bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4990: Epidermal growth factor-induced expression of PTX3 regulates metastasis of head and neck squamous cell carcinoma
Authors: Chen Ben-Kuen , Wu Shuo-Lun , Tsai Jhih-Peng
Published: May 2015

Overexpression of epidermal growth factor receptor (EGFR) and production of proinflammatroy cytokines are common in head and neck squamous cell carcinoma (HNSCC) and correlates with enhanced invasion and metastasis. However, molecular mechanisms associated with activation of EGFR and productions of cytokines in regulating metastasis of HNSCC remain poorly understood. Here, we identified PTX3 as a metastasis-promoting factor in HNSCC to regulate EGF-induced metastasis. We found that EGF induced the expression of PTX3, and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt/NF-κB and AP-1 signaling pathways in the EGF-induced PTX3 gene expression was confirmed by knockdown of RelA and c-Jun, respectively. The expression of dominant negative IκB also repressed the activation of NF-κB and inhibited EGF-induced PTX3 expression. Furthermore, EGF increased the binding of NF-κB and c-Jun to the AP-1 binding site of the PTX3 promoter through the activation of the Akt/NF-κB pathway, which resulted in activating PTX3 promoter activity. In addition, EGF stimulated the secretion of PTX3 from cancer cells, resulting in enhancing cancer metastasis and the interaction between cancer cells and endothelial cells. EGF-enhanced metastasis-related molecules, such as fibronectin and MMP-9, and reduction of E-cadherin were reversed in PTX3 knockdown cells. These findings suggest that autocrine production of EGF-induced PTX3 regulates metastasis of HNSCC by mediating the expression levels of metastatic molecules fibronectin, MMP-9 and E-cadherin. The EGF-induced PTX3 could be a potential diagnostic marker and target for metastasis in the cancer therapy.

Citation Format: Ben-Kuen Chen, Shuo-Lun Wu, Jhih-Peng Tsai. Epidermal growth factor-induced expression of PTX3 regulates metastasis of head and neck squamous cell carcinoma. [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 4990. doi:10.1158/1538-7445.AM2014-4990
Abstract 4993: IFI27 and NOV, downstream regulated genes by S100A4, are playing important roles in pancreatic carcinogenesis
Authors: Chen Na , Saiki Yuriko , Sekine Hitoshi , Sunamura Makoto , Fukushige Shinichi , Motoi Fuyuhiko , Egawa Shinichi , Unno Michiaki , Horii Akira
Published: May 2015

S100A4 is a member of the Ca2+-dependent S100 protein family, and positive association between S100A4-upregulation andmetastasis/invasion was reported. We reported a significant association between upregulation of S100A4 and perineural invasion in pancreatic cancer. Furthermore, siRNA-mediated knockdown of S100A4 promoted cell death mainly mediated by induction of apoptosis only in cancer cells with high expression of S100A4, and forced expression of S100A4 induced accelerated cell motility only in cancer cells with low expression. To explore the molecular mechanisms of cell motility after the forced expression of S100A4, we analyzed gene expression profiles and identified some candidate genes including IFI27 and NOV (CCN3) that are regulated by S100A4-upregulation, and we further focused on IFI27 and NOV. IFI27 showed significant upregulation after the forced expression of S100A4 and downregulation after siRNA mediated knockdown of S100A4, while NOV seemed to show an inverse relationship with S100A4. Using 93 primary resected tumors, we performed immunohistochemical analyses and identified significant positive association between S100A4 and IFI27 expressions. Although NOV did not show significant inverse-association, siRNA-mediated knockdown in high level expressing cells showed significant acceleration of cell motility. Clinicopathologic characteristics demonstrated positive associations between IFI27 expression and intrapancreatic neural invasion (P=0.0023) and negative associations between NOV expression and invasion pattern (P=0.017) were observed. Our present study suggests that IFI27 and NOV may be downstream regulated genes of S100A4 and that expressional changes may play important roles in invasion of pancreatic cancer.

Citation Format: Na Chen, Yuriko Saiki, Hitoshi Sekine, Makoto Sunamura, Shinichi Fukushige, Fuyuhiko Motoi, Shinichi Egawa, Michiaki Unno, Akira Horii. IFI27 and NOV, downstream regulated genes by S100A4, are playing important roles in pancreatic carcinogenesis. [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 4993. doi:10.1158/1538-7445.AM2014-4993
Abstract 4996: Interferon consensus sequence binding protein (ICSBP) promotes epithelial to mesenchymal transition (EMT)-like phenomena, cell motility, and invasion via TGF-β signaling in U2OS cells
Authors: Sung Jee Young , Park Seog-Yun , Kim June Hyuk , Kang Hyun Guy , Yoon Jong Hyung , Na Yoon Sook , Kim Yong-Nyun , Park Byung-Kiu
Published: May 2015

Interferon consensus sequence binding protein (ICSBP) is a transcription factor induced by interferon gamma (IFN-γ) and a member of the interferon regulatory factor (IRF) family. ICSBP is predominantly expressed in hematopoietic cells and regulates the immune response and cell growth and differentiation. However, little is known about its function in non-hematopoietic cells. Here we show a novel function for ICSBP in epithelial to mesenchymal transition (EMT)-like phenomena (ELP), cell motility, and invasion in human osteosarcoma cell lines, including U2OS cells. IFN-γ treatment induced ICSBP expression and EMT-like morphological change in U2OS cells, which were suppressed by ICSBP knock-down. To further investigate the role of ICSBP in ELP, we established a stable U2OS cell line that overexpresses ICSBP. ICSBP expression caused U2OS cells to have a more elongated shape and an increased vimentin and fibronectin expression. ICSBP expression also promoted adhesiveness, motility, and invasiveness of U2OS cells. ICSBP up-regulated transforming growth factor (TGF)-β receptors and activated TGF-β signaling cascades, which were responsible for ELP as well as increased cell motility and invasion. In addition, ICSBP-induced TGF-β receptor activation resulted in the up-regulation of Snail. Knock-down of Snail attenuated the ICSBP-induced augmentation of cell motility and invasion. Up-regulation of Snail, ELP, and increased invasion by ICSBP expression were also observed in other osteosarcoma cell lines, such as Saos-2 and 143B. Furthermore, ICSBP and TGF- β receptor I were expressed in 45/54 (84%) and 47/54 (87%) of human osteosarcoma tissues, respectively, and showed significant correlation (r= 0.47, p= 0.0007) with respect to their expression levels. Taken altogether, these data demonstrate a novel function for ICSBP in ELP, cell motility, and invasion through the TGF-β and Snail signaling pathways

Citation Format: Jee Young Sung, Seog-Yun Park, June Hyuk Kim, Hyun Guy Kang, Jong Hyung Yoon, Yoon Sook Na, Yong-Nyun Kim, Byung-Kiu Park. Interferon consensus sequence binding protein (ICSBP) promotes epithelial to mesenchymal transition (EMT)-like phenomena, cell motility, and invasion via TGF-β signaling in U2OS 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 4996. doi:10.1158/1538-7445.AM2014-4996
Abstract 4997: MMP14 as PTP4A3 downstream target is involved in uveal melanoma cell dissemination
Authors: Maacha Selma
Published: May 2015

Abstract: Uveal melanoma is the most common intraocular malignancy in adults, representing 5% of all melanomas. Although at diagnosis over 95% of patients have disease limited to the eye, about 50% will develop metastases after a median period of 36 months. High expression levels of Protein Tyrosine Phosphatase 4A3 (PTP4A3), a dual phosphatase, is highly predictive of metastasis development and PTP4A3 overexpression in uveal melanoma cells increases their in vitro migration and in vivo invasiveness. The PTP4A3 mechanism of action in the tumoral process is poorly understood. We identified the metalloprotease MMP14 as an interacting partner of PTP4A3. MMP14 is more abundant at the cell membrane in PTP4A3 invasive cells compared to control cells (inactive catalytic site mutant GFP-PTP4A3(C104S) or EGFP) and inhibition of MMP14 expression decreases PTP4A3-induced cell invasiveness. The MMP14-differential cell membrane localization in presence of PTP4A3 is currently investigated by studying the trafficking of MMP14 in these cells.

Citation Format: Selma Maacha. MMP14 as PTP4A3 downstream target is involved in uveal melanoma cell dissemination. [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 4997. doi:10.1158/1538-7445.AM2014-4997
Abstract 4999: Paracrine regulation of glioma invasion by astrocytes is mediated by glial derived neurothropic factor
Authors: Amit Moran , Shabtay-Orbach Ayelet , Binenbaum Yoav , Gil Ziv
Published: May 2015

Purpose: Glial cells have been shown to play a role in glioma progression. Here we investigate the mechanism by which astrocytes which are abundant in glioma tumors, promote cancer cell invasion.

Experimental Design: In this study, we evaluated the effects of astrocytes on glioma biology both in vitro and in vivo and determined the downstream paracrine effect of glial derived neurotropic factor (GDNF) on tumor invasion.

Results: Astrocytes conditioned media (ACM) significantly increased human and murine glioma cells migration compared to controls. This effect was inhibited when the activity of GDNF on glioma cells was blocked by RET-Fc chimera or anti-GDNF Ab and by siRNA directed against GDNF expression by astrocytes. Glioma cell incubation with ACM led to time dependent phosphorylation of the GDNF receptor, RET and downstream AKT phosphorylation. Tumor migration and GDNF-RET-AKT activation was inhibited by the RET small molecule inhibitor pyrazolopyrimidine-1 and by the AKT inhibitor LY294002. Finally, blocking of RET by pyrazolopyrimidine-1 or knockout of the RET co receptor GFRα1 in glioma cells reduced the size of brain tumors in immunocompetent mice.

Conclusions: We suggest a mechanism by which astrocytes attracted to the glioma microenvironment facilitate brain invasion by secretion of GDNF and activation of RET/GFRα1 receptors expressed by the cancer cells.

Note: This abstract was not presented at the meeting.

Citation Format: Moran Amit, Ayelet Shabtay-Orbach, Yoav Binenbaum, Ziv Gil. Paracrine regulation of glioma invasion by astrocytes is mediated by glial derived neurothropic factor. [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 4999. doi:10.1158/1538-7445.AM2014-4999
Abstract 5: Real-time in vivo imaging of osteosarcoma angiogenesis
Authors: Uehara Fuminari , Tome Yasunori , Maehara Hiroki , Kanaya Fuminori , Miwa Shinji , Hiroshima Yukihiko , Yano Shuya , Yamamoto Mako , Matsumoto Yasunori , Hoffman Robert M.
Published: May 2015

We report here real-time color-coded imaging of osteosarcoma-induced angiogenesis in vivo. Gelfoam® (5×5 mm) treated with β fibroblast growth factor (bFGF) was initially transplanted subcutaneously in the flank of transgenic nestin-driven green fluorescent protein (ND-GFP) nude mice (n=12). In ND-GFP mice, nascent blood vessels are labeled with GFP, including those growing in Gelfoam®. Seven days after transplantation of Gelfoam®, skin flaps were made and human 143B osteosarcoma cells expressing GFP in the nucleus and red fluorescent protein (RFP) in the cytoplasm were injected into the transplanted Gelfoam®. The control group had only Gelfoam® transplanted without subsequent cancer-cell inoculation. Skin flaps were made at days 14, 21, 28 after transplantation of the Gelfoam® to allow observation of vascularization of the Gelfoam® using fluorescence imaging after both with and without cell inoculation. ND-GFP expressing nascent blood vessels penetrated and spread into the Gelfoam® in both the non-cellular control and after cancer-cell inoculation. The mean length of ND-GFP expressing blood vessels of mice with osteosarcoma cells seeded on the Gelfoam® increased compared to the Gelfoam®-only control at days 14, 21, 28 after transplantation of the Gelfoam® (at day 14, 21 ; p<0.05, at day 28 ; p<0.01). The results demonstrate that the osteosarcoma cells stimulated angiogenesis within the Gelfoam®. This model enables facile imaging of cancer-cell-induced angiogenesis and the study of its mechanism and inhibition.

Citation Format: Fuminari Uehara, Yasunori Tome, Hiroki Maehara, Fuminori Kanaya, Shinji Miwa, Yukihiko Hiroshima, Shuya Yano, Mako Yamamoto, Yasunori Matsumoto, Robert M. Hoffman. Real-time in vivo imaging of osteosarcoma angiogenesis. [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 5. doi:10.1158/1538-7445.AM2014-5
Abstract 5008: The acetylenic tricyclic bis(cyanoeneone), TBE-31 inhibits non-small cell lung cancer cell migration through direct binding with actin
Authors: Chan Eddie , Saito Akira , Honda Tadashi , Guglielmo John D.
Published: May 2015

During metastasis tumor cells undergo epithelial to mesenchymal transition (EMT), where cell-cell junctions dissolve and actin stress fibers are formed. This transition unmasks the migratory and invasive potential of the tumor cells. Here we show that the tricyclic compound TBE-31 binds to purified actin as well as actin from cell lysates. Furthermore, TBE-31 inhibits linear and branched actin polymerization in vitro as well as stress fiber formation in fibroblasts. We also observed that TBE-31 inhibits stress fiber formation in non-small lung cancer cells during TGFβ-dependent EMT. Interestingly, TBE-31 does not interfere with TGFβ-dependent signaling or changes in E- and N-cadherin protein levels during EMT. Finally, we observed that TBE-31 inhibits non-small cell lung tumor cell migration. Our results suggest that TBE-31 targets linear actin polymerization to alter cell morphology and inhibit cell migration.

Citation Format: Eddie Chan, Akira Saito, Tadashi Honda, John Di Guglielmo. The acetylenic tricyclic bis(cyanoeneone), TBE-31 inhibits non-small cell lung cancer cell migration through direct binding with actin. [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 5008. doi:10.1158/1538-7445.AM2014-5008
Abstract 5009: Thymoquinone downregulates n-cadherin, twist and snail expression and inhibits migration and invasion in cancer cells
Authors: Khan Md. Asaduzzaman , Yang Manman , Wei Chunli , Gan Lin , Fu Junjiang
Published: May 2015

Background: Metastasis is the major characteristic of malignant carcinomas, which has been found to be linked with epithelial to mesenchymal transitions (EMT). Regulation of EMT process can provide a significant beneficiary effect to control metastasis, as well as to treat cancers. In this study we have investigated the effects of natural product Thymoquinone in metastatic cancer cell lines to evaluate their role in metastatic characteristics linked to EMT process.

Methods: We have treated HeLa and MDA-MB-435 human cancer cell lines with Thymoquinone, and analyzed the cell proliferation, migration and invasion, which are the major metastatic characteristics, by using the real-time cell analyzer. The real-time PCR and Western blot analysis was employed for the determination of the cellular expression of major EMT-associated proteins N-cadherin and E-cadherin; their transcription factors Twist, Snail, Slug and Zeb; and another important metastatic protein Vimentin.

Results: Thymoquinone was found to inhibit the migratory and invasive characteristics in both cancer cell lines dose dependently, and effective in a low dose eventually (1-5 μM). Its cytotoxicity has also been confirmed by MTT assay for cell viability. Genetic expression analysis showed that Thymoquinone significantly down-regulates the mRNA expression of cell adhesion protein N-cadherin in HeLa cell. Thymoquinone also down-regulates the transcription factor Twist, which is being considered as an oncoprotein. Thymoquinone has mild to moderate effect on the expression pattern of other metastatic proteins in HeLa cells. In MDA-MB-435, Thymoquinone treatment downregulates Twist, Snail, Vimentin and N-cadherin. However, N-cadherin expression was found in extremely low in both untreated and treated MDA-MB-435.

Conclusions: We report that the prospective anticancer molecule Thymoquinone down-regulates N-cadherin and its transcription factors like Twist and Snail, which might have a significant influence on the effects of Thymoquinone in controlling cell migration and invasion. Further research is necessary for the investigation of this compound in specific cancer types with mechanisms in detail.

Fund support: This work was supported in part by the National Natural Science Foundation of China (81172049, 30371493), Science and Technology Innovation Team of Colleges and Universities of Sichuan Province (13TD0032).

Citation Format: Md. Asaduzzaman Khan, Manman Yang, Chunli Wei, Lin Gan, Junjiang Fu. Thymoquinone downregulates n-cadherin, twist and snail expression and inhibits migration and invasion in 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 5009. doi:10.1158/1538-7445.AM2014-5009
Abstract 5015: TCR usage analysis in blood reveals different mechanisms of action of CTLA-4 and PD-1 blockade in patients
Authors: Robert Lidia , Harview Christina L. , Emerson Ryan , Mok Stephen , Homet Blanca , Comin-Anduix Begonya , Koya Richard C. , Robins Harlan , Tumeh Paul C. , Ribas Antoni
Published: May 2015

Immune-checkpoint blockade therapies are providing long-lasting responses in a subset of patients with malignant metastatic melanoma. In an effort to better understand the underlying mechanism, the T-cell population in peripheral blood mononuclear cells (PBMCs) was characterized. The complementarity determining region 3 (CDR3) of the rearranged T cell receptor variable ß chain genes (TCR Vß) was sequenced. This was performed using gDNA extracted from the PBMCs of twenty-one patients that were treated with antibody to Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) (tremelimumab) and seven patients that were treated with antibody to the Programmed Death-1 (PD-1) blockade (MK-3475) at baseline and at day 30-60 post first treatment. Four healthy donors were also sequenced as controls. Control PBMCs displayed random distribution with three patients showing a decrease and one showing an increase in the number of unique productive sequences (UPS) from baseline to the time after first cycle. In PBMCs from patients receiving the CTLA-4 antibody, two out of 21 samples showed a decrease in total number of UPS, while 19 out of 21samples experienced an increase. In PBMCs from patients receiving PD-1 antibody, the reponse was more similar to healthy donors as 5 out of 7 (71%) displayed a decrease and 2 out 7 (29%) an increase in total UPS from the pre to post timepoint. There was an increase in the absolute lymphocyte count (ALC) after CTLA-4 blockade therapy (p=0.03), but not in the samples from patients treated with PD-1 antibody (p=0.53). A direct correlation between ALC increase and increase in UPS for CTLA-4 blockade was ruled out (p=0.1 Spearman Correlation). When analyzing according to clinical response status, all responders to CTLA-4 blockade (4 out of 19) experienced an increase in the number of circulating clones. However, samples from clinical responders to PD-1 blockade showed an increase (2 out of 5) or decrease (1 out of 2) in the circulating pool. Considering the concerning toxicity profile for CTLA-4-blockade versus the mild toxicity for PD-1 antibodies, this data supports a model where CTLA-4 blockade induces a non-specific systemic expansion of T cells, while PD-1 blockade may have more specific effects directly in the tumor.

Citation Format: Lidia Robert, Christina L. Harview, Ryan Emerson, Stephen Mok, Blanca Homet, Begonya Comin-Anduix, Richard C. Koya, Harlan Robins, Paul C. Tumeh, Antoni Ribas. TCR usage analysis in blood reveals different mechanisms of action of CTLA-4 and PD-1 blockade in patients. [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 5015. doi:10.1158/1538-7445.AM2014-5015
Abstract 5046: What do they do? Patient navigator actions and timely treatment within 30 days of diagnosis in Latinas with breast cancer: The Six Cities Study
Authors: Ramirez Amelie G. , Perez-Stable Eliseo J. , Talavera Gregory A. , Penedo Frank , Carrillo Emilio J. , Fernandez Maria E. , Holden Alan E. , Munoz Edgar , Gallion Kipling J.
Published: May 2015

Background: Breast cancer is the leading cause of cancer deaths in Latinas, primarily due to screening and treatment disparities. Patient navigation has emerged as an effective means to reduce these disparities, although how this is achieved is insufficiently documented.

Methods: We analyzed navigator logs of activities conducted on behalf of 42 navigated Latinas diagnosed with breast cancer from July 2008-January 2011. Women were navigated by locally trained navigators who resolved patient-reported barriers using one of 10 specific actions: referral, accompaniment, transportation, telephone support, records assistance, health education, appointment reminders, family support, translation services, or health care system intervention. We calculated the frequency of patient-reported barriers to cancer treatment, their association with navigator actions (correlation), and the association of these actions on time to primary treatment initiation within 30 days of confirmed diagnosis (Chi-squared analysis).

Results: Patients reported 323 potential barriers to care between diagnosis and initial treatment. Translation (44.3%), specific or generalized fear (14.9%), and transportation (6.5%) were the most commonly reported barriers. Barriers were resolved utilizing activities defined above as determined by navigators; some barriers were resolved with as few as one action. Correspondence (correlation) between reported barriers and navigator actions was high (r=0.985 to r=1.000). Five navigator actions were associated with earlier treatment relative to navigated women not utilizing these specific services (accompaniment: p=.006; transportation: p=.007; telephone support: p=.034; family support: p=.030; translation services: p=.004).

Conclusions: Specific patient navigation activities significantly increase the proportion of Latinas with breast cancer women who begin treatment within 30 days of diagnosis. It likely results in reduction of mortality in this group.

Citation Format: Amelie G. Ramirez, Eliseo J. Perez-Stable, Gregory A. Talavera, Frank Penedo, Emilio J. Carrillo, Maria E. Fernandez, Alan E. Holden, Edgar Munoz, Kipling J. Gallion. What do they do? Patient navigator actions and timely treatment within 30 days of diagnosis in Latinas with breast cancer: The Six Cities Study. [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 5046. doi:10.1158/1538-7445.AM2014-5046
Abstract 5051: Retrospective analysis of direct inpatient charges and mortality of leukemia pediatric patients with Methicillin-resistant Staphylococcus aureus, Candida, or Aspergillus infections in the United States
Authors: Nuño Tomas , Skrepnek Grant H.
Published: May 2015

Objective: The purpose of this study was to assess risk factors that are associated with inpatient charges and mortality rates with Methicilin-resistant Staphylococcus aureus (MRSA), Aspergillus, and Candida in children with leukemia. We hypothesize that MRSA and opportunistic fungal infections are associated with higher inpatient charges and worse outcomes relative to those without infections. Identifying the risk factors that affect mortality and inpatient charges of these infections should add to the current knowledge of treating and preventing these infections in immune compromised patients.

Methods: Retrospective cohort study using the Agency for Healthcare Research Quality's Healthcare Cost and Utilization Project 2009 KIDS database. Overall, 33,020 individual hospital visits were analyzed for pediatric leukemia patients.

Results: Predictors of increased mortality were: Age (OR=1.1, SE=0.02), MRSA (OR=7.2, SE=5.2), Aspergillus (OR=6.3, SE=2.1), Candida (OR=5.7, SE=1.3), and Deyo-Charlson comorbidity scores (OR=1.7, SE=0.13). Significant predictors of increased inpatient charges were: MRSA (OR=2.2, SE=0.35), Aspergillus (OR=2.7, SE=0.25), Candida (OR=2.3, SE=0.15), Female Sex (OR=1.1, SE=0.04), Deyo-Charlson comorbidity scores (OR=1.2, SE=0.04), Urban Hospitals (OR=1.9, SE=0.24), and the Southern Region (OR=0.84, SE=0.2=07). Significant predictors of increased length of stay were similar to predictors of inpatient charges.

Conclusions: Although uncommon in leukemia cases involving pediatrics or young adults, risks of higher mortality, length of stay, and inpatient charges were noted in cases involving MRSA, Aspergillus, and Candida. The burden of these illnesses requires further attention in order to improve outcomes among patients with leukemia.

Citation Format: Tomas Nuño, Grant H. Skrepnek. Retrospective analysis of direct inpatient charges and mortality of leukemia pediatric patients with Methicillin-resistant Staphylococcus aureus, Candida, or Aspergillus infections in the United States. [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 5051. doi:10.1158/1538-7445.AM2014-5051
Abstract 5062: Serum microRNA profiling in non-muscle invasive bladder cancer
Authors: Lian Jie , Lin Shu-Hong , Luo Sherri , Huang Maosheng , Gu Jian , Kamat Ashish M. , Dinney Colin P. , Wu Xifeng
Published: May 2015

MicroRNAs (miRNAs) are associated with the development of nearly all cancers and serum miRNAs are promising biomarkers for early detection, diagnosis, and prognosis of cancer. We sought to identify serum miRNAs as potential diagnostic biomarkers for bladder cancer. To this end, global miRNA profiling was performed on sera in a pilot sample set containing matched non-muscle-invasive bladder cancer (NMIBC) and healthy controls to identify highly abundant serum miRNAs. Eighty nine miRNAs were stably detectable in cases and controls and selected for further testing. These 89 miRNAs were simultaneously quantified by high-throughput Taqman analysis using the Fluidigm BioMark™ HD System in a discovery set (140 NMIBC patients and 139 control subjects) and a validation set (140 NMIBC patients and 139 control subjects). In the discovery phase, 12 miRNAs showed significant differential expression between NMIBC patients and controls. In the validation phase, expression of one miRNA, miR-409-3p, remained significantly down-regulated in patients with NMIBC as compared to controls. The risk estimates of bladder cancer for miR-409-3p by tertile distributions in controls showed a significant trend for increased risk at the highest tertile for the whole sample set (odds ratio (OR) = 2.26; 95% confidence interval (CI) =1.42-3.59; P = 5.95 × 10−4) as well as for age > 65 (OR = 2.32; 95% CI =1.24-4.34; P =4.60 × 10−3) and ever smokers (OR = 2.34; 95% CI =1.31-4.18; P =4.05 × 10−3). Analyses of joint effects of this risk factor showed that the OR was statistically significantly elevated to 5.21 (95% CI =2.72-10.00; P =6.84 × 10−7) for the sample set including both the lowest level of miR-409-3p and ever smokers. Thus the differential expression miR-409-3p in serum distinguishes NMIBC and controls and may contribute to bladder cancer development.

Citation Format: Jie Lian, Shu-Hong Lin, Sherri Luo, Maosheng Huang, Jian Gu, Ashish M. Kamat, Colin P. Dinney, Xifeng Wu. Serum microRNA profiling in non-muscle invasive bladder 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 5062. doi:10.1158/1538-7445.AM2014-5062
Abstract 5065: Fine-mapping the HOXB region detects common variants tagging a rare coding allele: Evidence for synthetic association in prostate cancer
Authors: Kote-Jarai Zsofia , Saunders Edward , Dadaev Tokhir , Leongamornlert Daniel , Jugurnauth-Little Sarah , Tymrakiewicz Malgorzata , Govindasami Koveela , Wiklund Fredrik , Olama Ali Amin Al , Benlloch Sara ,   The PRACTICAL Consortium, Easton Douglas , Muir Keneth , Eeles Rosalind
Published: May 2015

The HOXB13 gene has been implicated in prostate cancer susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 prostate cancer cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with prostate cancer risk, described by rs117576373, OR 1.30, P = 2.62×10-14. Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene, G84E, rs138213197, which has been identified recently as a moderate penetrance prostate cancer susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.

Citation Format: Zsofia Kote-Jarai, Edward Saunders, Tokhir Dadaev, Daniel Leongamornlert, Sarah Jugurnauth-Little, Malgorzata Tymrakiewicz, Koveela Govindasami, Fredrik Wiklund, Ali Amin Al Olama, Sara Benlloch, The PRACTICAL Consortium, Douglas Easton, Keneth Muir, Rosalind Eeles. Fine-mapping the HOXB region detects common variants tagging a rare coding allele: Evidence for synthetic association in prostate 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 5065. doi:10.1158/1538-7445.AM2014-5065
Abstract 5067: An expressed retrogene of master embryonic stem cell factor OCT4 alters prostate cancer susceptibility
Authors: Breyer Joan , Dorset Daniel , Clark Travis , Bradley Kevin , Wahlfors Tiina , McReynolds Kate , Maynard William , Chang Sam , Cookson Michael , Smith Joseph , Schleutker Johanna , Dupont William , Smith Jeffrey R.
Published: May 2015

Genetic association studies of prostate and other cancers have identified a major risk locus at chromosome 8q24, but a causal gene and a mechanism for cancer predisposition has remained elusive. The locus harbors the POU5F1B retrogene and several non-coding RNA genes, and is also proximal to the MYC oncogene. The open reading frame of the retrogene is preserved with 96% identity to that of the parent POU5F1 gene on chromosome 6, encoding the master embryonic stem cell factor Oct4. We observed that 8q24 risk alleles are significantly correlated with reduced expression of the POU5F1B retrogene in normal prostate tissue. The alleles were not correlated with the expression of MYC or other flanking genes in normal prostate tissue. Predicted deleterious POU5F1B missense germline variants were also associated with risk of prostate cancer. Thus, two independent lines of genetic evidence support a potential causal role for POU5F1B in the transformation of normal prostate tissue. A plausible hypothesis of POU5F1B function is dysregulation of Oct4; POU5F1 is transcriptionally regulated by the encoded Oct4 transcription factor. The POU5F1B retrogene on 8q24 and POU5F1 on 6p21 were significantly co-expressed. These results suggest that a pathway critical to self-renewal of embryonic stem cells may also have a role in the origin of cancer.

Note: This abstract was not presented at the meeting.

Citation Format: Joan Breyer, Daniel Dorset, Travis Clark, Kevin Bradley, Tiina Wahlfors, Kate McReynolds, William Maynard, Sam Chang, Michael Cookson, Joseph Smith, Johanna Schleutker, William Dupont, Jeffrey R. Smith. An expressed retrogene of master embryonic stem cell factor OCT4 alters prostate cancer susceptibility. [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 5067. doi:10.1158/1538-7445.AM2014-5067
Abstract 507: ERβ1 decreases breast cancer cell survival by regulating the unfolded protein response
Authors: Thomas Christoforos , Rajapaksa Gayani , Nikolos Fotis , Bado Igor , Gustafsson Jan-Ake
Published: May 2015

Estrogen receptors (ERs) regulate cellular processes that influence the development and response of breast cancer to hormonal therapy. Unfolded protein response (UPR) has been identified as a key mechanism that determines endocrine responsiveness and cellular survival in breast cancer. UPR assists the cells to cope with the stress caused by the accumulation of unfolded proteins in the endoplasmic reticulum (ER). Although ERα is known to affect the cellular response to ER stress, the role of ERβ in regulating the UPR has not been investigated. Here we show that the wild-type ERβ (ERβ1) enhanced apoptosis in breast cancer cells in response to treatment with the ER stress inducers thapsigargin and bortezomib. Targeting the Bcl-2 in the ER of the ERβ1-expressing cells prevented the apoptosis induced by ER stress but not by non-ER stress apoptotic stimuli indicating that ERβ1 promotes ER stress-regulated apoptosis. ERβ1 promoted ER stress-induced apoptosis by suppressing the inositol-requiring enzyme-1 (IRE-1) pathway of the UPR. ERβ1 repressed the transcription of the IRE-1α gene and the subsequent splicing of the X-box binding protein-1 (XBP-1). These results suggest a potential role of ERβ1 in influencing stress and therapy response in breast cancer by regulating the UPR.

Citation Format: Christoforos Thomas, Gayani Rajapaksa, Fotis Nikolos, Igor Bado, Jan-Ake Gustafsson. ERβ1 decreases breast cancer cell survival by regulating the unfolded protein 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 507. doi:10.1158/1538-7445.AM2014-507
Abstract 5085: Inducing multipolarity of acentrosomal mitotic spindles as a novel tumor-specific targeting strategy revealed by the antimitotic effect of mdivi-1
Authors: Wang Jingnan , Qian Wei , Shuda Masahiro , Li Jianfeng , Santana-Santos Lucas , Sobol Robert W. , Houten Bennett Van
Published: May 2015

Traditional antimitotic drugs for cancer chemotherapy often have undesired toxicity to healthy tissue, limiting clinical application. Developing tumor-specific antimitotic strategies is necessary to improve the efficacy of drugs in the selective eradication of tumor cells. In this study, we discovered mdivi-1 (mitochondrial division inhibitor-1), which was originally reported as an inhibitor of mitochondrial fission protein dynamin-related protein 1 (Drp1), specifically disrupts M phase cell cycle progression only in human tumor cells and not in non-transformed fibroblasts and epithelial cells. The antimitotic effect of mdivi-1 is Drp1-independent, as M phase abnormality induced by mdivi-1 was observed in both Drp1 wild-type and Drp1 knockout MEF cells. We also identified that the tumor transformation process required for the antimitotic effect of mdivi-1 is downstream of SV40 large T and small t antigens - but not hTERT-mediated immortalization. Mdivi-1 induces multipolar mitotic spindles in tumor cells regardless of centrosome number. Acentrosomal spindle poles, which do not contain bona-fide centrosome components γ-tubulin and centrin-2, were found to contribute to the spindle multipolarity. The formation of such aberrant mitotic spindles leads to gross genome instability and apoptotic cell death through Bax/Bak-mediated mitochondrial outer membrane permeabilization (MOMP). Gene expression profiling comparing non-transformed and transformed cells revealed that the genes involved in assembly of acentrosomal spindles are highly up-regulated in tumor cells, thus providing the mechanism underlying the preferential formation of acentrosomal multipolar spindles in tumor cells compared to normal cells after mdivi-1 treatment. Taken together, our studies imply that mdivi-1 represents a novel class of quinazolinone compounds that function as acentrosomal spindle inducers (ASI). We suggest that promoting the assembly of multipolar mitotic spindles composed of acentrosomal poles could serve as a novel strategy in achieving a tumor-specific antimitotic effect.

(Work was supported by P30CA047904, GM087798, UPCI and PA Dept of Health CURE program)

Note: This abstract was not presented at the meeting.

Citation Format: Jingnan Wang, Wei Qian, Masahiro Shuda, Jianfeng Li, Lucas Santana-Santos, Robert W. Sobol, Bennett Van Houten. Inducing multipolarity of acentrosomal mitotic spindles as a novel tumor-specific targeting strategy revealed by the antimitotic effect of mdivi-1. [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 5085. doi:10.1158/1538-7445.AM2014-5085
Abstract 5086: BEX protein attenuates the mitotic checkpoint and induces preneoplastic aneuploidy
Authors: Lee Jin-Kwan , Ha Geun-Hyoung , Lee Janet , Lee Chang-Woo
Published: May 2015

The mitotic checkpoint plays a critical role in preventing chromosome missegregation and the adaptation of aneuploid cells. BubR1 kinase is a member of the mitotic checkpoint machinery. To understand the function of BubR1-mediated mitotic checkpoint, we have screened a novel BubR1-interating protein, BEX, by performing yeast two-hybrid systems. Here, we show that overexpression of BEX protein with sustained spindle poison results in a production of aneuploid cells and less apoptotic cell death. Inhibition of BubR1 expression increases aneuploid cell populations, whereas knockdown of both BEX and BubR1 avoid polyploidy by undergoing apoptosis in BubR1-depleted aneuploid cells. In addition, forced BEX expression significantly induces the colony forming potential and accelerates the proliferation rate. Interestingly, BEX is localized on X chromosome, and seems to be selectively expressed at cancer cells and tissues. These results indicate that BEX expression leads to mitotic dysfunction, and contributes to unstable chromosome aneuploid cells to be preneoplastically adapted.

Citation Format: Jin-Kwan Lee, Geun-Hyoung Ha, Janet Lee, Chang-Woo Lee. BEX protein attenuates the mitotic checkpoint and induces preneoplastic aneuploidy. [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 5086. doi:10.1158/1538-7445.AM2014-5086
Abstract 5093: Nucleolin phosphorylation profiling under normal and cellular stress conditions
Authors: Ng Kenneth , Rodriguez Allana , Saxena Anjana D.
Published: May 2015

Nucleolin (NCL) is a ubiquitous nucleolar phosphoprotein that integrates critical cellular processes, from cell growth (ribosome biogenesis) and cell proliferation to cell cycle arrest and cell death. Deregulation of these processes often lead to different pathological conditions including cancer and heightened levels of nucleolin are often found in a variety of tumors. Nucleolin is highly phosphorylated at the N-terminus by two major kinases: interphase casein kinase 2 (CK2) and mitotic cyclin-dependent kinase 1 (Cdk1). Although increased nucleolin phosphorylation by CK2 is finely regulated in exponentially dividing cells, the role of nucleolin phosphorylation in regulating cell cycle remains largely unexplored. The high content of acidic stretches in the N-terminus of nucleolin protein limits the effective use of mass-spectrophotometry as well as our ability to generate various phosphorylation-specific nucleolin antibodies. In this study, we used novel phosphate-binding tag to analyze nucleolin phosphorylation in human osteosarcoma cells. With phosphate affinity gel electrophoresis and subsequent western analyses, we have enabled the detection and quantification of different phosphorylation states of nucleolin during interphase as well as in mitosis. CK2 phosphorylated nucleolin (as in interphase) has multiple bands that migrate slower when bound to phos-tag as compared to hypo-phosphorylated nucleolin mutant (6/S*A, where six consensus CK2 sites were modified from serine to alanine and hence defective in undergoing phosphorylation). In contrast, a single hyper-phosphorylated nuclolin band was predominant in mitotic arrested cells. Furthermore, we elucidated nucleolin phosphorylation patterns under various cellular stresses e.g. DNA damage (UV, CPT) as well as kinase stimulation (e.g. arachidonic acid) or inhibition by CK2-specific inhibitor CX4945. Our data provide for the first time informative nucleolin phosphorylation patterns during different cellular conditions. This profiling of nucleolin phosphoprotein is essential in understanding the role of nucleolin phosphorylation in various cellular processes as well as during cellular response to stress. This work is supported by grants PSC/CUNY 66740-00 44 and CA175794.

Citation Format: Kenneth Ng, Allana Rodriguez, Anjana D. Saxena. Nucleolin phosphorylation profiling under normal and cellular stress conditions. [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 5093. doi:10.1158/1538-7445.AM2014-5093
Abstract 51: Elevated levels of E2F1, EZH2 and SUZ12 lead to invasive progression of superficial bladder cancers
Authors: Lee Se-Ra , Roh Yun-Gil , Kim Won-Tae , Kim Seon-Kyu , Heo Jeonghoon , Chu In-Sun , Leem Sun-Hee
Published: May 2015

Bladder cancer is increasing a rate of occurrence in aging societies. A superficial bladder cancer is noninvasive that is presented as a good prognosis after receiving treatment. However, about 20∼50% of superficial bladder cancer patients progressed to invasive tumor which represent the poor survival rates within 5 years. In previous study, we addressed if the transcriptional characteristics of the superficial bladder cancer could be used as predictive biomarkers for the progression of superficial tumors to invasive ones. Using gene expression data from 165 bladder cancer patients, we identified a gene expression signature that could predict the likelihood of progression to invasive tumors. Gene network analyses of the signature revealed that E2F1 and its downstream effectors EZH2 and SUZ12 could be important mediators for the invasive and metastatic progression of superficial tumors. In this study, we investigated how these genes may affect the invasive and metastatic progression of superficial tumors. For confirmation of the expression of E2F1, EZH2 and SUZ12 in two groups of bladder cancer cells, we performed quantitative RT-PCR and western blot assay. Both of mRNA and protein expression of E2F1, EZH2 and SUZ12 in superficial bladder cancer were significantly lower than invasive bladder cancer cells (p< 0.0001). Next, we performed an invasion and migration assay. The overexpression of E2F1, EZH2 and SUZ12 presented an increase of invasiveness and migratory in UC9 superficial bladder cancer. On the other hand, the silencing of gene expression in EJ invasive cell was shown a significantly decreasing of invasiveness and migratory ability. Also, we determine the effect of proliferation and colony formation in superficial and invasive bladder cancer. The depletion of E2F1, EZH2 and SUZ12 in EJ and 5637 invasive bladder cancer cells that significantly decreasing of forming colonies on soft agar. Furthermore, we founded the reduction of tumor size when injected cells depleted E2F1, EZH2 and SUZ12 than control by xenograft assay. Together, our findings reveal that the estimating the roles of E2F1, EZH2 and SUZ12 for the invasive and metastatic progression in superficial bladder cancer.

Citation Format: Se-Ra Lee, Yun-Gil Roh, Won-Tae Kim, Seon-Kyu Kim, Jeonghoon Heo, In-Sun Chu, Sun-Hee Leem. Elevated levels of E2F1, EZH2 and SUZ12 lead to invasive progression of superficial bladder cancers. [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 51. doi:10.1158/1538-7445.AM2014-51
Abstract 5105: A novel metabolite from an extremophile Streptomyces with apoptosis regulator function
Authors: Moazami Nasrin , Hakami Fatoulah , Ofoghi Hamideh , Ghaffarpour Massoud
Published: May 2015

Apoptosis or programmed cell death is essential for the normal functioning and survival of most multi-cellular organisms. The morphological and biochemical characteristics of apoptosis are highly conserved during the evolution. Therapeutic strategies based on exogenous delivery of the native form of superoxide dismutase (SOD), a free radical scavenger, are limited because of its short half-life (approximately 6 min) in vivo and poor permeability across the blood barrier and cell membrane. In this study, the spectrum of in vivo anti cancer activity of a Streptomyces SOD with a carrier protein designated Kavir-48by apoptotic function was assessed. Two xenograft models including LXFl 529 and LXFL H460 lung cancer cells were used. Purified protein complex was administrated through intra- peritoneal injection (ip) for 4 weeks. The results showed that treatment with 300 mg/kg of kavir-48 significantly reduced the growth of xenografted tumor with a tumor growth inhibition (TGI) of 70 % for LXFI 529 cell line. In addition, no adverse effects were observed based on general appearance, weight loss or reduction in weight gain. Finally, Kavir-48, demonstrated a highly anti-tumor efficacy in vivo and a tolerability profile amenable to intra peritoneal administration. It acts as a promising therapeutic target against cancer.Further analysis on this antitumor metabolite on gene expression profiles involved in regulation of apoptosis and oxidative stress pathways in different cancer cells in progress.

Note: This abstract was not presented at the meeting.

Citation Format: Nasrin Moazami, Fatoulah Hakami, Hamideh Ofoghi, Massoud Ghaffarpour. A novel metabolite from an extremophile Streptomyces with apoptosis regulator function. [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 5105. doi:10.1158/1538-7445.AM2014-5105