bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1297: DDAIP improves the pharmacokinetic profile of PrevOnco® in different species: Comparison of DDAIP, CMC and PEG-300/400 formulations in mice, beagle dogs and cynomolgus monkeys
Authors: Dines Kevin , Incardona Francesca , Hachicha Mohamed , Martin Richard , Damaj Bassam 
Published: June 2012

Abstract
Our study in the accompanying abstract demonstrates that a low dose of PrevOnco® in combination with doxorubicin was efficacious in a liver cancer model. In this study we investigated the pharmacokinetic profile of PrevOnco® when formulated with 20% DDAIP or 20% PEG-300 in mice, dogs and cynomolgus monkeys. The goal was to evaluate the potential of formulation in DDAIP to increase PrevOnco® exposure in vivo.
Methods: PK plasma analyses of PrevOnco® administered orally at 100 mg/Kg in 1% carboxy methyl cellulose (CMC) or in 10% PEG-400 were evaluated in nude mice. 20% PEG-300 and 20% DDAIP formulations were evaluated in mice (100 mg/Kg), dogs (5 mg/Kg) and monkeys (5 mg/Kg).
Results: Compared to 20% PEG-300, administration of PrevOnco® in 20% DDAIP induced 7-fold, 8-fold and 2-fold improvements in AUC in mice, dogs and cynomolgus monkeys, respectively. In mice, Cmax reached 4,700 ng/mL in DDAIP compared to 1,000 ng/mL in PEG-300 formulation. PrevOnco® levels were detectable up to 4 hours in DDAIP compared to 2 hrs in PEG-300. In dogs, PrevOnco® in 20% PEG-300 formulation had a Cmax of 125 ng/mL at Tmax = 1 hr. This concentration was maintained up to 2 hrs with levels undetectable at 4 hrs. PrevOnco® in 20% DDAIP formulation had a Cmax of 1,600 ng/mL at Tmax=1 hr and T1/2=3hrs. AUC values were 3,941 and 477 for DDAIP and PEG, respectively. In monkeys, PrevOnco® plasma levels following 5 mg/Kg oral administration reached a Cmax of 120 ng/mL in 20% DDAIP and 90 ng/mL in 20% PEG-400. Tmax was 1 hour and 0.5 hour while AUCs were 390 versus 154 (both DDAIP vs. PEG-400).
Conclusion: Formulating with DDAIP increased plasma levels of PrevOnco® following oral administration in mice, dogs and monkeys. Thus, DDAIP facilitated higher Cmax and AUC values as well as a longer T1/2. DDAIP formulation will allow a lower dose of PrevOnco® to be used while maintaining efficacy and reducing cytotoxicity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1297. doi:10.1158/1538-7445.AM2011-1297
Abstract 1323: Reciprocal regulation of Stat3 and caveolin-1 in normal fibroblasts and breast carcinoma lines
Authors: Geletu Mulu , Mohan Reva , Arulanandam Rozanne , Joshi Bharat , Nabi Ivan Robert , Raptis Leda Helen 
Published: June 2012

Abstract
Membrane tyrosine kinases known to activate the signal transducer and activator of transcription-3 (Stat3) concentrate in caveolae, where they are sequestered in an inactive state through binding to the main caveolae protein, caveolin-1 (cav1). We previously demonstrated that cell-to-cell adhesion can cause a dramatic increase in Stat3 activity in cultured cells. Therefore, to examine the effect of cav1 upon Stat3, experiments were conducted at several confluences. Our results indicate that cav-1 downregulation through expression of anti-sense or shRNA constructs or treatment of cells with the pharmacological inhibitor, methyl-cyclo-dextran which destroys caveolae, activates Stat3 as well as Erk1/2, at all densities. Conversely, cav1 overexpression downregulates Stat3 and induces growth retardation or apoptosis in NIH3T3 fibroblasts and in breast cancer lines. In all cases, apoptosis was inhibited by co-expression of the constitutively active form of Stat3, Stat3C. Taken together, these findings point to cav1 as an inhibitor of Stat3 activity. In addition, it was previously demonstrated that cav1 upregulates p53, although the exact mechanism is unclear. Since Stat3 is known to inhibit p53 transcription through promotor binding, these data also point to the possibility that cav1 upregulation may, in fact, activate p53 through Stat3 inhibition. Our results further demonstrate for the first time that, in a feedback loop, Stat3 inhibition results in a dramatic increase in cav1 levels, indicating that Stat3 also downregulates cav1 expression. The above findings reveal the presence of a potent, negative regulatory loop between cav1, p53 and Stat3 that plays a crucial role in cellular survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1323. doi:10.1158/1538-7445.AM2011-1323
Abstract 1327: Analysis of metal content and distribution in profiling normal and tumor tissues from three human carcinomas
Authors: Farah Ibrahim O. , Nguyen Phoung X. 
Published: June 2012

Abstract
Studies have shown that elemental/metal homeostasis is very essential to the development of the cancer phenotype in many cancers including lung and liver carcinomas. The balance in the composition of trace elements/metals was recognized to be essential to normal homeostasis. Low Zn levels were implicated in the development of prostate as well as other cancers. The aim of this study was to investigate the differential relationship of metal concentrations and profiles in cancer and normal tissues of humans. It is hypothesized that essential elements/metal concentrations and profiles will show significant differences between cancer and normal tissues as well as between different tissue types in human tissue material. The study will establish critical element/metal profiles that provide correlations with the development of three major carcinomas. Normal human and tumor tissues of lung, breast and liver tissues used in this study were obtained from US Biomax Company. Tissue samples were prepared using standardized digestion procedure and the ICP-AES (Inductively Coupled Plasma-Atomic Emission Spectrometry) was used to determine the concentrations and profiles of 21 elements including Ag, Al, As, Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Na, Ni, Pb, Sb, Se, Sr, Tl, V, and Zn. Results showed that nine major elements of Al, Ba, Ca, Cr, Cu, Fe, Mg, Na, and Zn were found to be significantly different in term of their concentration profiles in normal and tumor tissues of human lung, breast and liver. It is concluded that metal/elemental homeostasis is essential for normal tissue function and that shifts in elemental distribution and content are tissue specific as well as carcinoma specific. These results are promising and warrant further studies to exploit the possibility of manipulating elemental content and distribution as a cancer therapeutic modality.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1327. doi:10.1158/1538-7445.AM2011-1327
Abstract 1330: p27 suppresses arsenite-induced Hsp27/Hsp70 expressions through inhibiting JNK2/c-Jun- and HSF-1-dependent pathways
Authors: Zhang Dongyun , Liu Jinyi , Yu Yonghui , Zuo Zhenghong , Guo Wei , Zhao Xuewei , Li Jingxia , Hu Yu , Yang Wancai , Shi Xianglin , Huang Chuanshu 
Published: June 2012

Abstract
p27 is an atypical tumor suppressor, which can regulate the activity of cyclin-dependent kinases (CDKs) and G0 to S phase transitions. More recent studies reveal that p27 may also exhibit its tumor suppressive function through regulating many other essential cellular events. However, the molecular mechanisms underlying these anti-cancer effects of p27 are largely unknown. In current studies, we found that depletion of p27 expression by either gene knockout or knockdown approaches resulted in upregulation of both Hsp27 and Hsp70 expressions at mRNA and promoter-derived transcription as well as protein levels upon arsenite exposure, indicating that p27 provided a negative signaling for regulating the expressions of Hsp27 and Hsp70. Consistently, arsenite-induced activation of JNK2/c-Jun and HSF-1 pathways was also markedly elevated in p27 knockout (p27-/-) and knockdown (shRNA p27) cells. Moreover, interfering the expression or function of JNK2, c-Jun and HSF-1, but not JNK1, led to dramatic inhibition of arsenite-induced Hsp27 and Hsp70 expressions. Collectively, our studies demonstrated that p27 suppressed Hsp27 and Hsp70 expressions at transcriptional level specifically through JNK2/c-Jun- and HSF-1-dependent pathways upon arsenite exposure, which provided additional important molecular mechanism for the tumor suppressive function of p27.
Key words: Arsenite, p27, Hsp27, and Hsp70
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1330. doi:10.1158/1538-7445.AM2011-1330
Abstract 1338: MicroRNAs in a mouse model of oral carcinogenesis
Authors: Tang Xiao-Han , Gudas Lorraine 
Published: June 2012

Abstract
MicroRNAs (miRNAs) can function as oncogenes or tumor suppressor genes. Aberrant expression of microRNAs has been reported in human tongue squamous carcinoma cells. In this study, we investigated the effects of the carcinogen, 4-nitroquinoline 1-oxide (4-NQO), on the expression of several miRNAs in mouse tongues by using a seminal mouse model of oral carcinogenesis that was established by our laboratory and demonstrates similarities to human oral tumors in terms of morphological, histopathological, and molecular characteristics. In addition, we studied the effects of the DNA methyltransferase (Dnmt) inhibitor 5-Aza-2′-deoxycytidine (5-Aza, 0.25 mg/kg body weight), all-trans retinoic acid (RA, given at 100 μg/kg body weight and 1 mg/kg body weight, respectively), and the combination of 5-Aza and the low dose RA on murine oral cavity carcinogenesis induced by 4-NQO and on mouse tongue miRNA expression levels in this mouse model. Compared with control mice (not treated with 4-NQO), 4-NQO treatment caused a remarked reduction in the expression of miR-26a and miR-124a in mouse tongues and an increase in CDK2 (one of miR-124a's targets) mRNA expression. Among all drug treatments, the combination of 5-Aza and the low dose RA attenuated the reduction in the expression of miR-124a caused by the 4-NQO treatment. To some extent, mice in all drug treatment groups showed a reduction in the degree of decrease in the expression of miR-26a in mouse tongues induced by 4-NQO. These results correlate with the data on neoplastic tongue lesion numbers and tongue lesion severity. Moreover, we found that RA, 5-Aza, and the combination of RA and 5-Aza all enhanced the expression of miR-26a and miR-124a in a human tongue squamous cell carcinoma cell line, SCC-15, and that the combination of RA and 5-Aza had the greatest effects. Collectively, our results show that miRNAs have potential as a strategy to reduce oral cavity cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1338. doi:10.1158/1538-7445.AM2011-1338
Abstract 134: The regulatory role of microRNA 338-3p in malignant gliomas
Authors: Hervey-Jumper Shawn , He Xiaobing , Zhu Thant , Gurrea Mikel , Talsma Caroline , Crowley Jessica , Costello Mark , Flack Callie , Jason Heth , Muraszko Karin , Fan Xing 
Published: June 2012

Abstract
Introduction: Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults. Even with optimal therapy, more than 70% of GBM patients will die within 2 years of diagnosis. MicroRNAs (miR) are important regulators of gene expression through posttranscriptional silencing of target mRNA. MicroRNA roles in cell proliferation, invasion, angiogenesis, and glioma stem cell activity are little known. In this study, we focus on the expression and function of microRNAs in human gliomas.
Methods: Using RNA extracted from 15 GBM patient samples and serum collected from 2 glioma patients, miR 338-3p expression, relative to normal brain and control serum, was examined using RT PCR. Regional miR expression within a single tumor was identified. A DNA fragment containing the hsa-miR-338-3p locus was amplified and cloned into a lentiviral vector, then transduced into GBM neurosphere lines. MicroRNA 338-3p and its downstream target, expression was assessed by RT PCR and western blot. GBM neurosphere growth was examined in vitro.
Results: Over-expression in miR 338-3p is associated with decreased glioma cell proliferation and neurosphere formation. MicroRNA 338-3p shows decreased expression in the core of malignant gliomas with increased expression at the tumors rim and migrating edge. MiR 338-3p expression induces cleaved caspase 3 expression. MiR 338-3p targets Histone deacetylase 4 (HDAC4).
Conclusion: MicroRNA 338-3p inhibits GBM neurosphere growth in vitro through reducing proliferation and inducing apoptosis possibly via targeting of HDAC4.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 134. doi:10.1158/1538-7445.AM2011-134
Abstract 135: MicroRNA repression of BIRC4/XIAP in lung cancer
Authors: Xie Yili , Camps Jordi , Awad Keytam S. , Wangsa Danny , Yang Jianhui , Yoo Nina , Ried Thomas , Kwong King F. 
Published: June 2012

Abstract
Background: MicroRNAs (miRNAs, miR) are short ∼22 nucleotide (nt) noncoding RNA molecules capable of regulating gene expression by targeting mRNA. Baculovirus IAP repeat containing protein-4 (BIRC4/XIAP) is the most potent member of the Inhibitor of apoptosis family of proteins (IAP) and an important cellular pro-survival stimulus. BIRC4 mRNA contains a long 3’ untranslated region (UTR) and its function remains unclear. Previously, we have shown that 17 candidate miRNAs can be identified that potentially interacted with BIRC4's 3’ UTR by using a computerized heuristic algorithm. An inverse relationship was discovered between miR-24 and BIRC4 in non-small cell lung cancers (NSCLC). The objective of this study is to determine whether miR-24 can directly target BIRC4 and consequently regulate apoptosis in NSCLC.
Methods: miRNA precursors and anti-miRNA inhibitors were transfected in NSCLC cells and their effect on BIRC4 protein expression was evaluated by western blot and their interaction with the BIRC4 3’UTR was detected by using luciferase reporter plasmids containing the BIRC4 3’UTR (wild type & mutant). Lentiviral p-Receiver-lv19-BIRC4 was transduced into A549 cells to generate stable clones overexpressing BIRC4 in order to examine miR-24's effects on a transcript devoid of the native 3’-UTR. The effects of miRNA on cell apoptosis signaling was determined by MTT cell viability assay, TdT apoptosis assay and Western blot for caspase-3 activation and PARP cleavage. Cytogenetic analyses (SKY &CGH) were performed to detect chromosomal abnormalities that may account for reduced expression of miRNA.
Results: miR-24 transfection down-regulates BIRC4 expression in NSCLC cells. Luciferase assay confirmed that miR-24 targets the BIRC4 3’ UTR at nucleotide positions 2294-2310. miR-24 also sensitizes intrinsically TRAIL-resistant A549 cells to TRAIL-induced cell apoptosis, which can be reversed by ectopic expression of miR-24-insensitive BIRC4. miR-24 sensitized-apoptosis is modulated via the canonical apoptosis pathway. Genomic deletion in the miR-24 coding region was found in NSCLC cells with corresponding low levels of miR-24. NSCLC or normal lung cells with normal/high levels of miR-24 did not exhibit cytogenetic deletion in the miR-24 coding region.
Conclusions: miR-24 down-regulates BIRC4 expression by directly targeting the BIRC4 3’UTR and can sensitize NSCLC cells to TRAIL-induced apoptosis. Genomic deletion contributes to the reduced expression of miR-24 in NSCLC. This finding raises the possibility that miR-24 mimetics may be of value in combination with TRAIL or other therapeutic strategies in the future treatment of lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 135. doi:10.1158/1538-7445.AM2011-135
Abstract 1371: Antitumor activity of a new quinoxalinyl-piperazine compound
Authors: Lee Young Bok , Chun Gina , Kim Deog J. , Ahn Chang H. , Kong Young D. , Jeon Moon K. , Kong Jae Y. 
Published: June 2012

Abstract
Novel 1-[(5 or 6-substituted alkoxyquinoxalinyl)aminocarbonyl]-4-(hetero)arylpiperazine derivatives were synthesized and evaluated as an anti-tumor agent. Despite their structural similarity to the quinoxalinyl-piperazine core scaffold, the IC50 values of the compounds against human cancer cells depends on the substitution at the quinoxaline ring but also from substituents at the phenyl ring. The best compound showing IC50 values ranging from 11 to 21 nμ was selected and characterized further both in vitro and in vivo. This compound was more potent against paclitaxel resistant HCT-15 colorectal cells compared to paclitaxel itself. Combined treatment of this compound with known anti-cancer drugs, such as paclitaxel, doxorubicin, cisplatin, gemcitabine or 5-fluorouracil, displayed synergistic growth inhibition of cancer cells. In mice bearing tumor xenografts, treatment with the compound completely inhibited the growth of various human tumors, enhanced tumor regression without effects on body weight compared to control animals. Mechanistic studies have shown that this quinoxalinyl-piperazine compound is a G2/M-specific cell cycle inhibitor and inhibits anti-apoptotic Bcl-2 protein with p21 induction. The results clearly demonstrate that our new quinoxalinyl-piperazine compound could become a novel class of anti-tumor chemotherapeutics.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1371. doi:10.1158/1538-7445.AM2011-1371
Abstract 1377: Identification and characterization of small molecule inhibitors of the activator protein-1 pathway
Authors: Miller Nicole R. , Huang Ruili , Xia Menghang 
Published: June 2012

Abstract
The activation of transcription factor activator protein-1 (AP-1) plays a critical role in multiple stages associated with carcinogenesis. The AP-1 complex is a dimeric transcription factor typically made up of proteins from JUN, FOS, ATF, and MAF families. Growth factors including EGF activate AP-1 via cell surface receptors such as EGF receptor (EGFR). EGFR activation of MAPK cascades lead to phosphorylation and nuclear translocation of AP-1 subunits. Discovery of selective inhibitors of the AP-1 pathway would lead to invaluable tools in the study, treatment and prevention of multiple cancers. To screen for AP-1 pathway inhibitors, a FRET-based AP-1 β-lactamase reporter was used to measure AP-1 activation in a ME-180 cervical cancer cell line. Approximately 75,000 compounds were screened, each at 7-15 concentrations, in a quantitative high-throughput screening (qHTS) format. Several novel structure series were identified from this screen. Hits selected based on a structure-activity relationship analysis were confirmed and further investigated for mechanism of action because EGF-stimulated AP-1 activation can be inhibited by multiple mechanisms in the pathway. Inhibitors mechanisms of action in the EFGR-mediated pathway were determined in follow-up studies including receptor inhibition, MAPK inhibition, and direct disruption of the AP-1 signaling complex. The identification and characterization of novel AP-1 inhibitors will lead to compounds that serve as probes of the AP-1 pathway and potential candidates for anticancer drug development.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1377. doi:10.1158/1538-7445.AM2011-1377
Abstract 1379: High throughput screening to identify molecules that alter VHL stability
Authors: Ding Zhiyong , Feng Zhehui , Fikes Nelda A. , Gao Meng , Si Wendy , Sobieski Mary M. , Stephan Clifford C. , Mills Gordon B. , Jonasch Eric 
Published: June 2012

Abstract
Von Hippel-Lindau (VHL) germ line and somatic mutations play determining roles in renal-cell carcinomas (RCC) as well as other diseases, including hemangioblastomas and pheochromocytomas. Although molecules upregulated as a consequence of VHL deficiency have been employed as drug targets in RCC cancer therapy, modulation of pVHL itself has not been explored as a therapeutic strategy in the treatment of VHL derived diseases.
Approximately one third of VHL mutations are point mutations, which destabilize pVHL and decrease pVHL intracellular levels, despite in some cases possessing residual functionality. Therefore, interventions that restabilize mutated pVHL may restore physiological protein levels and function.
We established a high-throughput screening system to identify small molecules that alter VHL stability. We fused an unstable W117A VHL mutant to a fluorescent protein Venus and transduced the VHL null 786-0 RCC cell line. The fluorescence and protein levels of W117A VHL-Venus were low in untreated cells, and increased significantly after treatment with the proteasome inhibitors MG132 or bortezomib. The fluorescence level served as a VHL protein stability readout for the screen. We then performed a screen on the Prestwick drug library and identified multiple candidates that stabilized VHL protein. Certain candidates have been shown to functionally regulate VHL stability as well as its downstream effecter HIF1a. Our work shows that the high-throughput screening system we established could efficiently identify small molecules that alter VHL stability and functionality, and facilitates exploring VHL as a drug target in the treatment of RCC as well as other VHL diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1379. doi:10.1158/1538-7445.AM2011-1379