bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3698: Chemopreventive efficacy of pioglitazone on lung cancer in mice
Authors: Wang Yian , James Michael , Wen Weidong , Lu Yan , Szabo Eva , Lubet Ronald A. , You Ming 
Published: June 2012

Abstract
Pioglitazone is a ligand of PPARγ nuclear receptor. Activation of PPARγ has been associated with anticancer activities in a variety of cancer cell lines through inhibition of proliferation and promotion of apoptosis. We examined the effect of pioglitazone, which is approved for the treatment of type II diabetes mellitus, on lung cancer development in carcinogen-induced non-small cell lung cancers in mice. When pioglitazone was administered beginning 8 weeks after the first dose of carcinogen treatment, pioglitazone significantly inhibited tumor load (sum of tumor volume per lung in average) by 64% (P &lt; 0.05) in p53(wt/wt) mice and 50% (P &lt; 0.05) in p53(wt/Ala135Val) mice in the lung adenocarcinoma model. Delayed administration of pioglitazone caused a limited (35%, P &lt; 0.05) decrease in lung squamous cell carcinoma. Induction of apoptosis occurred in both model systems. These data show that pioglitazone significantly inhibited progression of both adenocarcinoma and SCC in the two mouse model systems.
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 3698. doi:10.1158/1538-7445.AM2011-3698
Abstract 3700: Proteomic credentialing in a model for chemoprevention studies of urinary bladder cancer
Authors: Townsend Reid R. , Rohrs Henry , LeDuc Richard , Malone James P. , Erdman-Gilmore Petra , Hill Donald L. , Grubbs Clinton J. , You Ming , Lubet Ronald A. 
Published: June 2012

Abstract
Molecular markers for the development and response of tumors to agents are essential for efficacy assessment of cancer chemoprevention. The discovery, verification and validation of biomarkers for tumor monitoring require animal models that have been shown to share molecular features with human cancers. At the transciptomic level, the rat 4-hydroxybutyl(butyl) nitrosamine (OH-BBN) model has been shown to share many of the pathways that are commonly activated in human bladder cancer. To qualify the model at the proteomics level, global protein analyses on bladder tumors and on paired urine samples were performed, and the findings correlated with transcriptomic data and literature knowledge of upregulated proteins in human bladder cancer. We used a high-resolution LC-MS platform that consisted of optimized, reproducible sample preparation methods for tissue and urinary proteins, robust nano-LC hybrid (linear quadrupole-Orbitrap) mass spectrometry, and a data analysis pipeline to align and annotate differential peptides from LC-MS analyses of multiple samples. To date, samples from ∼ 150 individual animals have been analyzed using this quantitative proteomics platform. We have used this platform to correlate urinary candidate abundances with tumor burden and response to chemopreventive agents. In one experiment that compared the urine from control and tumor-bearing animals, it was found that 3,032 of the 15,557 detected peptides changed by &gt; 3-fold. Among the proteins that were only detected in tumor-bearing animals (at least a 1000 fold increase) were Annexins (I, II and VII), S-100 proteins-4, 6 and 11, calpactin and galectin.
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 3700. doi:10.1158/1538-7445.AM2011-3700
Abstract 375: The cellular distribution and related response of different peptide modified gold nanoparticles in cervical cancer cells
Authors: Tsai Tsung-Lin , Wu Ping-Ching , Hou Chia-Cheng , Li Ying-Ying , Shieh Dar-Bin , Su Wu-Chou 
Published: June 2012

Abstract
Nanoparticles (NPs) are ideal vectors to deliver analytic probes or therapeutic agents into cells and subcellular compartments. Among many nanomaterials, gold NPs is widely used as a model platform for biomedical research because of their favorable physical and chemical properties. Thus, gold NPs has been employed for various applications, especially in medicine. Through surface modification of gold NPs with functional bio-macromolecules (i.e., peptides, nucleic acids and antibodies) may improve the ability of imaging, clinical diagnostics and therapeutics. Cellular uptake of gold NPs is highly dependent on their size, shape, and surface properties. For targeted therapy, the common strategy for specific cells or cellular compartments delivery is to modify NPs with peptides or lignads. The outcome is highly dependent on the peptide sequence and cell types. Therefore, we treated CaSKi, HeLa and SiHa cervical cancer cells with different peptide-modified gold NPs for 24 hours and determined the cellular localization of the NPs from laser confocal microscopy equipped with DIC channel. We found that gold NPs modified with the nuclear localization signal (NLS) peptide from SV40 virus (GNP-PEG/SV40) accumulated around the cytoplasmic side of nuclear membrane (perinuclear accumulation) in CaSKi and HeLa carcinoma cells and translocate into nucleus in SiHa squamous cells. For adenovirus (ADV) peptide modified NPs (GNP-PEG/ADV), nuclear localization was observed in all cervical cancer cells. We then performed cell survival test (MTT assay) for various time intervals (24 to 96 hours) to identify the relationship between NPs’ distribution and cellular response. The particles exhibited perinuclear and nuclear accumulation decreased cell survival greater than cell and particles control (GNP-PEG) did. For perinuclear accumulation in HeLa cells, through annexin V/PI stain, there was no increase in apoptosis after long-term treatment with GNP-PEG/SV40 particles, but a significant increase in LC3-II expression in the GNP-PEG/SV40-treated group, suggesting activation of autophagy. On the contrary, an apoptotic cell population was found in nuclear accumulated SiHa cells. These findings suggest that different cellular distribution of NPs may link with specific death pathways. In conclusion, this study may have implications in the development of new therapeutic modality for specific cancer cells or prevention of long-term toxicities from treatment with different peptide modified NPs.
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 375. doi:10.1158/1538-7445.AM2011-375
Abstract 3861: Bladder cancer-associated gene expression signatures identified by profiling of exfoliated urothelia
Authors: Rosser Charles J. , Urquidi Virginia , Liu Li , Sun Yijun , Whiting Bryant , Villicana Patrick , Goodison Steve 
Published: June 2012

Abstract
PURPOSE: Bladder cancer is the fifth most commonly diagnosed malignancy in the United States and one of the most prevalent worldwide. It harbors a probability of recurrence of &gt;50%; thus, rigorous, long-term surveillance of patients is advocated. Flexible cystoscopy coupled with voided urine cytology is the primary diagnostic approach, but cystoscopy is an uncomfortable, invasive procedure and the sensitivity of voided urine cytology is poor in all but high-grade tumors. We sought to define a robust genetic signature that can be used to diagnose bladder cancer in a non-invasive manner.
METHODS: Gene expression microarrays were utilized to analyze the transcript profiles of 52 urine samples from subjects with bladder tumors and 40 subjects without bladder tumors (cohort I). Data from microarrays containing 56,000 targets were subjected to a panel of statistical analyses to identify bladder cancer-associated gene signatures. Hierarchical clustering and supervised learning algorithms were used to classify samples on the basis of tumor burden. Furthermore, supervised machine learning and a cross-validation approach were used to build a 40-gene molecular classifier which was then validated in voided urine samples by quantitative PCR (qPCR) in an independent group of patients (cohort II – 46 subjects with bladder cancer and 37 subjects without bladder cancer).
RESULTS: Hierarchical clustering classified normal urothelium and bladder cancer with 84% accuracy. A genetic profile consisting of 40 probes was identified in those patients (cohort I) with bladder cancer. In an independent experiment, 14 of the 40 genes indentified above were validated in voided urine samples by qPCR in cohort II. Utilizing this 14 gene signature, the diagnostic accuracy of detecting bladder cancer was 81%.
CONCLUSION: Our results show that it is possible to achieve the detection of bladder cancer using molecular signatures present in exfoliated tumor urothelia. Further investigation and validation of the cancer-associated profiles in a diverse cohort may reveal important biomarkers for the detection and surveillance of bladder 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 3861. doi:10.1158/1538-7445.AM2011-3861
Abstract 4017: DLC1 and α-catenin protein interaction enhances DLC1 antioncogenic activity by stabilizing adherens junctions and suppressing NFκB signaling
Authors: Tripathi Veenu , Zimonjic Drazen B. , Popescu Nicholas C. 
Published: June 2012

Abstract
Adherens junctions (AJs), which are cell-cell adhesion complexes closely associated with actin cytoskeleton, play an important role in maintaining epithelial tissue homeostasis. Both malignant transformation, and tumor progression to metastasis are often associated with major changes in cytoskeletal organization, the cell-cell adhesion, and aberrant adhesion-mediated signaling. The tumor suppressor gene DLC1 (Deleted in Liver Cancer 1) encodes a RhoGTPase activating protein (GAP) that acts as a negative regulator of the Rho family of small GTPases, which are implicated in cytoskeleton organization and regulation of AJs. A yeast two-hybrid screening identified α-catenin, a component of AJs, as a potential DLC1's binding partner. We relied on this finding and investigated the role of DLC1 in the regulation of AJs and in adhesion-mediated signaling. Using human embryonic kidney (HEK 293) cells we demonstrated that DLC1 interacted with α-catenin and associated with E-cadherin and β-catenin, both constitutive AJs proteins. Co-immunoprecipitation using various deletion constructs of DLC1 and of α-catenin established that the N-terminal (340-435 aa) of DLC1 interacted with the N-terminal (39-161 aa) of α-catenin. Immuno-fluorescence staining and western blot of cellular membrane and cytoplasmic fractions, demonstrated that binding of DLC1 to α-catenin recruited α-catenin to the plasma membrane and required DLC1 GAP activity. In contrast, the DLC1 GAP mutant (R718E) failed to produce the same effect. Fluorescence Recovery After Photobleaching (FRAP) analysis demonstrated that DLC1-α-catenin interaction increased the GFP-E-cadherin mobility at cell-cell junctions, whereas phalloidin staining showed intact actin cable formation around the cell periphery, resulting in the stabilization of AJs. The DLC1-α-catenin interaction is instrumental for a maximal oncosuppressive effects of DLC1 (i.e., by inhibiting proliferation and abolishing colony formation of prostate carcinoma cells); DLC1 mutant defective for α-catenin binding failed to reproduce such an effect. Loss of α-catenin is usually accompanied by an increase in the activation of NFkB, which is associated with increased cell proliferation and resistance to apoptosis. We demonstrated that, by immobilizing NFkB to the AJ complex, DLC1-α-catenin interaction effectively inhibited NFkB phosphorylation and, therefore, its activation. Together, these results unravel a new mechanism through which DLC1 exerts its oncosuppressive function by stabilizing AJs and suppressing NFkB signaling.
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 4017. doi:10.1158/1538-7445.AM2011-4017
Abstract 4410: Initiative for Molecular Profile and Advanced Cancer Therapy (IMPACT): A personalized medicine Phase I clinical trials program at MD Anderson Cancer Center
Authors: Tsimberidou Apostolia M. , Hong David S. , Wheler Jennifer , Fu Siqing , Piha-Paul Sarina , Naing Aung , Falchook Gerald , Luthra Raja , Iskander Nancy G. , Wen Sijin , Kurzrock Razelle 
Published: June 2012

Abstract
Introduction: Ongoing clinical trials are based on targeting specific pathways in addition to the tumor histology. We examined the results of mutational analyses performed in patients with advanced cancer seen in the Phase I clinic at The University of Texas MD Anderson Cancer Center.
Methods: Mutational analysis was mostly performed in the Clinical Laboratory Improvement Amendments (CLIA)-certified pathology laboratory of MD Anderson. DNA was extracted from microdissected paraffin-embedded tumor samples, and analysis was performed on specific exons, depending on the test ordered, for the following genes: PIK3CA (exon 9: codons 532-554; exon 20: codons 1011-1062); BRAF (exon 15: codons 595 to 600); KRAS and NRAS (codons 12, 13, and 61); EGFR (exons 18 to 21 of the kinase domain); KIT (exons 9, 11, 13, and 17); and RET (exon 10: codons 609, 611, 618, and 620; codon 634 of exon 11; codon 918 of exon 16). The loss of the tumor suppressor nuclear protein, PTEN, was determined using immunohistochemical staining.
Results. Tumor mutational analysis was ordered for 952 patients. Overall, 103 patients did not have adequate tissue. Of the remaining 849 patients, 354 (41.69%) had ≥ 1 mutation and 495 did not have a mutation. More women (45%) than men (38%) had a mutation (p = 0.02), but age was not associated with the presence of mutations (p=0.76). Of the patients with mutations, 313 had 1 mutation, 38 had 2 mutations, and 3 had 3 mutations. The distribution of mutations by diagnosis is shown in the Table. The total distribution of mutations in our patient population was as follows: BRAF, 19.01%; KRAS, 18.74%; PIK3CA, 9.85%; NRAS, 8.17%; EGFR, 3.38%; KIT, 2.13%; and PTEN loss, 21.20%.
Conclusion: Testing for PIK3CA, KRAS, NRAS, BRAF, EGFR, KIT, and RET mutations and PTEN loss in 849 patients with available tissue demonstrated that molecular driver aberrations are common in advanced 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 4410. doi:10.1158/1538-7445.AM2011-4410
Abstract 4449: Deep penetration of PDT drugs into tumors via non-covalent drug-gold nanoparticle conjugates
Authors: Meyers Joseph D. , Cheng Yu , Broome Ann-Marie , Kenney Malcolm E. , Burda Clemens , Basilion James P. 
Published: June 2012

Abstract
In 2010, more than a million new cancer cases are expected to be diagnosed with half resulting in death, at an NIH estimated total yearly cost of $263.8 billion. Therefore, there is a critical need to improve both cancer diagnostics and therapeutics; future theranostics aim to combine both in a single visit. Consequently, efficient delivery of hydrophobic, theranostic drugs is necessary. This study presents a novel non-covalent PDT cancer drug-gold nanoparticle (Au NP) conjugate system that is able to perform rapid drug release deep into tumors within hours rather than days. The drug delivery mechanism of the PDT drug Pc 4 using Au NPs into tumors by passive accumulation was investigated via fluorescence imaging of Pc 4, elemental gold analysis, and histological staining. The pharmacokinetics of the conjugates over a 7 day period showed rapid drug excretion, as monitored via the fluorescence of Pc 4 which decreased significantly to near baseline levels. Moreover, the biodistribution of Au NPs indicated clearance of the conjugates from the mice. The spleen, liver, kidneys, and urinary tract showed accumulation of Au NPs and accounted for 33.6% of the injected dose at only 4 hrs, suggesting possible excretion pathways, since the total injected dose of Au NPs recovered from dissected organs decreased by 33.4%. Histological analysis corroborated these findings; Au NPs in the liver were found in liver sinusoids and hepatocytes, Au NPs in the spleen were found near macrophages, Au NPs in the kidney were located in the glomerulus, and Au NPs in the urinary tract were found in the stroma. At 4 hrs post-injection, ∼76% of the injected dose of Au NPs was recovered in harvested organs, and AuNPs accumulated passively in tumors with an average accumulation of 8 ± 6 % ID (or ∼62.46 μg/g of tumor tissue). The tumor (4 hrs post-injection) showed very high fluorescence intensities further suggesting the passive accumulation of Pc 4 via the Au NPs within the tumor. In vitro studies showed the conjugates delivered 389.4 moles of Pc 4 per mole of Au NP into cells in 4 hrs; in vivo studies showed approximately 10 RFUs (of Pc 4)/ μg of gold delivered into tumor tissues. Ultimately, this study suggests that Pc 4 non-covalently loaded Au NPs that penetrate deep into the tumor interior provide a very attractive approach to delivery cancer drugs to visualize carcinomas and track therapeutic responses.
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 4449. doi:10.1158/1538-7445.AM2011-4449
Abstract 4470: Kevetrin™, a novel small molecule, activates p53, enhances expression of p21, induces cell cycle arrest and apoptosis in a human cancer cell line
Authors: Kumar Ashok , Hiran Tej , Holden Sylvia A. , Chafai-Fadela Karima , Rogers Samantha , Ram Siya , Menon Krishna 
Published: June 2012

Abstract
We have previously shown that Kevetrin, a small molecule currently under development, has potent antitumor activity in human multi-drug resistant carcinoma xenograft models while being well tolerated. To investigate the mechanism of action for its potent antitumor activity, we assessed Kevetrin's effect on apoptosis, cell cycle progression, including underlying molecular mechanisms.
Here we report that Kevetrin strongly induced cell cycle arrest and apoptosis in a human lung adenocarcinoma cell line (A549) using the TUNEL assay and FACS analysis; similar results were observed using a human breast carcinoma cell line (MDA-MB-231). Treatment of A549 cells with 400 µM of Kevetrin for 48 hours resulted in G2/M phase cell cycle arrest that was associated with a marked decline in levels of G2/M regulatory proteins, including CDK1 and cdc25B, and increased expression of Wee1. Further, Kevetrin-mediated growth inhibition of A549 correlated with apoptosis induction that was characterized by cleavage of procaspase-3 and poly (ADP-ribose) polymerase (PARP).
The p53 tumor suppressor is a well characterized transcription factor controlling cell growth and apoptosis during times of cellular stress. The tumor suppressor p53 inhibits tumor growth primarily through its ability to induce apoptosis. In cancer development, the resistance of cells to apoptosis is one of the crucial steps. The reactivation of p53 in tumor cells should trigger massive apoptosis and eliminate the tumor. Interestingly, Kevetrin treatment caused enhanced activated p53 levels in A549 cells. Activation of p53 can lead to cell cycle arrest and apoptosis. Western blotting revealed a concentration dependent increase in phosphorylation of p53 at serine 15. The phosphorylation of p53 at serine 15 leads to reduced interaction between p53 and its negative regulator, the oncoprotein MDM2. We also found that Kevetrin increased expression of p53 target genes such as p21 (Waf1). The tumor suppressor protein p21 (Waf1) acts as inhibitor of cell cycle progression. Finally, we also found that p53 induced apoptosis by inducing the expression of PUMA.
Our study shows that Kevetrin activates p53 functions in tumor cells. Thus Kevetrin is a strong candidate as an anticancer drug that targets p53. Based on our studies we plan to initiate a Phase I clinical trial in 2011.
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 4470. doi:10.1158/1538-7445.AM2011-4470
Abstract 4479: Targeting non-small cell lung cancer cells harboring a PIK3CA mutation by a novel and oral PI3K selective inhibitor, PF-4989216
Authors: Walls Marlena , Mehta Pramod P. , Baxi Sangita M. , Liu Kevin , Li Chunze , Smeal Tod , Yin Min-Jean 
Published: June 2012

Abstract
Aberrant phosphatidylinositol 3-kinase (PI3K)/AKT signaling occurs commonly in cancer. Gene mutation, amplification, and copy number gains of the PI3K catalytic subunit p110α have been shown in a variety of human cancers. The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) dephosphorylates the 3-phosphoinositides and is frequently mutated, deleted, or down-regulated in many cancers to constitutively activate the PI3K pathway. In response to activation, PI3Ks phosphorylate membrane phosphatidylinositides to generate phosphatidylinositol 3,4,5-triphosphate (PIP3); PIP3 serves as an secondary messenger activating AKT and 3’-phosphoinositide-dependent kinase-1 (PDK1). Phosphorylation of AKT at threonine-308 (T308) by PDK1 and serine-473 (S473) by mTORC2 fully activates the AKT pathway to regulate various cellular processes including cell growth, proliferation, survival, and metabolism.
Several inhibitors targeting the PI3K pathway have been developed in preclinical discovery or clinical trials; however, a small molecule inhibitor has not yet been approved for cancer treatment. Most inhibitors have inhibitory activity against both PI3Ks and mTOR kinases. The mTORC1 and mTORC2 complexes control critical pathways regulating cell proliferation, apoptosis, angiogenesis, and metabolism through AKT-dependent and AKT-independent mechanisms. Therefore, agents targeting PI3K with additional mTOR kinase inhibitory activities may carry extra toxicity through the disruption of mTOR function in normal cells. To develop a drug selectively targeting PI3K, we have identified PF-4989216 as a novel potent and selective PI3K inhibitor. In this study, we describe the in vitro and in vivo anti-tumor activity of PF-4989216 in human non-small-cell lung cancer cells (NSCLCs). PF-4989216 inhibits the phosphorylation of PI3K downstream molecules and subsequently leads to inhibition in cell proliferation and xenograft tumor growth in NSCLCs harboring a PIK3CA mutation, including an erlotinib resistant line, NCI-H1975. Although PF-4989216 inhibits the phosphorylation of PI3K downstream molecules in the NSCLCs with PTEN loss (NCI-H1650), PF-4989216 does not sufficiently induce anti-tumor efficacy in NCI-H1650. Our results suggest that there may be a different tumorigenesis mechanism between PIK3CA mutation and PTEN loss in NSCLCs, and indicate that PF-4989216 is a potential cancer drug candidate for erlotinib resistant non-small-cell lung cancer patients with PIK3CA mutation.
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 4479. doi:10.1158/1538-7445.AM2011-4479