bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3831: Sodium butyrate induces differential expression of Th17 and inflammatory cytokines during apoptosis in human U937 leukemia cells
Authors: Pulliam Stephanie , Copper Roland S. , Adunyah Samuel Evans 
Published: February 2011

Abstract
Sodium butyrate (NaB) is a sodium salt of butyric acid. It is a strong HDAC1 inhibitor, which has been implicated in many studies as a potential therapy for various forms of cancer including prostate cancer. Also, it has been suggested as a potential therapy for hemoglobin disorders including sickle cell diseases and leukemia because of its ability to promote both total globin and gamma globin synthesis during erythroid differentiation. Previously NaB has been shown to active apoptosis in several cancer cell lines including U937 and K562 leukemia cell lines. However, it is not known whether it has the capability to modulate cytokines expression in cancer cells and alter the cancer microenvironment, which was the purpose of this study. We exposed U937 leukemia cells to NaB at 5 mM or 10 mM for 24 or 48 hours, conditions under which NaB is known to induce apoptosis in these cells. The culture media of the cells were harvested and analyzed by Human Multi-Analyte Cytokine ELISArray method and by protein/antibody cytokine arrays for levels of TH17-type and Inflammatory cytokines. We also monitored cells for caspase 3 activation and cell viability as evidence of apoptosis. Our results indicate that NaB induces differential expression of several TH17-type and Inflammatory cytokines from 2 to 10-fold within 24 hours. The ranking order of induction of TH17-type cytokines by NaB was IL-17A&gt;IL-5&gt;IL-4&gt;G-CSF&gt;IL-10&gt;TNF&gt;IL-12&gt;IFNγ while induction of inflammatory cytokines was of the ranking order: IL-1A&gt;IL-8&gt;IL-10. Also within 24 hours, NaB treatment caused at least 2-fold activation of caspase 3 and reduced the cell viability by 60 %. These observations indicate that NaB induces differential expression of both TH17 and Inflammatory cytokines during induction of apoptosis. The data also suggest that while promoting cancer cell death by apoptosis, NaB also has the potential to influence cancer microenvironment by inducing differential expression and secretion of cytokines. Such an effect could influence the biology of both the normal and cancer cells and could alter the status of the patient who is receiving NaB therapy. Further studies are in progress to determine whether NaB has similar effects in human monocytes. Supported by NCI U54 cancer grants # 5 U54 CA091408-09.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3831.
Abstract 3835: Impaired pSTAT3 and pSTAT5 induction by IL-2 does not affect IFNγ production in NK cells of breast cancer patients
Authors: Konjevic Gordana M. , Radenkovic Sandra S. , Srdic Tatjana , Jelic Svetislav , Stamatovic Ljiljana , Inic Momcilo 
Published: February 2011

Abstract
Although pSTAT3 and pSTAT5 in tumors have oncogenic potential, STAT dysregulation has not been extensively investigated in peripheral blood lymphocytes (PBL) of breast cancer patients. Alterations in JAK-STAT pathway in cancer patients contribute to immunosuppression and inadequate antitumor immune response. In this study baseline level and cytokine-mediated activation of pSTAT3 and pSTAT5 were investigated in PBL of breast cancer patients and healthy controls after in vitro treatment with IL-2 for 24h at 37C. Induction of pSTATs was assessed in cellular lysates by Western blotting using anti-pSTAT antibodies. PBL of breast cancer patients and controls were analyzed for intracellular IFNγ, CD3 and CD16 receptor expression and NK cell activity using Flow cytometry and 51Cr-release assay, respectively. The induction of pSTAT3 and pSTAT5 in PBL by IL-2 is significant for controls and patients, although the effect in patients is lower. Moreover, PBL and CD3-CD16+ NK cells of breast cancer patients compared to controls have significantly lower baseline level of IFNγ. IL-2 significantly increases the production of IFNγ in PBL inspite of impaired induction of pSTAT3 and pSTAT5 in breast cancer patients. Evaluation of NK cell subset shows highly significant induction of IFNγ by IL-2 in breast cancer patients and in healthy controls. Inspite of this, we found that NK cell activity of breast cancer patients is significantly lower compared to healthy controls suggesting that NK cell activity is more dependent on STATs inducibility than IFNγ production in these patients. These results provide evidence that evaluation of STAT expression and cytokine induction in PBL of breast cancer patients could be of diagnostic and therapeutic significance during non-specific active immunotherapy.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3835.
Abstract 3838: Akt isoform-specific signaling in breast cancer cell invasive migration
Authors: Chin Yuet Ming Rebecca , Toker Alex 
Published: February 2011

Abstract
Akt/PKB (protein kinase B) is a proto-oncogene that plays critical roles in cell survival, proliferation and metabolism. There are three mammalian Akt isoforms: Akt1, Akt2 and Akt3. They share a high degree of amino acid similarity and are activated by similar mechanisms. The current paradigm is that all three Akt isoforms promote cancer cell survival and growth. Interestingly, recent studies from our laboratory have shown that Akt1 inhibits breast cancer cell migration and invasion. Conversely, Akt2 has been shown to promote breast cancer cell migration. We therefore seek to test the hypothesis that Akt isoforms regulate breast cancer cell invasive migration in a distinct manner, and investigate the mechanistic basis for this selectivity. Current experiments are undertaken to identify novel substrates of Akt1 and Akt2, which modulate cell motility, with a combination of shRNA and phospho-proteomic approaches. shRNAs specific to Akt1 or Akt2 have been generated and delivered into human breast cancer cells by lentiviral vectors. Using an antibody that recognizes phosphorylated serine/threonine residues contained within a consensus Akt motif (RXRXXS/T), we showed that palladin, a component of actin-containing microfilaments, is phosphorylated at serine 507 by Akt1 but not Akt2. Downregulation of palladin using RNA interference enhances migration and invasion of breast cancer cells and induces abnormal branching morphogenesis in 3D cultures, indicative of an anti-migratory function for palladin. Importantly, palladin is required for Akt1-mediated inhibition of breast cancer cell migration, whereby the migratory effect induced by palladin silencing is reversed by wild-type but not a S507A mutant. Finally, palladin phosphorylation by Akt1 is functionally required for bundling F-actin and maintaining an organized actin cytoskeleton network in cells. These findings identify palladin as an Akt1-specific substrate that regulates cell motility and further provide a molecular mechanism that accounts for the functional distinction between Akt isoforms in breast cancer cell migration.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3838.
Abstract 3840: Bone morphogenetic proteins require the type II TGFβ receptor for growth arrest in mammary tumor cells
Authors: Owens Philip , Gorska Agniesszka E. , Aakre Mary E. , Moses Harold L. 
Published: February 2011

Abstract
Bone Morphogenetic Proteins (BMPs) are members of the Transforming Growth Factor β (TGFβ) superfamily of signaling molecules. BMPs can elicit a wide range of effects in many cell types and have previously been shown to induce growth arrest in cancers as well as normal epithelia. Recently, it has been demonstrated that BMP4 and BMP7 are overexpressed in human breast cancers. We sought to understand how a potential tumor suppressor could be overexpressed in human breast cancers. We analyzed several tumor cell lines and normal mammary epithelia and found that BMPs are sufficient to induce growth arrest in normal and transformed mammary epithelia. Surprisingly, when we treated cells derived from the PyVmT mouse model lacking the type II TGFβ receptor with BMP-4, these cells failed to undergo growth arrest. We determined by flow cytometry that BMP treated cells did not undergo apoptosis. Cell cycle analysis demonstrated that cells with functional TGFβ signaling were arrested in G1 and cells lacking TGFβ signaling capabilities remained in a typical distribution of the cell cycle. We also found that Smads which mediate both BMP and TGFβ signaling were not only still present, but also responsive to BMP stimulation resulting in BMP Smad1/5/8 phosphorylation. Furthermore, we assessed the ability for synergy between BMP-4 and TGFβ1 and found that BMP-4 could induce an increased growth response in the presence of maximal TGFβ inhibition. We conclude that the dual functions of TGFβ as a tumor suppressor and promoter are connected to a BMP mediated tumor suppressive mechanism that shares common and distinct pathways.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3840.
Abstract 3841: An integrin αvβ3/c-Src oncogenic unit promotes anchorage independence and tumor progression
Authors: Desgrosellier Jay S. , Seguin Laetitia , Barnes Leo A. , Shields David J. , Huang Miller , Lau Steven K. , Prevost Nicolas , Tarin David , Shattil Sanford J. , Cheresh David A. 
Published: February 2011

Abstract
Integrins regulate adhesion-dependent growth, survival and invasion of tumor cells. In particular, expression of integrin αvβ3 is associated with progression of a variety of human tumors. We recently described an adhesion-independent role for integrin αvβ3 in pancreatic cancer and other carcinomas resulting in increased anchorage-independent tumor growth in vitro and lymph node metastases in vivo. These effects required recruitment of c-Src to the β3 integrin cytoplasmic tail, leading to c-Src activation. Pharmacological blockade of c-Src kinase activity with Dasatinib or genetic suppression of endogenous c-Src not only inhibited anchorage-independent growth, but also suppressed metastasis in vivo. We now show that αvβ3 exerts these effects through ligand-independent clustering of the integrin on the surface of non-adherent tumor cells. Self-assembly/clustering appears to be a unique property of αvβ3 relative to other integrins and is dependent on c-Src recruitment to αvβ3. These data describe a c-Src-dependent self-assembly property of αvβ3 leading to increased anchorage-independence and malignancy of tumor cells expressing this integrin. These findings also underscore the potential benefits of using Src inhibitors, such as Dasatinib, for treating patients with αvβ3-expressing solid tumors.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3841.
Abstract 3851: Protein switches that activate a prodrug in the presence of HIF-1a
Authors: Wright Chapman M. , Eshleman James , Ostermeier Marc 
Published: February 2011

Abstract
We have engineered yeast cytosine deaminase (CD) to be activated by the tumor marker, hypoxia-inducible factor 1-alpha (HIF-1a) - turning on its ability to convert 5-fluorcytosine (5FC) into the anticancer drug 5-fluoruracil (5FU). HIF-1a is overexpressed in many types of cancer but is virtually undetectable in normal tissue due to rapid degradation. We sought a “tumor-sensing” protein whose prodrug converting activity is activated in the presence of HIF-1a. Such a protein could be used in a therapeutic treatment similar to gene-directed enzyme prodrug therapy (GDEPT). However, our approach would have an advantage over GDEPT because the “suicide” gene could be delivered using very efficient methods for gene delivery, whether or not they were selective, since the selectivity occurs at the protein level and not the gene delivery level.
To create our desired protein, we constructed a library of fusion proteins between CD and the CH1 domain of p300 - a domain known to interact with HIF-1a. This library was subjected to a two-tiered genetic selection in E. coli designed to identify genes that conferred increased sensitivity to 5FC when HIF-1a was co-expressed. We identified two library members (#3 and #59), which conferred to E. coli sensitivity to 5FC equivalent to wildtype CD but only in the presence of co-expressed HIF-1a. In the absence of HIF-1a, #3 conferred a 5-fold higher LC50 to 5FC and #59 did not confer any sensitivity to 5FC. Both proteins were purified and characterized in vitro for their activity in the presence and absence of HIF-1a. Protein #3 exhibited a 4-fold increase in its CD activity in the presence of HIF-1a, whereas protein #59's activity did not have a significant dependence on HIF-1a. Currently, the two genes are being examined in human cancer cell lines for their ability to confer sensitivity to 5FC in the presence of HIF-1a.
Using advanced protein engineering techniques, we have created two proteins that confer sensitivity to 5FC in the presence of the tumor-marker, HIF-1a. We believe that these genes have therapeutic potential for the treatment of cancers that exhibit elevated HIF-1a levels. Our strategy circumvents a limitation of GDEPT by not requiring selective delivery of the gene to cancer cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3851.
Abstract 3856: A highly selective Erk-inhibitor with antiproliferative efficacy and the potential for combination therapy with modulators of the PI3K pathway
Authors: Seipelt Irene , Blumenstein Lars , Baasner Silke , Mueller Gilbert , Aicher Babette , Teifel Michael , Guenther Eckhard , Gerlach Matthias 
Published: February 2011

Abstract
The Ras/Raf/Mek/Erk signal transduction is a key oncogenic pathway in a variety of human cancers. The mitogen activated protein kinase Erk is an important regulator of cell proliferation and was shown to be over-activated by dysregulated or mutated tyrosine kinase associated cell-surface receptors, Ras or Raf in diverse human tumors.
We have established a small molecular compound class that inhibits Erk in the low nanomolar range and shows an excellent selectivity profile. Other serine threonine, lipid or tyrosine kinases are not inhibited at concentrations up to 10µM. Further characterization experiments revealed an ATP competitive mode of action and the potent inhibition of the cellular downstream target Rsk1 in tumor cells. The lead structure AEZS-131 produces cell cycle arrest in G1 and results in growth inhibition of cancer cells. Furthermore, the potential of combination therapy of AEZS-131 with inhibitors of the PI3K pathway was addressed and the analysis of combination effects on tumor cell proliferation is presented.
These results support the evaluation of selective Erk inhibitors as anti-proliferative agents either as monotherapy or in combination with inhibitors of the PI3K/Akt pathway.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3856.
Abstract 386: Real-time noninvasive optical imaging of angiogenesis and vasculogenesis inhibition and normalization
Authors: Zhang Qingbei , Bindokas Vytas , Shen Jikun , Hoffman Robert M. , Xing H. Rosie 
Published: February 2011

Abstract
We have developed and optimized non-invasive in vivo imaging to continuously visualize and characterize tumor angiogenesis and vascular response to anticancer therapies in real time in live mice. Tumor vessels could be monitored longitudinally undergoing vasculogenesis and angiogenesis the same mouse. Morphometric changes of the same vessel prior to and after drug treatment were captured with high resolution. Differences in vascular responses to the mTOR inhibitor rapamycin and to an anti-VEGF antibody were imaged. The multi-channel imaging capability of the OV100 small animal imaging system (Olympus) enabled visualization of the functional integrity (permeability) of tumor vessels before and after anti-angiogenic therapies using the near-infrared blood pool reagent Angiosense750. We observed real-time tumor vessel normalization as demonstrated by significantly reduced leakiness and subsequent improved delivery of BODPY-Paclitaxel upon administration of low-dose and short-term anti-angiogenic therapy. Further, alterations in Angiosense750 tumor retention in response to different treatments were confirmed and quantified using noninvasive fluorescent molecular tomography (VisEN FMT). Histological, and immunofluorescence staining (CD31, lectin, SMA, NG2) along with confocal microscopy, confirmed the in vivo imaging observations. Thus, imaging is a powerful tool for investigating tumor angiogenic progression and for preclinical drug screening of anti-angiogenic agents.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 386.
Abstract 387: Development of a model of acquired resistance to a multi targeted VEGFR TKI and strategies to target resistance mechanisms through combination
Authors: Garza Scott J. , Hook Kenneth E. , Lira Maruja E. , Ching Keith , Yuan Jing , Kan Julie , Hu-Lowe Dana , Christensen James G. 
Published: February 2011

Abstract
Anti angiogenic agents that target the VEGF pathway (bevacizumab, sorafenib and sunitinib (SU)) have demonstrated improved clinical benefit as single agents or in combination with chemotherapy in a variety of solid tumor types. Although this class of agents has provided an improved treatment option to certain tumor types, it is evident that some patients do not respond to therapy or will relapse despite an initial response to treatment due to an acquired resistance. To better understand this mode of acquired resistance to this class of agents, a model of Renal Cell Carcinoma (RCC) which has shown regression, eventually developed evasive resistance during long term administration of the single agent sunitinib (a small-molecule inhibitor of the VEGF-1, 2, 3, PDGF-α,β, KIT, CSF-1R and FLT-3 receptor tyrosine kinases). Despite the observation that resistant tumors under continuous treatment with sunitinib (60 mg/kg PO, QD) demonstrated a gross phenotypic reduction of micro-vascular density (MVD), they continued to show a progressive increase in size. Because the observed low MVD phenotype was suggestive of an ability of resistant tumor cells to survive in an increasingly hypoxic environment with a reduced functional vasculature, emphasis was placed on identifying tumor cell derived resistance factors. Gene expression and/or proteomic profiling studies accompanied by confirmatory immunoblotting indicated a subset of differentially expressed genes and/or proteins in resistant vs. sensitive treated tumors. Although profiling studies did not clearly elucidate definitive resistance mechanisms, the dysregulation of EGFR, FGFR1, & TGFB1 pathways and downstream signaling through PI3K and MEK were potentially implicated. Comparative genomic hybridization studies did not identify any resistance mechanisms at the cytogenetic level. Sunitinib combination studies designed to target pathways potentially involved in resistance (SU + a PI3K/mTOR inhibitor; SU + a MEK inhibitor) demonstrated the ability to restore sensitivity in the sunitinib resistance model. The ability to identify and characterize resistance mechanisms and circumvent resistance through combination approaches may have utility in developing future combination regimens for anti angiogenic therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 387.
Abstract 3874: Single-agent Chk1 inhibition is anti-proliferative in leukemia cells in vitro and in vivo
Authors: Davies Kurtis D. , Humphries Michael J. , Sullivan Francis , von Carlowitz Ira , Huerou Yvan Le , Mohr Peter J. , Wang Bin , Blake Jim F. , Lyon Michael A. , Gunawardana Indrani , Chicarelli Mark , Wallace Eli , Gross Stefan 
Published: February 2011

Abstract
Chk1 is a serine/threonine kinase that plays important roles in the cellular response to genotoxic stress. For this reason, there is a great deal of interest in using inhibitors of Chk1 to potentiate the effects of DNA-damaging chemotherapeutics. In addition, multiple studies have demonstrated that Chk1 activity is essential during an unperturbed cell cycle to ensure proper DNA replication and maintain genomic integrity. Therefore, it is plausible that a Chk1 inhibitor could also be efficacious as a single-agent therapeutic for human cancer. Here we show that treatment with Chk1-A, a potent and selective inhibitor of Chk1, alone is anti-proliferative against a wide array of cancer cell lines with varying degrees of potency. We sought to understand the mechanisms by which Chk1 inhibition derives the observed anti-proliferative effect. Employing the human leukemia cell line HEL92.1.7, a line particularly sensitive to Chk1 inhibition in terms of proliferation, we characterized the biochemical and functional effects of Chk1-A treatment. We observed concentration-dependent increases in phosphorylation of H2A. X, Chk1, and Chk2, which are markers of DNA damage and cell-cycle checkpoint activation. These biochemical events correlated with S-phase accumulation and eventual apoptosis. In vivo, we found that HEL92.1.7 tumor xenografts were sensitive to oral administration of Chk1-A at a dose that was well tolerated. Together, these studies suggest that inhibition of Chk1 results in DNA damage that induces apoptosis and that use of a Chk1 inhibitor as a single-agent could be an effective strategy to treat certain types of human cancers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3874.