bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3428: Effect of a non cardiotoxic Doxorubicin analog, 13-deoxy, 5-imino doxorubicin on decatenation of DNA by Topoisomerase II.
Authors: Frank Nicole , Olson Richard , Walsh Gerald M. , Talley Todd , Cusack Barry 
Published: August 2014

Abstract
Anthracyclines such as doxorubicin are widely used to treat solid and hematological cancers. However, within the course of treatment they have the potential to cause life threatening chronic cardiotoxicity which limits their potential use. The cause of cardiotoxicity is not thoroughly understood, with previous research indicating the generation of reactive oxygen species and free iron accumulation as possible causes for cardiomyocyte death. Recent publications have shown the interaction between doxorubicin and Topoisomerase IIβ plays a key role in anthracycline induced cardiotoxicity. Topoisomerase enzymes are utilized during the coiling and uncoiling of DNA within the cell and are active targets of anthracyclines not only in tumoricidal action (Topoisomerase IIα) but also in the pathogenesis of cardiotoxicity (Topoisomerase IIβ). In this research we seek to further evaluate the interaction between doxorubicin, doxorubicin analogues and Topoisomerase IIβ. The analogues were selected due to previous chronic in vivo experiments in rabbits where classical manifestations of cardiotoxicity (including reduced left ventricular shortening fraction and pathological changes in cardiac tissue) were not observed. Furthermore, one analogue (13-deoxy, 5-imino doxorubicin) has shown promising clinical data suggesting a strong antineoplastic effect without the cardiotoxic effects. Doxorubicin and this analogue were placed in the presence of catenated DNA for 6 hours at 37°C prior to exposure to Topoisomerase IIα and β enzymes. The reaction was allowed to proceed for 30 minutes at 37°C and analyzed for decatenation of the DNA by the enzyme. This experiment was then repeated in cardiac H9c2 cells to assay possible differential inhibition at the cellular level.
Citation Format: Nicole Frank, Richard Olson, Gerald M. Walsh, Todd Talley, Barry Cusack. Effect of a non cardiotoxic Doxorubicin analog, 13-deoxy, 5-imino doxorubicin on decatenation of DNA by Topoisomerase II. [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 3428. doi:10.1158/1538-7445.AM2013-3428
Abstract 3429: Coordination of cell cycle repression and reduced cytoskeletal tension by the small molecule natural product, Schweinfurthin A.
Authors: Turbyville Thomas , Brafman Alla , Chen De , Romanchuck Kathryn , Beutler John , Reilly Karlyne , Lockett Stephen 
Published: August 2014

Abstract
Malignant Peripheral Nerve Sheath Tumors (MPNST) are a frequent cause of morbidity and mortality in Neurofibromatosis type 1 patients, and arise in part from loss of the tumor suppressor function of the NF1 gene product, neurofibromin. We have previously shown that MPNST tumor cell lines, as well as astrocytoma cell lines, derived from both patients and a Nf1-/+;Trp53-/+ (NPcis) mouse model are differentially sensitive to the natural product, Schweinfurthin A (SA). In addition to its anti-proliferative effects, SA caused dramatic reorganization of the actin cytoskeleton. When the NF1 Ras-regulatory domain was re-expressed in an Nf1-/- astrocytoma cell line derived from the NPcis model, these cells became resistant to the effects of SA. This led us to hypothesize that SA mediates its effects on the actin cytoskeleton and proliferation by phenocopying neurofibromin in its regulation of Rho and mitogenic signaling pathways. Our objective is to understand if and how this is the case.
To further that end, the goal of this study was to begin to probe the coordination of proliferation and cytoskeletal tension, as has been previously reported in other studies. We cultured individual SA- and DMSO-treated MPNST cells derived from the NPcis model onto pre-defined micropatterns of fibronectin. By constraining cell shape, quantitative structural properties of cells were revealed that were otherwise masked when cells were grown on standard coverslips. We observed dose-dependent increases in the concave curvature of cell edge segments not attached to the underlying fibronectin. Such curvature is known to represent decreased cell tension exerted by the actin cytoskeleton. Across the same SA doses, we measured a decrease in cyclin D1 and cyclin D3 total protein levels and a decrease in retinoblastoma protein phosphorylation, which was consistent with flow cytometry data showing a G1 blockade. Thus, we conclude that proliferation and cytoskeletal tension are coordinated in cells sensitive to the candidate drug, SA.
Funded by NCI Contract No. HHSN261200800001E.
Citation Format: Thomas Turbyville, Alla Brafman, De Chen, Kathryn Romanchuck, John Beutler, Karlyne Reilly, Stephen Lockett. Coordination of cell cycle repression and reduced cytoskeletal tension by the small molecule natural product, Schweinfurthin A. [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 3429. doi:10.1158/1538-7445.AM2013-3429
Abstract 3434: Inecalcitol, an analogue of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system.
Authors: Ma Yingyu , Yu Wei-Dong , Hidalgo Alejandro A. , Luo Wei , Delansorne Remi , Johnson Candace S. , Trump Donald L. 
Published: August 2014

Abstract
Epidemiological data suggest an important role of vitamin D signaling in cancer progression, and experimental studies demonstrate that the active vitamin D metabolite 1α, 25-dihydroxyvitamin D3 (1,25D3) has broad spectrum anti-tumor activity. Hypercalcemia has often been suggested to limit the clinical application of these data. The 14-epi-analog of 1,25D3, inecalcitol (19-nor-14-epi-23-yne-1,25-(OH)2D3; TX522), was developed to have superagonistic anti-tumor activities but low hypercalcemia potential. We examined the anti-tumor activity of inecalcitol and the underlying mechanisms in a murine squamous cell carcinoma (SCC) model system. Compared to 1,25D3, inecalcitol showed enhanced vitamin D receptor (VDR)-mediated transcriptional activity. Inecalcitol suppressed SCC cell proliferation in a dose dependent manner with an IC50 value 30 times lower than that of 1,25D3. Both inecalcitol and 1,25D3 induced a comparable level of G0/G1 cell cycle arrest in SCC cells. The level of apoptosis induced by inecalcitol was markedly higher than that of 1,25D3. Apoptosis was mediated through the activation of the caspase 8/10- caspase 3 pathway. Further, inecalcitol markedly inhibited the mRNA and protein expression of c-IAP1 and XIAP compared to 1,25D3. In vivo, inecalcitol inhibits SCC tumor growth at 80 μg dose without hypercalcemia. Inecalcitol (320 μg) or 1,25D3 (0.312 μg) markedly inhibited tumor growth. Notably, inecalcitol induced a significantly higher level of apoptosis in the SCC xenograft model. We show that inecalcitol has potent anti-tumor activity in the SCC model system and this is associated with a stronger induction of apoptosis. These findings support the further development of inecalcitol in cancer treatment.
Citation Format: Yingyu Ma, Wei-Dong Yu, Alejandro A. Hidalgo, Wei Luo, Remi Delansorne, Candace S. Johnson, Donald L. Trump. Inecalcitol, an analogue of 1,25D3, displays enhanced antitumor activity through the induction of apoptosis in a squamous cell carcinoma model system. [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 3434. doi:10.1158/1538-7445.AM2013-3434
Abstract 3437: P276, a cyclin-dependent kinase inhibitor with antitumor activity against high-risk human cervical cancer.
Authors: Shangary Sanjeev Kumar , Deshpande Gandhali , Sonawane Vinay , Venkatasubbaiah Venkatesha , Jalota-Badhwar Archana , Joshi Asavari , Mayekar Manoj , Shirsath Nitesh , Pandey Prashant , Agarwal Veena R. 
Published: August 2014

Abstract
Cervical cancer is the third most common cancer worldwide in women. While preventive vaccines have been approved for cervical cancer, treatment options are limited to chemotherapy drugs. An unmet need, thus, exists for the treatment of cervical cancer. High-risk human papilloma viruses (HPVs), type 16 and 18, account for 70% of the cervical cancer. Viral oncoproteins E6 and E7 bind and inhibit the p53 and Rb tumor suppressors, respectively. One attractive strategy for the treatment of cervical cancer is to attenuate the expression of E6 and E7 viral oncoproteins by a pharmacological inhibitor of cyclin-dependent kinases (CDKs). P276 is a CDKs inhibitor with potent activity against CDK4, CDK1 and CDK9 (Joshi et al, Mol. Cancer Ther. 2007; 6:918-25). The therapeutic potential and mechanism of action of P276 in cervical cancer was investigated using high-risk HPV type 16 (SiHa and Caski) and type 18 (HeLa) human cervical cancer cell line. P276 inhibited cell growth with sub-micromolar IC50 values (0.5-0.8 μM), induced cell cycle arrest and apoptosis in cervical cancer lines. E6 negatively regulates p53 protein stability in HPV-infected cervical cancer. P276 downregulated mRNA and protein expression of E6 in SiHa cells with concomitant upregulation of p53 protein and its downstream target p21, indicating activation of the p53 pathway. It also downregulated E7 mRNA expression in SiHa and HeLa cell lines. Further, it is known that hyperphosphorylation of Rb relieves its interaction with E2F, leading to Rb inactivation and E2F activation. Treatment with P276 dephosphorylated Rb at Ser780, indicating Rb activation. P276 demonstrated significant (p&lt;0.01) in vivo efficacy in HPV type 16 SiHa human cervical cancer xenograft model when administered by i.p. route, Treatment with 25 mg/kg of P276 for 21 days induced 59% of tumor growth inhibition without body weight loss in this model. Conclusion: P276, a CDKs inhibitor, is efficacious against high-risk cervical cancer.
Citation Format: Sanjeev Kumar Shangary, Gandhali Deshpande, Vinay Sonawane, Venkatesha Venkatasubbaiah, Archana Jalota-Badhwar, Asavari Joshi, Manoj Mayekar, Nitesh Shirsath, Prashant Pandey, Veena R. Agarwal. P276, a cyclin-dependent kinase inhibitor with antitumor activity against high-risk human cervical 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 3437. doi:10.1158/1538-7445.AM2013-3437
Abstract 3439: Suppression of pancreatic cancer cell growth by NISC-6 through activation of Par-4 and death receptor 5.
Authors: Karelia Deepkamal , Pandey Manoj K. , Irby Rosalyn , Amin Shantu , Sharma Arun K. 
Published: August 2014

Abstract
Pancreatic cancer is one of the deadliest cancers, with a median survival of 6 months and a 5 year survival rate of 3-5%. The poor prognosis of pancreatic cancer is attributable to its tendency for late presentation, aggressive local invasion, early metastases, and poor response to chemotherapy. Currently used drugs result in marginal survival advantage and are associated with multiple adverse events and drug resistance. Thus, there is a need for novel therapeutic agents and strategies involving less toxic agents that can sensitize pancreatic cancer cells to chemotherapy. Through extensive structure-activity relationship studies, we have recently developed an Akt pathway inhibitor, NISC-6, designed by incorporating an isoselenocyanate (-N=C=Se) functionality into naphthalimide structure, rendering it lethal to cancer cells at a dose that is non-toxic to normal cells. Our hypothesis is that the Akt inhibitor, NISC-6, in conjunction with Prostate apoptosis response protein 4 (Par-4), will induce apoptosis in pancreatic tumor cells through the TRAIL pathway. This is based on the observation that Par-4 causes apoptosis in cancer, but not in normal, cells, often in response to an apoptotic agent and is often inactivated in cancer cells through interaction with Akt1. In pancreatic cancer, Par-4 expression is often reduced through deletion of a chromosome segment containing 12q21, the location of the PAR-4 gene. Activation of Par-4 through inhibition of Akt by NISC-6 thus holds promise as a possible strategy for pancreatic cancer treatment. Our studies have shown NISC-6 to be effective in reducing cell proliferation in three different pancreatic cancer cell lines e.g. MiaPaCa-2, Panc-1, and BxPC-3. The treatments of NISC-6 for 48 h reduced the cell viabilities of pancreatic cancer cells with an IC50 of between 1-2.5 μM. In addition, treatment of MiaPaCa-2 cells with NISC-6 for 24 h showed significant activation of Par-4 and death receptor 5 (DR5). This activation was associated with the down-regulation of anti-apoptotic protein Bcl-xL and Survivin. Furthermore, NISC-6 potentiated the apoptotic effects of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL/APO-2L). Taken together, these results suggest that NISC-6 may represent a novel therapeutic agent to sensitize pancreatic cancer cells to TRAIL and chemotherapeutic drugs. Detailed results of these investigations will be presented.
Citation Format: Deepkamal Karelia, Manoj K. Pandey, Rosalyn Irby, Shantu Amin, Arun K. Sharma. Suppression of pancreatic cancer cell growth by NISC-6 through activation of Par-4 and death receptor 5. [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 3439. doi:10.1158/1538-7445.AM2013-3439
Abstract 3455: Elafin is a candidate biomarker that underlies the similarities between basal-like breast cancer and ovarian cancer.
Authors: Labidi-Galy Intidhar , Clauss Adam , Ng Vivian , Duraisamy Sekhar , Ganesan Shridar , Drapkin Ronny 
Published: August 2014

Abstract
We recently reported that Elafin, a serine proteinase inhibitor encoded on chromosome 20q12-13.2, is overexpressed and secreted by High grade serous carcinoma of the ovary (HGS-OvCa) and is associated with poor overall survival and chemotherapy resistance. Here we show that Elafin confers a proliferative advantage to HGS-OvCa cells through activation of the MAP kinase pathway. Mutations in the anti-proteinase domain of Elafin did not interfere with its ability to stimulate cell growth. This mitogenic effect can be neutralized by RNA interference, specific antibodies targeting Elafin and small molecule inhibitor against MEK kinase. We also observed that IC50 to cisplatin and paclitaxel are significantly higher in OvCa cell lines (n=11) highly expressing Elafin. A phosphoproteome array among 20 cell lines derived from patient's ascites samples showed that expression of Elafin significantly correlates with increased expression of RAD50 and STAT5A, two proteins involved in platinum resistance.
HGS-OvCa shared genomic features with basal-like breast cancer (BLBC) including frequent TP53 mutations, genomic instability, and poor prognosis. Thus, we looked at the expression of Elafin in BC. A meta-analysis of gene-expression profiling from 7 publicly available BC datasets including more than 1,300 tumors showed that Elafin is significantly highly expressed in BLBC compared to luminal and HER-2 subtypes and this observation has been confirmed by IHC on BC tumors (n=25) and on BC cell lines. Additionally, we observed that RNA interference against Elafin reduces proliferation of BLBC cell lines.
Citation Format: Intidhar Labidi-Galy, Adam Clauss, Vivian Ng, Sekhar Duraisamy, Shridar Ganesan, Ronny Drapkin. Elafin is a candidate biomarker that underlies the similarities between basal-like breast cancer and ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3455. doi:10.1158/1538-7445.AM2013-3455
Abstract 3460: Tumor budding is a predictive feature for lymph node metastasis in invasive ductal breast cancer.
Authors: Trippel Mafalda , Pfaltz Katrin , Salhia Bodour , Grogg André , Zlobec Inti , Tapia Coya F. 
Published: August 2014

Abstract
Background: Tumor budding is a phenomenon associated with epithelial mesenchymal transition and correlates with tumor invasiveness and metastasis in colon cancer. In breast cancer this histomorphological feature has not yet been determined. In this study we investigated the prognostic value of peritumoral budding (PTB) and intratumoral budding (ITB) in invasive ductal breast cancer and its correlation with lymph node status. Method: Two pathologists counted tumor buds within the tumor (ITB) and at the periphery (PTB) of 90 primary invasive ductal breast cancers. ITB and PTB were scored on whole tissue sections stained with a PanCK antibody. Budding was defined as isolated single cancer cells or microscopic cell clusters composed of ≥1 or up to 5 cells. A tumor was designated to have high-grade budding if it had an average of &gt;10 buds. PTB and ITB were then correlated with pathological features of breast cancer. Results: Forty-eight percent (n=43) and 50% (n=45) were considered high-grade for either ITB or PTB, respectively. High-grade PTB was significantly (p=0.0044) associated with lymph node metastasis and ITB was significantly (p=0.0018) associated with hormone receptor positive tumors. ITB and PTB were frequent in Her2 negative (50% and 53%) tumors and breast cancer with higher T-category &gt;T3 (57%). Neither PTB nor ITB showed an association with tumor grade or proliferation index as measured by Mib-1 staining. Conclusion: For the first time, we report that PTB is a strong (p=0.0044) predictive tumor feature of lymph node metastasis in invasive ductal breast cancer. The association of PTB with metastatic disease may be due to an increased occurrence of lymph vessels found at the tumor periphery. Additional studies are ongoing to determine if tumor budding can select for more aggressive subtypes of invasive breast cancer.
Citation Format: Mafalda Trippel, Katrin Pfaltz, Bodour Salhia, André Grogg, Inti Zlobec, Coya F. Tapia. Tumor budding is a predictive feature for lymph node metastasis in invasive ductal 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 3460. doi:10.1158/1538-7445.AM2013-3460
Abstract 3466: Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro.
Authors: Hayashi Mitsuhiro , Shinriki Satoru , Jono Hirofumi , Nakamura Takuya , Guo Jianying , Yamamoto Yutaka , Iwase Hirotaka , Ando Yukio 
Published: August 2014

Abstract
Background: CYLD was originally identified as a tumor suppressor that is mutated in familial cylindromatosis. CYLD has deubiquitinase activity and can negatively regulate NF-κB pathways. Recent study has revealed that CYLD plays important roles in tumor progression as well as immune response and osteoclastogenesis. CYLD loss of function has been associated with several tumors. Despite the broad relevance of CYLD to various tumors, its clinical and biological significances in breast cancer are still largely unknown.
Materials and Methods: We assessed CYLD expression in 171 primary breast cancer tissues by immunohistochemistry and examined the correlations with CYLD expression and clinicopathological factors as well as patients’ prognosis. In addition, we investigated effects of CYLD knockdown by using siRNA on malignant state in breast cancer cell lines.
Results: Our immunohistochemical analysis revealed a significant correlation between loss of CYLD expression and poor patients’ disease free survival (log-rank, p = 0.004), particularly in luminal and triple negative breast cancer patients. Multivariate analysis revealed that loss of CYLD expression was an independent poor prognosis factor (Hazard ratio 2.95, 95% CI 1.20 - 7.98, p = 0.02) in addition to hormone receptor expression status. Loss of CYLD expression correlated with high nuclear grade but not hormone and HER2 status.
Consistent with our clinical data, repression of CYLD increased CD44 high/ CD24 low cancer stem-like cell population with acquisition of resistance to apoptosis induced by conventional therapy in MDA-MB-231 cells. Moreover, CYLD knockdown promoted migration through downregulation of Maspin which is a potent suppressor of breast cancer metastasis.
Conclusions: CYLD expression was an independent prognostic factor in primary breast cancer. Reduced CYLD function may promote breast cancer progression and treatment resistance.
Citation Format: Mitsuhiro Hayashi, Satoru Shinriki, Hirofumi Jono, Takuya Nakamura, Jianying Guo, Yutaka Yamamoto, Hirotaka Iwase, Yukio Ando. Reduced expression of CYLD is an independent prognostic factor in breast cancer and confers treatment resistance and migratory activity in vitro. [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 3466. doi:10.1158/1538-7445.AM2013-3466
Abstract 3469: The expression and prognostic significance of neutrophil gelatinase-asssociated lipocalin (NGAL) in primary breast cancer.
Authors: Kim Lee-Su , Kim Hae Sung 
Published: August 2014

Abstract
Introduction:
Neutrophil gelatinase-associated lipocalin (NGAL; also known as lipocalin 2), a member of the lipocalin family that transports small lipophilic ligands, has gained recent attention as both a potential biomarker and a modulator of human cancers including breast cancer. In this study, we examined the expression of
NAGL in breast carcinoma and evaluated the prognostic value of its expression.
Methods:
Tissue microarray (TMA) blocks were made with formalin-fixed paraffin-embedded tissues from 207 breast cancer patients and the immunohistochemical staining was done using an anti-NGAL antibody. The correlation between NGAL expression and the clinicopathologic parameters such as age, tumor size, lymph node status, Ki-67 labeling index, histologic grade, hormone receptors and HER2/neu expression as well as clinical outcome was evaluated.
Results:
NGAL was expressed in 60 breast carcinomas (21.9%). A higher NGAL expression was noted in the younger (p=0.018) and premenopausal women (p=0.036). NGAL expression correlated with a high Ki-67 labeling index (p=0.001) and poor histologic grade (p=0.002). No significant association between NGAL expression and hormone receptor status and HER2/neu overexpression. With a median follow-up of
63 months, NGAL expression was associated with decreased disease-free survival, especially for patients with estrogen receptor negative group (p=0.013) and lymph node positive group (p=0.005), but not associated with overall survival.
Conclusion:
NGAL is expressed in approximately one-fifth of the breast carcinomas and its expression is correlated with several poor prognostic markers and decreased disease-free survival. This results show that NGAL expression may be a predictor of poor prognosis in primary human breast cancer, especially with more aggressive clinical features
Citation Format: Lee-Su Kim, Hae Sung Kim. The expression and prognostic significance of neutrophil gelatinase-asssociated lipocalin (NGAL) in primary 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 3469. doi:10.1158/1538-7445.AM2013-3469