bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4009: Regulation of mTOR pathway by the orphan nuclear receptor NR4A1 (TR3/Nur77) in non-small cell lung cancer: Role of TR3 in AMPK activation
Authors: Lee Syng-Ook , Andey Terrick , Jin Un-Ho , Kim Kyounghyun , Singh Mandip , Safe Stephen 
Published: June 2012

Abstract
The orphan nuclear receptor NR4A1 (TR3/Nur77) is overexpressed as a nuclear protein in multiple human tumors and this receptor exhibits pro-oncogenic activity in many tumor types. A recent study in this laboratory has shown that deactivation of TR3 decreases proliferation and induces apoptosis through inhibition of Sp1-dependent anti-apoptotic genes. In this study, we show that TR3 is overexpressed in human non-small cell lung cancer (NSCLC) tissues compared with adjacent normal lung tissues and high TR3 expression levels are correlated with shorter survival for patients with NSCLC (P = 0.0112). Treatment of NSCLC cells with small interfering RNAs for TR3 or the TR3 deactivator, 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl)methane (DIM-C-pPhOH), decreased cell proliferation and induced apoptosis through dual-targeting of mTOR pathway and Sp1 transcription factor. Knockdown of TR3 inhibited mTOR and its two major downstream targets, p70S6K and 4E-BP1 through LKB1-independent activation of AMPK but not through inactivation of AKT nor Sp1. We also observed that AMPK activation by TR3 knockdown is primarily due to induction of sestrin2 by enhancing p53-dependent transactivation activity. Furthermore, DIM-C-pPhOH (30 mg/kg/day) induced apoptosis and inhibited tumor growth in an orthotopic mouse model of human NSCLC, and decreased tumor number and size in a lung metastatic tumor model using tail vein injection. These results demonstrate for the first time that endogenous nuclear TR3 regulates AMPK-mediated mTOR pathway and TR3 deactivation represents a novel approach for treatment of NSCLC.
Grant support: National Institutes of Health (R01CA124998)
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 4009. doi:10.1158/1538-7445.AM2011-4009
Abstract 4387: Diversity Outbred: a new, highly diverse mouse stock for toxicology and cancer
Authors: Fancher Karen S. , Svenson Karen L. , Chesler Elissa J. , Churchill Gary A. 
Published: June 2012

Abstract
The Diversity Outbred (J:DO) stock is a new heterogeneous, highly diverse mouse resource designed for complex trait analysis and toxicology studies as well as to facilitate rapid mapping with single gene resolution. This stock was derived from crossing partially-inbred Collaborative Cross strains, which are a mixture of eight genetically well-defined JAX® Mice inbred strains, including three wild-derived. Subsequent maintenance follows a randomized outcross non-sibling mating scheme to retain maximum genetic diversity. Each Diversity Outbred mouse is genetically unique, representing a novel combination of alleles present in the founder strains. To determine the extent to which this genetic variation leads to phenotypic variation, over 50 metabolic measurements including plasma glucose, insulin, triglycerides, cholesterol, and body composition were collected, under both standard chow and high fat diet conditions. The Diversity Outbred animals displayed a wide spectrum of metabolic phenotypes, home cage nesting behavior and aggressiveness. Mouse-to-mouse variation is demonstrated by fold-differences in plasma triglycerides and creatine kinase levels, both as high as 11-12. Plasma glucose, free fatty acids, thyroxine, and percentage of fat all showed differences of 3-fold or greater. These fold-changes are comparable to the variation among unique inbred mouse strains, and mimic the diversity within human populations. The J:DO stock represents a new powerful tool for rapid gene mapping, toxicology/pharmacogenomic screens and compound evaluation for a wide variety of human diseases, including cancer and metabolic 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 4387. doi:10.1158/1538-7445.AM2011-4387
Abstract 4389: Copper and platinum uptake in cultured rat dorsal root ganglion neurons
Authors: Liu Johnson J. , Kim Yaeseul , Mercer Julian F.B. , McKeage Mark J. 
Published: June 2012

Abstract
Peripheral neuropathy is a dose-limiting toxicity of platinum drugs due to their accumulation in the dorsal root ganglia (DRG) and damage to sensory neurons. Our previous studies showed a specific pattern of expression of copper transporters in rat DRG tissue (Liu JJ et al 2009; Ip V et al 2010). Here we aimed to investigate their functional activity in the uptake of copper and platinum in cultured DRG neurons in vitro. Dissociated rat DRG neurons were cultured in N2-supplemented Neurobasal-A medium. Cellular metal levels were measured by the inductively coupled plasma mass spectrometry. The copper content of the cultured DRG neurons increased linearly with time (R2, 0.7952 ∼ 0.8903) during a one hour exposure to 3 ∼ 100 µM of CuCl2. The rate of cellular uptake of copper had nonlinear dependence (R2, 0.9629) on the exposure concentration of CuCl2, with a maximal uptake rate of 0.237 ± 0.041 nmole/min/mg protein and CuCl2 concentration achieving half-maximal uptake of 49.1 µM. The uptake of copper was temperature-dependent, stimulated by ascorbate and inhibited by zinc. CTR1 mRNA was detectable in cultured DRG neurons and its protein co-localised with microtubule-associated protein 2-positive neuronal cell bodies. Oxaliplatin inhibited copper uptake by DRG neurons and their platinum content increased linearly with time (R2, 0.916) during a one hour oxaliplatin exposure. In conclusion, CTR1 is functionally expressed by rat DRG neurons in primary culture. Oxaliplatin accumulates and inhibits copper uptake in DRG neurons. Supported by research grants from Cancer Society of New Zealand and McBeath Child Cancer Trust Fund.
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 4389. doi:10.1158/1538-7445.AM2011-4389
Abstract 4395: Functional domains in glyceraldehyde-3-phosphate dehydrogenase modulating its enzymatic activity and intracellular localization
Authors: Phadke Manali S. , Mishra Anurag , Krynetkaia Natalia , Krynetskiy Evgeny 
Published: June 2012

Abstract
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional protein that plays a pivotal role in energy homeostasis of cancer cells. In response to several types of stress including genotoxic stress, GAPDH accumulates in the nucleus; its intranuclear functions remain to be elucidated. Earlier we demonstrated that, following genotoxic stress and intranuclear translocation in human lung carcinoma cells, GAPDH binds yet to be identified nuclear components. Using site mutagenesis, we prepared several mutated variants of GAPDH containing T99I and K259N amino acid substitutions, or a stop codon at position 263. Wild type GAPDH and mutated variants were expressed in BL21(DE3) bacterial system and purified by Ni-chromatography. Catalytic properties of the mutant proteins were compared with the wild type GAPDH. Catalytic activity of GAPDH protein was significantly reduced in the T99I mutant variant (Vmax 1.6±0.33 U/mg vs Vmax 40±1.9 U/mg of wild type GAPDH), while there was no significant difference in Vmax between the K259N variant and wild type GAPDH (p = 0.97). Truncated GAPDH (K263STOP) did not reveal any detectable catalytic activity. To assess the effects of mutations on intracellular localization of GAPDH, we prepared synthetic constructs coding for GFP-fusion variants of GAPDH (T99I, K259N, K263STOP) and used them for transient transfection of isogenic human carcinoma cell lines HCT116 (40-16; p53+/+ and 379.2; p53-/-) and SW48 (297; p53+/+ and 213; p53-/-). Intracellular distribution of wild type and mutant GAPDH was assessed by confocal microscopy and image analysis. Consistent with previous findings, wild-type GAPDH was excluded from the nucleus in the absence of stress, and accumulated in the nucleus following treatment with genotoxic agent cytarabine. In contrast, both T99I and K259N mutations significantly increased intranuclear content of GAPDH before and after stress. Truncated variant GAPDH (1-262) was evenly distributed in cytosolic and nuclear compartments. No significant difference was found in GAPDH localization between p53-proficient and p53-deficient isogenic cell lines indicating that p53 does not mediate GAPDH intranuclear localization. Our results identify the important functional domains of GAPDH that determine GAPDH intracellular localization. These domains are involved in interactions with intranuclear components of the cells experiencing genotoxic stress.
* both have contributed equally to this work
This work was partially supported by NCI grant R01 CA104729
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 4395. doi:10.1158/1538-7445.AM2011-4395
Abstract 440: Characterization and comprehensive proteomic analysis of exosomes derived from prostate cancer cell lines
Authors: Hosseini-Beheshti Elham , Pham Steven , Adomat Hans , (Tomlinson) Guns Emma S. 
Published: June 2012

Abstract
Background: Exosomes are extracellular nano-vesicles which are secreted upon fusion of multivesicular bodies with the plasma membrane and present in most body fluids. They have been shown to be derived from a multitude of cell types and, while it is postulated that they are important for membrane trafficking as communication vesicles, their relevance in cancer and specifically prostate tumour growth and progression has yet to be determined. Factors such as stage of cancer, cell type and cell cycle could affect the amount and composition of exosomes formed and secreted. While the mechanisms underlying exosome formation and secretion are not fully understood, characterization of exosomes derived from different androgen dependent and independent prostate cancer cell lines (LNCaP, C4-2, VCaP, DU-145, PC-3) versus normal epithelial prostate cell line (RWPE-1) indicate novel information about their possible role in prostate cancer.
In Addition proteomic analysis of exosomes derived from different prostate cancer cell lines reflects differential protein content within these entities and could be considered for prognostic potential. Other studies on tumour-related microvesicles suggest the role of these selectively enriched exosomes in cancer progression therefore the presence of differential protein markers in and on prostate cancer cell derived exosomes may yield potential biomarkers for cancer diagnosis and therapeutic response. In this study we characterized exosomes derived from different prostate cancer cells and explain the role of specific proteins present within exosomes which are involved in prostate cancer progression.
Methods and Results: Exosomes were purified from the conditioned media(CM) from a panel of five prostate cancer cells and ‘normal’ RWPE-1 cells after 72 hours serum free media treatment. Using differential centrifugation cell debris and protein aggregates were removed from CM. Finally exosomes were isolated in a 30% sucrose cushion using ultracentrifugation. Further analysis using transmission electron microscopy detected the integrity of purified exosomes. Western blot analysis was also used to probe for different exosome markers including Actin, HSP70, HSP90, Rab5, CD9 and CD63. Our proteomic data shows that exosomes derived from specific prostate cancer cells present potential markers of prostate cancer progression.
Conclusion: This study highlights a potential for differential protein composition of exosomes as a source of diagnostic biomarkers in addition to therapeutic targets for prostate cancer via non-invasive testing.
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 440. doi:10.1158/1538-7445.AM2011-440
Abstract 4424: Antitumor activities of targeted therapeutic agents in preclinical models of gastric cancer
Authors: Fan Conglin , Pascual Bernadette , Wu Ying , Whalen Pamela , Wang Yuli , Pocalyko David , Li Gang 
Published: June 2012

Abstract
Gastric cancer (GC) is one of the most prevalent cancer types in Asia, and the 2nd most common cause of cancer deaths worldwide. Although considerable advances have been made with the use of improved surgical techniques and chemotherapy regimens, the prognosis for most GC patients remains poor. Therefore there is an urgent medical need for novel, effective targeted therapeutic agents for GC. One of the key drivers for a successful drug discovery program is utilization of predictive preclinical models that represent the patients of interest. Through internal efforts and collaborations we have developed subcutaneous (SC), orthotopic, syngeneic and patient-derived xenograft (PDX) models for target validation and pharmacological studies. Here we report the establishment of various cell line-derived mouse models of GC, and their validation with targeted therapeutic agents. In SC models of MKN-74, NCI-N87 and MKN-45, sunitinib malate significantly inhibited tumor growth. To establish orthotopic GC model, luciferase-expressing MKN-74 and NCI-N87 cells were first SC implanted in athymic nude mice. Four weeks after in vivo propagation, tumor fragments (1 mm3) were surgically implanted to the stomach wall in the greater curvature region. Primary tumor growth and spontaneous metastasis were monitored by bioluminescent imaging. Sunitinib malate treatment inhibited primary tumor growth but the effect on metastasis was inconclusive. Furthermore, PF-299804, an orally available irreversible pan-HER tyrosine kinase inhibitor, inhibited in vivo growth of NCI-N87 (with ERBB2 amplification), but not of AGS (without ERBB2 amplification). Both sunitinib malate and PF-299804 were well tolerated by the animals during the course of the studies. These results support anti-angiogenesis and as a valid approach for effective treatment of GC, and preclinically demonstrated the importance of patient selection for targeted agents.
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 4424. doi:10.1158/1538-7445.AM2011-4424
Abstract 4451: Targeted therapy of lung cancer using ScFvEGFR-Heparin-Cisplatin nanoparticles
Authors: Peng Xianghong , Wang Yiqing , Wang Yuxiang , Huang Donghai , Chen Zuo Georgia , Nie Shuming , Shin Dong M. 
Published: June 2012

Abstract
The clinical use of cis-diamminedichloridoplatinum(II) (cisplatin, CDDP) is restricted by severe side effects, including nephrotoxicity, peripheral neuropathy, and ototoxicity. Although the nanoparticles has been used for CDDP delivery in animal models and demonstrated to reduce the side effects and increase the antitumor effects of CDDP, most of studies used none-targeted nanoparticles for CDDP delivery via enhanced permeability and retention (EPR) effect. However, utilizing EPR effect for delivery of CDDP achieves only passive tumor targeting. We have developed novel nanoparticles by conjugating single-chain antibodies to epidermal growth factor receptor (ScFvEGFR) to modified heparin, and loaded CDDP into the targeted nanoparticles (EHDDP). Our results showed that the intracellular Pt was significantly higher in EHDDP treated cells (27.91± 2.45 ng Pt/105 cells) than that of free DDP (2.49± 0.39 ng Pt/105 cells) (P=0.004) and non-targeted nanopartcles HDDP(2.14± 0.20 ng Pt/105 cells) (P=0.003) at 4 hrs, while the internalization of Pt in free CDDP treated cells didn't show any significant difference as compared with that in HDDP (P=0.25). The Pt (166.05±21.17pg Pt/ug DNA) which was intercalated into DNA in EHDDP treated cells increased significantly as compared with that in CDDP(42.34±10.57pg Pt/ug DNA) (P=0.015) and HDDP(20.27±2.88 pg Pt/ug DNA) (P=0.008) treated cells. We found that the CDDP-loaded nanoparticles could significantly change the biodistribution of Pt in mice comparing with the free CDDP. Accumulation of Pt in subcutaneous tumor lesions in EHDDP group (13.45±2.15ng/mg dry tissue) was significant higher than that in HDDP (4.87±0.67ng/mg dry tissue) (P=0.026) and CDDP groups (1.48±0.52ng/mg dry tissue) (P=0.02) 24 hours after the intravenously injection (Pt, 2.5mg/kg) into nude mice bearing H292 tumors. The systemic delivery of EHDDP (2.5 mg/kg; 5 times treatment at 3 days intervals) to mice showed significant enhanced antitumor activity with no body weight loss or damages to kidney, liver, and spleen, while the mice that received free CDDP had significant weight loss and massive organ damages. Our results suggest that EHDDP nanoparticles have the potential to be used for targeted therapy of cancer which expresses EGFR with reduced side effects. (Supported by P50CA128613).
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 4451. doi:10.1158/1538-7445.AM2011-4451
Abstract 4454: Cancer therapy using pulsed HIFU and a rose bengal derivative
Authors: Kim Yoo-Shin , Rubio Valentina , Xia Rongmin , Qi Jianjun , Shi Zheng-Zheng , Peterson Leif , Tung Ching-Hsuan , O'neill Brian E. 
Published: June 2012

Abstract
High intensity focused ultrasound (HIFU) has been combined with a Rose Bengal derivative (RB2) to provide a synergistic cytotoxicity requiring the presence of both ultrasonic cavitation and drug. Unlike most sono-sensitizers, RB2 is not a photo-sensitizer, meaning it has no side effects associated with ambient light. In vitro tests have shown that a short treatment (less than 30s) of pulsed HIFU at 1 MHz with power sufficient for cavitation destroys &lt;90% of breast cancer cells in suspension with 15uM of the compound. Neither the pulsed HIFU nor the RB2 compound was found to have any significant impact on the viability of the cells when used alone. Introducing an antioxidant (N-acetylcysteine, NAC) reduced the effectiveness of the treatment, suggesting the possibility of an oxidative mechanism. In vivo tests using these same cells growing as a xenograft in mice were also done. Using similar treatment parameters in vivo necessitated the use of ultrasound contrast agents to initiate cavitation. When this was done, we were able to demonstrate rapid tumor regression for combination pulsed HIFU and RB2 treatments. RB2 was delivered in large doses of 25 mg/kg i.v. without any adverse side effects. In some animals, ablating a tumor with cavitation resulted the subsequent regression of both treated and control tumors. We believe it should be possible to develop this technology into an alternative safe and effective means of tumor ablation for breast cancer treatment.
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 4454. doi:10.1158/1538-7445.AM2011-4454
Abstract 4464: Ciclopirox Olamine alters PEAK-1-mediated cytoskeleton organization and invasion of metastatic cancer cells
Authors: Weems Jessica M. , Klemke Richard L. 
Published: June 2012

Abstract
The majority of cancer patients die from metastatic disease because there are no drugs available to prevent the spread of cancer and eradicate metastases in patients. The antimycotic drug ciclopirox olamine (CPX) is under investigation as a repositioned drug candidate which has anti-tumor and anti-angiogenesis activity in experimental models. Because CPX has been FDA tested and shows exceptionally low side effects in patients even at high doses, it has significant potential as both a therapeutic to prevent cancer recurrence after surgical resection and for the long term systemic treatment of cancer patients with overt metastatic disease. However, CPX has not yet been tested for its ability to inhibit metastatic cell function. In this study we examined the ability of CPX to inhibit metastatic cancer cell migration, invasion, and proliferation, and evaluated the signal transduction pathways that regulate these processes. Interestingly, CPX was observed to inhibit the expression of the tyrosine kinase, pseudopodium-enriched atypical kinase 1 (PEAK1), which is necessary for proper remodeling of the actin cytoskeleton and focal adhesion dynamics in metastatic cancer cells (PNAS, 107(24), 10920-5). Associated with the decrease in PEAK1 expression by CPX was decreased total cellular tyrosine phosphoprotein content, pseudopodium protrusion, cancer cell spreading, movement, and proliferation on extracellular matrix proteins. Collectively, our findings indicate that at therapeutic doses, CPX potently alters cytoskeletal signaling, cancer cell movement, and proliferation by modulating PEAK1 activity. These findings are important in light of the fact that PEAK1 amplification and cytoskeleton modulation have been linked to anchorage-independent cell growth, cell migration, and tumor progression in human gastrointestinal cancers. The exceptional safety record of CPX and our findings support the notion that CPX has significant potential as a repositioned therapeutic agent to combat cancer recurrence and spread in patients.
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 4464. doi:10.1158/1538-7445.AM2011-4464