bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3366: An inhibitor of the NF-kappaB pathway targets cancer stem cells and prevents tumor recurrence
Authors: Gomez-Cabrero Azucena , Liao Debbie , Nguyen Giang , Reisfeld Ralph 
Published: August 2012

Abstract
Multidrug resistance and tumor recurrence are two of the major challenges in cancer treatment. Cancer stem cells (CSCs), found in most solid tumor types, have been proposed as the root cause of cancer growth and recurrence. These CSCs share similarities with normal Stem Cells, such as “stemness” gene profile expression, overexpression of Sox2, Nanog and Oct4, as well as ability to grow in spheres and to repopulate tumors. Additionally, CSCs also have a high resistance to chemotherapeutic agents, probably due to their dormancy and overexpression of ABC transporters. Since CSCs markers are highly variable between cell lines and tumor samples, we used a functional assay to select a drug candidate targeting CSCs, based on their capability to efflux dyes such as Hoechst 33324 by a side population (SP). This drug decreased SP and spheres formation in vitro, and reduced protein expression of CSC genes such as Sox2, Nanog, Survivin and Oct4. Another serious limitation of cancer chemotherapy is its toxic side effect due to poor targeting to the tumor and its microenvironment (TME). To address this issue, we developed targeted nanoparticles (tNP) to deliver chemotherapeutic drugs specifically to tumor cells and their TME, resulting in substantially reduced systemic toxicity, as well as eradication of tumors and prevention of their recurrence in a preclinical setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3366. doi:1538-7445.AM2012-3366
Abstract 3368: Efficient delivery of prostate cancer gene therapy via adipose-derived mesenchymal stem cells in vivo
Authors: Zolochevska Olga , Figueiredo Marxa L. 
Published: August 2012

Abstract
It is critical to develop new therapeutic approaches for prostate cancer, since there is no effective treatment for patients in the advanced stages of this disease. And although many gene therapy approaches have been evaluated to date, clinical responses unfortunately remain poor. We have examined the potential of developing more effective cell-based gene therapies for preventing prostate cancer progression, using adipose-derived mesenchymal stem cells (ASC) as vehicles. The present study reports promising preliminary observations using this novel gene therapy modality. ASCs can be isolated using simpler methods as compared to those involving bone marrow mesenchymal cells, and are much more easily expanded at early passage numbers to therapeutic quantities. And since current techniques allow isolation of ASCs from an individual's own adipose tissue, this could help prevent immune reaction, suggesting that ASCs could be far more efficient as a gene delivery vehicle than viral vectors currently in clinical trials. In this study we have examined the potential of new antiangiogenesis and proapoptotic therapies delivered by ASCs and evaluated their ability to reduce prostate tumor growth rate in vitro and in vivo. We expressed in ASCs several secreted antitumor gene therapies (PEDF, Mda7, or IFNb), and all were found to be highly effective in almost complete prevention of tumor progression in vivo using prostate cancer xenograft models. Overall, ASC-delivered PEDF prevented HUVEC tube formation in vitro and induced strong apoptosis of cocultured cancer cells, suggesting a potential bystander effect that might be useful for therapeutic applications. Similar antitumor findings were observed when Mda7 or IFNb were delivered by ASCs, with induction of strong cell cycle arrest, and viability reduction by an increase in the apoptosis of cocultured tumor cells as assessed by Caspase 3/7 detection. The transgene expression was overall non-toxic and did not appear to interfere with the normal differentiation potential of ASCs (osteogenesis or adipogenesis). Therefore, this novel cellular delivery method for gene therapy appears to be effective and highly promising for translational applications.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3368. doi:1538-7445.AM2012-3368
Abstract 3842: Methylseleninic acid, a novel potent and selective mutant-p53-rescue drug, reactivates mutant p53 by thiol modification
Authors: Qi Yanfeng , Saifudeen Zubaida R. , Morris Gilbert F. , Rowan Brian G. , Dong Yan 
Published: August 2012

Abstract
Mutations of the p53 tumor suppressor gene constitute the most frequent genetic alteration known in human cancers. The vast majority (∼80%) of the mutations is missense mutations, and the DNA-binding domain is the most frequently mutable region of p53. p53 mutation leads to checkpoint defects, genomic instability, and propagation of cells with genetic damage. Developing therapeutic agents that could directly bind to the mutant p53 and reconstitute p53 function has been intensively pursued and proven to be feasible. However, the challenge remains to develop a drug that specifically reactivates mutant p53 without activating the pro-apoptotic function of wild-type p53 in normal tissues. In the present study, we show that a small-molecule drug, methylseleninic acid (CH3SeO2H, MSA), can selectively reactivate mutant p53 to induce apoptosis in cancer cells. MSA can be used at a concentration at least one order of magnitude lower than that of other mutant-p53-rescue agents to achieve the same p53-reactivating and growth-inhibitory effects. MSA reduces redox-active free thiols in mutant p53 without the requirement of other proteins, potentially through forming adducts with thiols in mutant p53. The modification restores wild-type conformation to mutant p53, leading to increased DNA binding and transactivation as well as expression of growth-suppressive and pro-apoptotic target genes in both cultured cancer cells and an orthotopic tumor model. Although MSA also redox modifies recombinant wild-type p53, the modification does not lead to the induction of growth-suppressive or pro-apoptotic target genes in normal fibroblasts. Instead, the expression of p53-regulated DNA-repair genes is significantly induced in normal fibroblasts, suggesting that MSA may selectively modify p53 for DNA repair or apoptosis depending on the level of endogenous or exogenous DNA damage. Our findings, therefore, demonstrate the effectiveness and selectivity of MSA as a novel potent mutant-p53-rescue drug.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3842. doi:1538-7445.AM2012-3842
Abstract 3857: Smac mimetic TL32711 and TRAIL synergistically induce apoptosis of germinal center B lymphoma cells
Authors: Smith Mitchell R. , Joshi Indira , Weng David E. , Chunduru Srinivas , McKinlay Mark A. 
Published: August 2012

Abstract
TL32711, a Smac mimetic in clinical testing, potently targets Inhibitor of Apoptosis Proteins (IAPs, including cIAPs and XIAP) to unblock intrinsic and extrinsic pathways, enabling caspase-dependent apoptosis via multiple signals including TRAIL (Tumor Necrosis Factor-Related Apoptosis Inducing Ligand). TL32711 also inactivates canonical and activates non-canonical NF-κB signaling through cIAPs. We investigated the pro-apoptotic effects of TL32711, alone and in combination with TRAIL to activate the extrinsic pathway, in a panel of B cell lymphoma cell lines representing germinal center/follicular (GC) vs activated B cell (ABC) histologies. We hypothesized that the efficacy of this potential combination therapeutic strategy might differ between GC and ABC lymphoma types, as ABC are reported to be NF-kB dependent. We used the following EBV negative cell lines: WSU- FSCCL t(14:18)+ follicular lymphoma (FL), FC-TxFL2 t(14:18)+ transformed FL and SU-DHL4 GC-type diffuse large B cell lymphoma (DLBCL) as examples of GC origin lymphomas. U2932 and TMD8 served as ABC-type DLBCL. Apoptosis was determined by annexin V staining after 48 hr incubation (TL32711 added 2-3 hr after TRAIL). The contribution of the different apoptotic pathways was determined by caspase-3 (common), -8 (extrinsic), and-9 (intrinsic) activity, assessed by flow cytometric methods and Western blot. TL32711 had little effect as a single agent on any of these B cell lymphoma cell lines at ≤ 100nM, though apoptosis was induced at 10-20 µM in GC types. TRAIL alone (10-25 ng/ml) induced apoptosis in the 3 GC lines, but had little effect on the 2 ABC lines. Combination of TL32711 and TRAIL at low concentrations showed marked apoptosis in GC lines, with minimal to no effect for each agent alone. In the combination-treated GC types, caspases -3, -8 and -9 were significantly induced, confirming activation of both pathways. We had previously shown in FSCCL and TxFL2 that caspase-8 induction also cleaved tBID, activating the intrinsic apoptotic pathway via caspase-9. GC subtypes, including FL, transformed FL and GC-DLBCL were sensitive to TRAIL and TL32711 at clinically achievable concentrations for TL32711, with supra-additive combination effects. ABC-type DLBCL were not sensitive to either agent alone or in combination. We are investigating whether ABC-DLBCL are truly dependent on canonical NF-κB activation for survival or have other mechanisms of resistance to TRAIL and IAP inhibition. These data suggest that clinical trials of TL32711 may focus on FL and GC lymphoma in combination with TRAIL or TRAIL-agonists.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3857. doi:1538-7445.AM2012-3857
Abstract 3883: Miniaturizing the GloSensor™ cAMP assay for MC4R screening using the Echo® acoustic liquid handler
Authors: Worzella Tracy J. , Allison Tim , Stecha Pete , Cong Mei , Zimprich Chad , Kershner Kevin , Somberg Richard L. 
Published: August 2012

Abstract
As biological assays used for HTS and uHTS are miniaturized, it is critical to maintain assay sensitivity while minimizing reagent volumes and maximizing throughput. The GloSensor™ cAMP Assay provides an extremely sensitive and easy to use, real-time luminescent assay format for the interrogation of over expressed or endogenous GPCRs that signal via changes in the intracellular concentration of cAMP. Tipless, touchless transfers with the Echo® liquid handler eliminate the need for costly disposable tips and greatly simplify assay development efforts. Precise and accurate drop placement eliminates cross-contamination. In this work, we demonstrate optimization of the GloSensor cAMP Assay in low-volume format using a stably transfected HEK293 cell line model expressing the melanocortin 4 receptor (MC4R) and a cAMP-sensing variant of firefly luciferase. We show that the Echo liquid handler is able to titrate small molecule and peptide agonists and antagonists, as well as transfer the GloSensor cAMP Reagent, providing robust assay results that are achieved with significantly reduced volumes of cells and compound.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3883. doi:1538-7445.AM2012-3883
Abstract 3885: A bi-functional fluorescent assay for the assessment of cytotoxicity and proliferation
Authors: Niles Andrew L. , Zhou Min , Bernad Laurent , McDougall Mark , Lazar Dan 
Published: August 2012

Abstract
Cell-based models continue to be critical tools for cancer research. Therefore, the assessment of cytotoxic or cytostatic effects remains an obligate experimental activity. Although numerous enzyme activity chemistries exist for measuring cytotoxicity, biomarker degradation may cause underestimation of actual cytotoxicity and limit the utility of these activity measures when ascertained with long-term drug exposures (72hrs or more). We have developed a cell-impermeant probe which labels the DNA from cells with compromised membranes. The quantum efficiency (i.e. brightness) of this dye increases dramatically upon DNA binding, producing a fluorescent signal which can be measured using standard “green” fluorometry wavelengths (excitation 485nm/emission 530nm). Additionally, the dye is non-toxic and stable, allowing for introduction of the probe directly into the culture medium or compound dilutions prior to cell dosing. This “no step” addition feature allows for the measurement of cytotoxicity in real time or at a convenient endpoint. Furthermore, the dye is fully compatible with luminescent measures, allowing for same-well, multi-parametric assessment of the cytotoxic phenotype. Lastly, proliferative or anti-proliferative effects (relative to control) can be revealed by the introduction of a lytic detergent which enables the normally impermeant dye to bind to all DNA in the assay well. Herein, we detail our efforts to characterize and multiplex this dye when applied to suspension and adherent cell lines treated with agents which cause either primary or secondary necrosis in a 72hr time course.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3885. doi:1538-7445.AM2012-3885
Abstract 3888: Next generation cell engineering: the Jump-In cell engineering platform
Authors: Vogel Kurt W. 
Published: August 2012

Abstract
The stable introduction of genetic material into cell lines has become one of the most widely used methods since its introduction more than 3 decades ago. Cell engineering has become an indispensable tool for a wide range of areas in Life Science, such as cell biology, physiology, In-vivo modeling, drug discovery and bioproduction. However, most cell engineering strategies currently employed for the generation of stable cell lines require substantial commitment in respect to time, FTE hours and resources. In addition, most cell lines are generated by relying on random integration of genetic material into the genome, which typically results in a wide range of expression levels within a cell population. For these reasons the frequent generation of engineered cell lines is in general cumbersome and unpredictable. Life Technologies recently developed and validated the Jump-In™ cell engineering platform, a novel gene targeting technology based on R4 integrase mediated site specific homologous recombination. This technology allows the targeted integration of genetic material into a specific pre-engineered site, which by design reduces the effort required for generation of stable cell lines compared to standard methods. Isogenic expression from a defined genomic locus provides the ideal solution for comparative analysis of gene families, isotypes or orthologs. This technology was applied to two widely used cellular backgrounds, HEK293 and CHO-K1. We used these cellular backgrounds as case studies to demonstrate how this technology can be applied to rapidly generate engineered cell lines for a variety of cell based assay applications, including reporter assays for pathway analysis, GPCR activity assays and analysis of protein post-translational modifications. In summary, Jump-In™ technology enables researchers to accelerate the development of cellular assays by greatly reducing the amount of time and resources required for the upfront cell engineering process. For Research Use Only. Not intended for any animal or human therapeutic or diagnostic use.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3888. doi:1538-7445.AM2012-3888
Abstract 3895: Rational design of small molecule inhibitors that bind to an allosteric pocket on human heat shock protein 70 (Hsp70)
Authors: Taldone Tony , Patel Pallav D. , Kang Yanlong , Rodina Anna , Talele Tanaji T. , Chiosis Gabriela 
Published: August 2012

Abstract
The 70 kDa heat shock protein (Hsp70) plays an important role in cancer and its pharmacological modulation with small molecules may represent a useful therapeutic approach. The discovery of such agents has been hampered by the lack of a full length crystal structure of human Hsp70. We constructed a homology model of the human Hsp70, which we investigated for potential druggable sites using SiteMap tool. An allosteric site in the nucleotide binding domain was identified and used to design potent Hsp70 modulators. Analysis of the Glide docking resulted in an understanding of important interactions between designed ligands, such as YK5, and the Hsp70 protein. When tested in breast cancer cells, YK5 led to depletion of onco-proteins, induced apoptosis and inhibited growth. YK5 is to our knowledge the first rationally designed small molecule inhibitor of Hsp70, and thus, represents a novel chemical tool to investigate its potential in cancer and other diseases.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3895. doi:1538-7445.AM2012-3895
Abstract 3910: Lead optimization of a series of 5-aminopyrazol-imidazopyridine compounds as potent anaplastic lymphoma kinase inhibitors active against clinically relevant ALK mutations
Authors: Yang Bin , Saeh Jamal C. , Peng Bo , Kamhi Victor , Harrison Rane , Harish Reema , Wu Allan , Whitston David , Wang Haiyun , Ye Minwei , Wang Suping , Code Erin , Rivard Caroline , Drew Lisa , Mazzola Anne Marie , Russell Daniel J. 
Published: August 2012

Abstract
Despite the success of Crizotinib in treating NSCLC patients with EML4-ALK fusions, cancers eventually develop resistance via a variety of mechanisms including mutations in the ATP binding site of the kinase domain. A series of 5-aminopyrazol-imidazopyridine compounds were identified to potently inhibit anaplastic lymphoma kinase and were found to be active against a number of mutations in vitro but suffered from strong Cyp inhibition and were found to be metabolically unstable by incubation in human hepatocytes and microsomes. Installation of a pyrimary alcohol group on the heteroaryl ethyl group of the scaffold consistently improved Cyp3A4 liability, and led to improvement in physical and DMPK properties as well as improvement of their metabolic stability in human Heps. The lead compound from this series was orally administrated to SCID mice in a Del xenograft model and achieved greater than 90% phospho-ALK inhibition over 6 hours post dose at 10 mg/kg dose. The lead compound was subsequently tested against Crizotinib-resistant ALK mutations in enzyme assays, and was shown to inhibit the clinically relevant ALK mutations, including L1196M. In enzyme assays, it was inactive against G1269S mutation, consistent with modeling studies. Subsequent profiling in an FDCP cell line over expressing ALK G1269S mutation showed potent anti-proliferative activity, suggesting off-target activity. Further characterization of this series identified AurB inhibition to be a key cell cycle kinase responsible for the off-target activity in the engineered cell line. The off target activity hinders it from assessing the primary pharmacology responsible for its preclinical efficacy in disease relevant models. In conclusion, we have identified a novel orally bioavailable compound that is a potent dual active ALK and AurB inhibitor that is active against clinically-relevant gatekeeper mutant.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3910. doi:1538-7445.AM2012-3910
Abstract 3913: Estrogen receptor beta and estrogen receptor beta 5 in triple negative breast cancer cells: IGF-II role in regulation of estrogen receptor beta 5
Authors: O'Bannon Chane’ 
Published: August 2012

Abstract
African American (AA) women with breast cancer are more likely to be diagnosed at a more advanced stage of the disease, have a higher recurrence rate and a poorer prognosis than Caucasian (CA) women. They also are more often diagnosed with high-grade breast tumors at an earlier age (pre-menopausal), most of which are negative for the estrogen and progesterone receptors (ER-, PR-). These factors result in a higher mortality rate among AA breast cancer patients. Our lab has demonstrated that AA women have increased levels of IGF-II coupled with lower levels of the IGF-II receptor needed to degrade IGF-II, thus leading to higher IGF-Ii signaling in contrast to CA women. AA women also have a higher expression of the insulin receptor A versus insulin receptor B when compared to CA women, which increases proliferation and decreases metabolic effects (Singh et. al 2011). We have also shown that IGF-II activates the estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-α) in the absence of the estrogen ligand (Richardson et. Al 2011). When co-expressed, ER-α counteracts the proliferative function of ER-α, however the role of ER-α in breast cancer is different in ER-α negative compared to ER-α positive tumors. Furthermore, there are 5 different isoforms of ER-α, of which ER-Δ5 is the most abundantly expressed form in AA women. Since IGF-II activates ER-α and ER-Δ5 is associated with increased mortality and decreased time recurrence, we have designed a study to determine if IGF-II regulates ER-Δ5. We hypothesize that in the absence of ER-α, ER-α may activate the ER-α signaling pathway, and that the elevated expression of ER-Δ5 and its heterodimerization with of ER-α1 contributes to the overall survival disparity. To test this hypothesis we characterized the levels of phophorylated ER-α (pER-α) and compared them to IGF-II levels in triple negative breast cancer cells and normal triple negative epithelial cells. IGF-II levels were analyzed using western blotting for protein, and RT-PCR for mRNA. AA women have a higher expression of IGF-II in both malignant and normal cells, and comparably higher levels of expression of the active form of ER-α when compared to CA breast cancer cell lines. IGF-II stimulation promoted the translocation of ER-Δ5 to different cellular compartments. We propose that ER-Δ5 impairs the inhibitory effects of ER-α and thus may contribute to the survival disparity among AA breast cancer patients.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3913. doi:1538-7445.AM2012-3913