter fails to induce Par-4 activation upon WA treatment in CRPC cells. Overall, our studies conclude that Par-4 is a target of FOXO3a, and Par-4 activation is required for induction of apoptosis in CRPC cells. Activation of FOXO3a is an attractive target for the treatment of CRPC and molecules such as WA can be explored further for the treatment of CRPC.
Citation Format: Trinath P. Das, Chendil Damodaran. Inhibition of AKT signaling promotes FOXO3a-dependent apoptosis in castration-resistant prostate cancer 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 843. doi:10.1158/1538-7445.AM2013-843
Abstract 860: In vitro and in vivo studies of a novel, functionalized, completely human serine protease targeting Her2/neu. Activity against Herceptin- and multi-drug resistant tumor cells .
Authors: Cao Yu , Mohamedali Khalid A. , Marks John W. , Cheung Lawrence H. , Hittelman Walter N. , Rosenblum Michael G. 
Published: August 2014

Abstract
A number of recombinant fusion constructs and drug conjugates demonstrate excellent efficacy in preclinical studies but the long-term clinical applicability of these agents may be limited by tolerability issues and the emergence of multi-drug resistance. To address these issues, we employed the human serine protease granzyme B (GrB) as a cytotoxic effector and the humanized scFv designated 4D5 targeting the Her2/neu extracellular domain. A human fusion construct designated GrB/4D5/26 containing the fusogenic peptide 26 was constructed. The GrB/4D5/26 fusion construct showed specific and rapid cellular uptake into Her2/neu positive but not Her2/neu negative cells. We demonstrated efficient, specific delivery of GrB to the cytosol of Her2/neu positive cells. Against a panel of Her2/neu-positive tumor cells, IC50 values of the fusion construct ranged from 10∼100 nM, compared to that of GrB which was in the μM range. Treatment with GrB/4D5/26 resulted in specific cell killing accompanied by activation of caspases, PARP cleavage and cytochrome C release from mitochondria. In contrast to studies from other groups, the cytotoxic effects of the GrB/4D5/26 fusion construct did not require the assistance of the endosomolytic reagent chloroquine. Treatment with GrB/4D5/26 also caused efficient downregulation of the PI3K/Akt and Ras/ERK signaling pathways. Tumor cell lines highly resistant to Lapatinib, Herceptin or chemotherapeutic agents were not cross-resistant to the GrB-based fusion protein. Consecutive intravenous injections of GrB/4D5/26 into nude mice bearing BT474 M1 tumors resulted in significant, long-term tumor growth suppression. Twenty-four hours after i.v. administration, excised tumors displayed an increase in GrB/4D5/26 concentration and apoptotic nuclei compared to saline controls. These studies demonstrate the impressive in vitro and in vivo activity of the the completely human Her2/neu targeted construct and suggest its further evaluation for clinical use. Research conducted, in part, by the Clayton Foundation for Research.
Citation Format: Yu Cao, Khalid A. Mohamedali, John W. Marks, Lawrence H. Cheung, Walter N. Hittelman, Michael G. Rosenblum. In vitro and in vivo studies of a novel, functionalized, completely human serine protease targeting Her2/neu. Activity against Herceptin- and multi-drug resistant tumor 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 860. doi:10.1158/1538-7445.AM2013-860