bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1025: Optimized DZNep exposure presensitizes pancreatic cancer cells to anticancer nucleoside analogues: potential clinical implications.
Authors: Hung Sau Wai , Mody Hardik , Marrache Sean , Bhutia Yangzom D. , Davis Franklin , Cho Jong Hyun , Dhar Shanta , Chu Chung K. , Govindarajan Rajgopal 
Published: August 2014

Abstract
We evaluated the potential of a histone methylation reversal agent 3-deazaneplanocin A (DZNep) in improving the chemosensitivity of pancreatic cancer to nucleoside analogs (i.e., gemcitabine). DZNep brought delayed but selective cytotoxicity to pancreatic cancer cells without affecting normal human pancreatic ductal epithelial (HPDE) cells. Co-exposure of DZNep and gemcitabine induced cytotoxic additivity or synergism in both well- and poorly-differentiated pancreatic cell lines. In contrast, DZNep exerted antagonism with gemcitabine against HPDE cells with significant reduction in cytotoxicity compared with the gemcitabine-alone regimen. DZNep marginally depended on purine nucleoside transporters for its cytotoxicity, but the transport dependence was circumvented by acyl derivatization. Drug exposure studies revealed that a short priming with DZNep followed by gemcitabine treatment rather than co-treatment of both agents produced a maximal chemosensitization response in both gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells. DZNep rapidly and reversibly decreased trimethylation of histone H3 lysine 27 but increased trimethylation of lysine 9 in an EZH2- and JMJD1A/2C-dependent manner, respectively. However, DZNep potentiation of nucleoside analog chemosensitization was found to be temporally coupled to trimethylation changes in lysine 27 and not lysine 9. Polymeric nanoparticles engineered to chronologically release DZNep followed by gemcitabine produced pronounced chemosensitization and dose-lowering effects. Together, our results identify that an optimized DZNep exposure can presensitize pancreatic cancer cells to anticancer nucleoside analogs and emphasize the promising clinical utilities of histone methylation reversal agents in future pancreatic cancer combination therapies.
Citation Format: Sau Wai Hung, Hardik Mody, Sean Marrache, Yangzom D. Bhutia, Franklin Davis, Jong Hyun Cho, Shanta Dhar, Chung K. Chu, Rajgopal Govindarajan. Optimized DZNep exposure presensitizes pancreatic cancer cells to anticancer nucleoside analogues: potential clinical implications. [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 1025. doi:10.1158/1538-7445.AM2013-1025
Abstract 1029: Involvement of endocytic pathway in vorinostat-induced EGFR degradation.
Authors: Elkenawi Asmaa E. , Cowell John K. 
Published: August 2014

Abstract
Epidermal growth factor receptor (EGFR) is frequently overexpressed or aberrantly activated in various malignancies. As a result, EGFR is considered an important target in cancer therapeutics. Strategies of EGFR targeting include blockade of its activation, inhibition of downstream signaling or induction of EGFR downregulation and/or degradation. Histone deacetylases (HDACs) inhibitors were previously shown to deplete EGFR through numerous mechanisms varying from suppression of EGFR transcription, attenuation of its mRNA stability and disruption of chaperone activity of HSP90. In this work, we are studying alteration of EGFR vesicular trafficking as another mechanism that may be involved in HDAC inhibitors-induced EGFR depletion. Cytotoxic and EGFR-degrading effects of vorinostat, a pan-HDAC inhibitor, were investigated in the EGFR-overexpressing cell lines, DU-145 (prostate cancer cells) and MDA-MB-231 (breast cancer cells). Using different experimental designs, dose- and time- effects of vorinostat were studied in both cell lines. Proliferation assay, annexin V staining, PARP and caspase 7 cleavage were used to evaluate overall cellular toxicity. Effects on total EGFR protein level and relevant ERK phosphorylation were also investigated by immunoblotting. Moreover, accumulation of acetyl-α-tubulin was verified through immunoblotting and immunofluorescence imaging. Finally, serum-starved vorinostat-treated cells were stimulated with EGF in order to elucidate effect of vorinostat on EGF-induced EGFR degradation, an endocytic trafficking-dependent process. As presented in this study, vorinostat exerted potent cytotoxic effects on DU-145 and MDA-MB-231 cells manifested by a dose-dependent decrease in proliferation and increase in percentage of apoptotic cells. In addition, vorinostat caused a dose-dependent cleavage of both PARP and caspase 7, two markers of apoptotic cascade activation. Furthermore, vorinostat elicited a dose- and a time-dependent depletion of EGFR total protein in both cell lines with a corresponding decrease in ERK activation. Add to that, vorinostat caused accumulation of acetyl-α-tubulin and promoted EGFR degradation upon EGF stimulation denoting accelerated endocytic trafficking. In conclusion, vorinostat demonstrated a potent anti-tumor activity against EGFR-overexpressing cell lines. Such activity was accompanied by EGFR depletion that may be contributed in part by vorinostat-induced deregulated vesicular trafficking.
Citation Format: Asmaa E. Elkenawi, John K. Cowell. Involvement of endocytic pathway in vorinostat-induced EGFR degradation. [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 1029. doi:10.1158/1538-7445.AM2013-1029
Abstract 1081: Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models.
Authors: Kitagawa Hiroshi , Cataisson Christophe , Handisurya Alessandra , Day Patricia M. , Yuspa Stuart H. , Dennis Phillip A. 
Published: August 2014

Abstract
Braf inhibitors are clinically important agents for the treatment of advanced melanoma however secondary cutaneous tumors are a common side effect; non-melanoma skin cancers (NMSCs) arise in 15-30% of patients on Braf inhibitor therapy and 60% of these harbor ras mutations. NMSC also occurs in 40% of organ transplant patients receiving immunosuppressive therapy, and switching from a calcineurin inhibitor-containing regimen to rapamycin reduces the incidence. To examine the effect of rapamycin on ras-driven epidermal squamous cell tumors, we treated mutant K-RasLA2 mice with rapamycin or vehicle by intraperitoneal injection and found that rapamycin prevented the development of squamous skin tumors (0/21 vs 6/24; p=0.04), and also rapidly reduced the tumor size. To explore this effect we employed a syngeneic orthotopic grafting model using H-Ras mutant primary murine keratinocytes to determine if rapamycin could hamper the ability of a Braf inhibitor to enhance squamous skin tumor growth. Similar to results in the K-RasLA2 model, rapamycin alone diminished the growth of tumors (size difference; 334.5 vs 22.3mm3; p=0.03), and decreased the volume even more in the presence of a Braf inhibitor (size difference; 699.6 vs 17.6 mm3; p=0.02). Treatment of established tumors with rapamycin resulted in significant tumor shrinkage even in the continuous presence of a Braf inhibitor. Size reduction was 78.7% and 66.7% in Braf inhibitor untreated and treated groups respectively. In vitro, Braf inhibition enhanced mutant H-Ras-induced activation of the Raf-ERK and mTOR pathways in keratinocytes, while rapamycin addition blocked the activation of signaling pathways and decreased cell proliferation. Taken together, rapamycin prevents murine skin tumor development arising from oncogenic mutations in two distinct types of ras gene alleles, and reduced the tumor size by inhibiting downstream oncogenic pathways. Rapamycin may have clinical application as a chemopreventive and therapeutic agent for patients at high risk to develop ras-driven NMSC, including those receiving Braf inhibitors.
Citation Format: Hiroshi Kitagawa, Christophe Cataisson, Alessandra Handisurya, Patricia M. Day, Stuart H. Yuspa, Phillip A. Dennis. Rapamycin is a chemopreventive and chemotherapeutic agent for ras-driven epidermal squamous cell carcinoma: evidence from mouse models. [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 1081. doi:10.1158/1538-7445.AM2013-1081
Abstract 1094: Breast cancer metastatic competency in the hepatic niche is driven by E-cadherin re-expression.
Authors: Taylor Donald P. 
Published: August 2014

Abstract
Nearly half of breast cancer metastases will become clinically evident 5 or more years after the cancer was seemingly ablated. This implies that metastatic cancer cells survived over this extended timeframe without emerging as detectable nodules. Breast cancer metastatic dormancy has yet to be universally defined, and is not well understood as a potential means by which clinically evident metastases emerge after being undetected for years (or decades) from the primary tumor diagnosis. Various mechanistic and microenvironmental factors may work independently, collaboratively (or both) in order to allow a dormant metastatic breast cancer cell (or small cluster) to survive long term. At least one tumor dormancy hallmark is likely required: that of E-cadherin re-expression in order to form heterotypic connections between the carcinoma cells and the liver parenchyma. This re-expression is known as the mesenchymal-to-epithelial-reverting-transition (MErT). This re-expression provides not only survival signals to the breast cancer cells but may also establish cell polarity and protection from autocrine signaling (or extracellular factors) that otherwise may prompt the breast cancer cells to initiate metastatic outgrowth.
The purpose of this study is to determine E-cadherin's function in the establishment of breast cancer metastases to the liver. The MDA-MB-231 human breast cancer cell line, that can undergo induced MErT ex vivo, was transfected with either exogenously expressing E-cadherin or shRNA to E-cadherin. Xenograft splenic injections of these cell line variants into mice were performed and tumors allowed to grow for 30-60 days until sacrifice. Immunohistochemistry was performed on the liver and splenic tissue sections in order to assess the number and size of metastatic depostis. Preliminary data demonstrate that cells expressing exogenously encoded E-cadherin developed large splenic tumors with fewer to no liver metastases. MDA-MB-231 wild type cells spawned liver metastases about half the time. In order to more fully probe E-cadherin's role in metastatic competency experiments are underway to develop a doxycycline-inducible E-cadherin bicistronic vector allowing for the down-regulation of E-cadherin in the primary tumor and the re-expression in the metastatic niche. Subsequent immunohistochemistry will determine the metastatic E-cadherin status across these MDA-MB-231 cell variants. These results will provide insights into the role of MErT in metastatic establishment.
Citation Format: Donald P. Taylor. Breast cancer metastatic competency in the hepatic niche is driven by E-cadherin re-expression. [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 1094. doi:10.1158/1538-7445.AM2013-1094
Abstract 1124: Site-specific DICER and DROSHA RNA products control the DNA-damage response.
Authors: d'Adda di Fagagna Fabrizio 
Published: August 2014

Abstract
The DNA damage response (DDR) is a signaling pathway that arrests the proliferation of cells undergoing genotoxic events to preserve genome stability and as such plays important tumor suppressing functions. DICER and DROSHA are crucial ribonucleases involved in RNA interference (RNAi). Components of RNAi are thought to have evolved to preserve genome stability from the attacks of viruses and mobile genetic elements. RNA products generated by DICER and DROSHA are involved in chromatin assembly, gene silencing and cancer. So far, RNAi and DDR pathways have not been demonstrated to directly interact.
We have recently shown in human, mouse and zebrafish that DICER and DROSHA, but not downstream elements of the RNAi pathway, are necessary to activate the DDR upon exogenous DNA damage and oncogene-induced genotoxic stress, as studied by DDR foci formation and by checkpoint assays. Indeed, oncogene-induced senescent cells, upon DICER or DROSHA inactivation, escape DDR-imposed arrest and proliferate again.
DDR foci are sensitive to RNase A treatment and DICER- and DROSHA-dependent RNA products are required to restore DDR foci in RNase-A-treated cells. Through RNA deep sequencing and the study of DDR activation at a single inducible DNA double-strand break, we demonstrate that DDR foci formation requires site-specific DICER- and DROSHA-dependent small RNAs, named DDRNAs, which act in a MRE11-RAD50-NBS1- complex-dependent manner to fuel DDR. DDRNAs, either chemically synthesized or in vitro generated by DICER cleavage, are sufficient to restore the DDR in RNase-A-treated cells, also in the absence of other cellular RNAs.
We propose an unanticipated direct role of a novel class of ncRNAs in the control of DDR activation at sites of DNA damage. The relevance of these findings in the context of tumor suppression will be discussed.
Citation Format: Fabrizio d'Adda di Fagagna. Site-specific DICER and DROSHA RNA products control the DNA-damage response. [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 1124. doi:10.1158/1538-7445.AM2013-1124
Abstract 1138: Rapid validation of a novel kinase target using a large scale genomic database and matched patient derived tumor models.
Authors: Broudy Thomas , Sanga Sandeep , Ricono Jill , Trikha Mohit , Mirsaidi Cyrus , Praveen Kesavan Nair 
Published: August 2014

Abstract
Target discovery and validation in oncology has largely relied on molecular and functional studies performed in cell lines. Recent advances in genomics have now afforded large databases based on well-characterized tumor tissue, which has enabled direct investigation of patient tumors for novel targets. Following these discoveries, it is routine to perform functional studies in cell line-based systems; however, it is often difficult to find relevant cell line model and if identified, they can be confounded with artifacts created from decades of culture. The result can be a target validation process which takes considerable time and does not readily translate to clinical relevance.
We report here the creation and use of a target validation platform based on a large-scale genomic database matched to patient-derived tumor models. The platform relies on Molecular Response's proprietary bank of more than 144,000 patient derived tumors, of which nearly 400 tumors have been genomically characterized and databased for target discovery studies. The database is growing, but currently features the following cancer indications: colon carcinoma, NSCLC, melanoma, ovarian carcinoma, prostate and non-hodgkins lymphoma. Upon discovery of a novel target, tumors of interest are immediately implanted into mice to perform functional studies in direct patient derived models–either in vivo or using mouse-passaged cells for broader ex vivo studies.
Through use of this platform, we have identified a novel kinase target for potential therapeutic development. We investigated prevalence of target overexpression across 7 cancer indications, and identified melanoma as a clinical indication of high interest. We examined growth characteristics from patient tumors featuring high kinase gene expression vs. low expression to help characterize the role of this target in oncology disease progression. Finally, we performed functional knockdown studies in patient derived models to further validate this novel kinase as a druggable target of pharmaceutical interest. Studies are ongoing to develop small molecule and antibody-based therapeutics that will serve as drug candidates for further development.
Citation Format: Thomas Broudy, Sandeep Sanga, Jill Ricono, Mohit Trikha, Cyrus Mirsaidi, Kesavan Nair Praveen. Rapid validation of a novel kinase target using a large scale genomic database and matched patient derived tumor models. [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 1138. doi:10.1158/1538-7445.AM2013-1138
Abstract 1165: Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma.
Authors: Lin Shih-Wen , Abnet Christian C. , Freedman Neal D. , Risques Rosana , Prunkard Donna , Rabinovitch Peter , Lu Ning , Qiao You-Lin , Dawsey Sanford M. 
Published: August 2014

Abstract
Objectives: Esophageal cancer is the fifth leading cause of cancer death worldwide. The five-year survival is approximately 16%. Patients can be successfully treated if diagnosed early, but current early detection screening tests are inadequate. Balloon cytology is a simple and inexpensive method of retrieving esophageal cells, but traditional cytologic examination of these cells has poor sensitivity and specificity. We examined whether telomere length, a marker for chromosomal instability, in DNA extracted from balloon cytology-collected esophageal cells is associated with precursor lesions of esophageal squamous cell carcinoma.
Methods: The Cytology Sampling Study 2, a population-based esophageal cancer early detection screening study, recruited over 700 healthy subjects from a high-risk population in Linxian, China. The screening study used a mesh-covered balloon to collect esophageal cells. All subjects underwent endoscopy, and precursor lesions were diagnosed by biopsy. Using a nested case-control study design, we examined the association between telomere length and dysplasia in 37 low-grade dysplasia cases, 52 high-grade dysplasia cases, and 92 matched controls. DNA was extracted from cells collected by balloon cytology, and telomere length was measured in triplicate by a quantitative PCR assay. Logistic regression models adjusted for age, sex, smoking tobacco, alcohol intake, and hypertension were used to examine the association between telomere length and risk of low-grade dysplasia and high-grade dysplasia, compared with normal controls.
Results: Telomere lengths were comparable among the low-grade dysplasia cases, high-grade dysplasia cases, and controls, with a median of 0.93 [interquartile range (IQR), 0.84-1.06], 0.94 (IQR, 0.82-1.09), and 0.93 (IQR, 0.78-1.05), respectively. Overall, telomere length was not associated with risk of low-grade dysplasia or high-grade dysplasia, with an odds ratio [OR, 95% confidence interval (CI)] of 1.16 (0.87-1.54) and 1.20 (0.92-1.56), respectively.
Conclusions: Given that esophageal cancers have very poor prognoses, it is of utmost importance to improve early detection. In this study, esophageal cell telomere length was not associated with esophageal precursor lesions and cannot serve as an early detection marker.
Citation Format: Shih-Wen Lin, Christian C. Abnet, Neal D. Freedman, Rosana Risques, Donna Prunkard, Peter Rabinovitch, Ning Lu, You-Lin Qiao, Sanford M. Dawsey. Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma. [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 1165. doi:10.1158/1538-7445.AM2013-1165
Abstract 1182: Ocimum gratissimum aqueous extract induces apoptotic signalling in human osteosarcoma cells.
Authors: Lin Chien Chung 
Published: August 2014

Abstract
Osteosarcoma (Osteosarcoma) is a kind of bone cancer. Eighty percent of this tumor will be metastatic to the lungs or liver. Therefore, these patients generally need to use chemotherapy to improve disease and increase survival possibility. Recently, it has been reported that Ocimum gratissimum (OG) aqueous extract has anti-tumor activity. In this study, we detected the effect of OG extract on human bone cancer cell growth and metastasis.
The results showed that the OG extract can inhibit cell growth and induce cell apoptosis in human bone cancer cells, but no effect in normal nerve cell. Therefore, we suggest that OG extract s may have anti-cancer ability, and can provide the use in the development of new anti-cancer drugs
Figure . OGE effect on the cell growth in two osteosarcoma cells. Cell growth was determined 0∼3 or 0∼5 days after subculture using the MTT assay as described in Materials and Methods. Absorbance values obtained from the cells on day 0 after subculture were taken as 100%.
Citation Format: Chien Chung Lin. Ocimum gratissimum aqueous extract induces apoptotic signalling in human osteosarcoma 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 1182. doi:10.1158/1538-7445.AM2013-1182
Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
Abstract 1224: Intratumoral chitosan/IL-12 neoadjuvant to tumor resection is safe and generates tumor specific immunity.
Authors: Vo Jimmy Loc Nhu , Yang Lirong , Zaharoff David 
Published: August 2014

Abstract
Interleukin-12 (IL-12) is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. Local delivery strategies capable of maintaining high concentrations of IL-12 in the tumor microenvironment while minimizing systemic exposure are under investigation. We have previously shown that intratumoral injections of IL-12 co-formulated with a solution of chitosan (chitosan/IL-12) can eliminate established primary tumors. Chitosan is an abundant, natural polysaccharide derived primarily from the exoskeletons of crustaceans. Chitosan has been shown to maintain high local concentrations of protein antigens and cytokines through viscous, electrostatic and bioadhesive interactions.
Because of IL-12’s well documented ability to generate tumor-specific cell-mediated immunity, we are exploring the anti-metastatic potential of intratumoral chitosan/IL-12 immunotherapy in a highly metastatic model of breast cancer (4T1). Previously, we have shown that intratumoral chitosan/IL-12 neoadjuvant prior to tumor resection confers long-term survival benefits and reduces metastasis. Recent studies reveal that chitosan/IL-12 is safe and generates tumor-specific systemic immunity to confer long-term survival benefits. Specifically, splenocytes from long term survivors demonstrated anti-tumor immunity in a cytotoxic T-lymphocyte (CTL) killing assay. After 1 week of in vitro stimulation, splenocytes were found to lyse approximately 40% of target tumor cells at an effector: target ratio of 50:1. In addition, toxicological studies reveal that chitosan/IL-12 does not adversely affect leukocyte levels or hematocrit. Based on data obtained thus far, intratumoral chitosan/IL-12 shows promising potential as a neoadjuvant immunotherapy to reduce metastatic disease while minimizing the toxicities that hindered the progress of IL-12 based cancer immunotherapy.
Citation Format: Jimmy Loc Nhu Vo, Lirong Yang, David Zaharoff. Intratumoral chitosan/IL-12 neoadjuvant to tumor resection is safe and generates tumor specific immunity. [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 1224. doi:10.1158/1538-7445.AM2013-1224