bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 4344: Ionizing radiation induces adhesion of breast cancer cells to fibronectin through upregulation of integrin alpha5beta1
Authors: Lee Shinhee , Cheng Huiwen , Wu Shiyong
Published: August 2012

Metastatic cancer is marked by the loss of integrity of extracellular matrix (ECM). Adhesion of tumor cells to the ECM mediated by integrins on the surface of the tumor cells is a key step in the initial phase of metastasis. Since ionizing radiation (IR), which is commonly used for cancer therapy can induce alterations of the cell surface, we investigated the effect of IR on the adhesion of breast cancer cells to ECM proteins. Results showed that in MDA-MB-231 breast cancer cell line, IR induced significant increase in both integrin expression and integrin-mediated adhesion to fibronectin, laminin, collagen I and IV. Soluble Arg-Gly-Asp peptide fragments or function-blocking antibodies directed against integrin alpha5beta1 inhibited IR-induced adhesion of MDA-MB-231 cells to fibronectin, indicating that IR-induced adhesion is caused by up-regulation of alpha5beta1 integrin fibronectin receptors. In contrast to MDA-MB-231 cells harboring mutant p53 (R280K), MCF-7 cells (WT p53) were unable to increase adhesion and up-regulation of alpha5beta1 integrin. Interestingly, knockdown of mutant p53 abrogated IR-induced integrin alpha5 integrin expression and adhesion to fibronectin. Our results indicate that mutant p53 coordinates breast cancer cell adhesion through up-regulation of alpha5beta1 integrin. This study suggests that alpha5beta1 integrin might be an effective target to improve the efficacy of radiotherapy in mutant p53 expressing cancers.

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 4344. doi:1538-7445.AM2012-4344
Abstract 4783: Proteomic analysis of acute lymphoblastic leukemia: de novo versus relapse
Authors: Kang Kee R. , Park Eun S. , Kang Dawon
Published: August 2012

Acute lymphoblastic leukemia (ALL) is a heterogeneous disease with distinct biological and prognostic grouping. The initial response to induction chemotherapy is the most important prognostic factor in patients with acute lymphoblastic leukemia. Patients with rapid early response (RER < 5% of blast in bone marrow at day 7 after induction chemotherapy) have better event-free survival compared to slow early responders (SER ≤ 25% of blast). However, no predictive marker for relapse or treatment failure is currently available. This study aimed to find plausible biomarkers of drug sensitivity in bone marrow mononuclear cells (BMMNCs) of childhood ALL cases using 2-dimensional gel electrophoresis and subsequent MALDI-TOF/mass spectrometry. The 714 spots in RER and 555 spots in SER were visualized in gels. Of these 28 up-regulated and 25 down-regulated proteins in SER_as compared to RER_were identified. The detected proteins were 60-kDa heat shock protein, actin, lamin-B1, heterogeneous nuclear ribonucleoprotein (hnRNP) K, and so on. HnRNPK, down-regulated in SER was further verified by Western blot analysis. In future studies, the roles of HnRNPK in drug sensitivity/resistance are undergoing to elucidate as a potential biomarker for ALL therapy. [Funding source: NRF grant (R13-2005-012-01003-0)].

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 4783. doi:1538-7445.AM2012-4783
Abstract 4865: Pak1 links the Wnt/β-catenin pathway to ErbB2 signaling in breast cancer cells
Authors: Romero Luis E. Arias , Cruz Olga Villamar , Chernoff Jonathan
Published: August 2012

Several studies suggest that Pak1 plays an important role in the genesis of breast cancer, but despite the similarity in their sequences, the contribution of the closely related enzyme Pak2 to this disease remains unclear. To establish the function of Paks in ErbB2 driven transformation, we used a three-dimensional tissue culture system of human mammary epithelial cells that stably co-express a chemically-activatable form of ErbB2 and doxycycline (DOX) inducible shRNAs against Pak1 or Pak2. We observed that silencing of Pak1 but not of Pak2 has a dramatic effect in cell proliferation and apoptosis. As expected, activation of ErbB2 induced growth factor-independent proliferation and disruption of 3D acinar-like structures via ERK and Akt signaling. In contrast, silencing of Pak1 compromised activation of ERK, resulting in reversion of the malignant phenotype and restoration of normal acinar architecture. Surprisingly, silencing of Pak2 also compromised ERK activation, but cannot restore normal morphology. Further, we found that ErbB2-amplified breast cancer cells expressing a DOX inducible shRNA against Pak1 formed significantly smaller tumors than cells expressing either GFP or a DOX inducible shRNA against Pak2 in SCID mice as the result of the inhibition of ERK. A phosphoproteomic analysis showed that several signaling pathways, e.g. Wnt and Mdm2-p53, are down regulated in our Pak1 deficient cell line. We found that the shPak1 cell line, but not the shPak2 deficient cell line has a dramatic reduction in total β-catenin levels, and that blocking β-catenin with chemical inhibitors restored normal acinar architecture. Finally, we found that targeting Pak and/or β-catenin in combination with trastuzumab sensitized trastuzumab-resistant breast cancer cells to trastuzumab, suggesting the potential clinical application of this strategy to overcome trastuzumab resistance.

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 4865. doi:1538-7445.AM2012-4865
Abstract 4890: Arsenic trioxide induces apoptosis through the activation of ASK1 and is enhanced by a thioredoxin reductase inhibitor
Authors: Kwan Stanley , Garnier Nicolas , Miller Wilson H. , Mann Koren K.
Published: August 2012

Arsenic trioxide (ATO) is an effective treatment for acute promyelocytic leukemia (APL). While it is undergoing clinical trials for numerous malignancies including multiple myeloma, myelodysplastic syndrome, lymphoma and solid tumors, it has demonstrated only limited efficacy as a single agent. However, it may hold promise as part of a combination therapy. Thus investigation to elucidate the mechanisms of action underlying these clinical responses may lead to generation of rational combination therapies to increase its therapeutic spectrum. Previous work has described a pathway required for ATO-induced apoptosis in APL cells involving the generation of reactive oxygen species (ROS), and the subsequent induction of a specific mitogen-activated protein kinase (MAPK) cascade that includes both stress-activated protein kinase (SAPK)/ERK kinase 1 (SEK1) and c-Jun N-terminal kinases (JNK) activation. However, the link between ROS production and activation of SEK1 remains to be elucidated. Apoptosis signaling kinase 1 (ASK1) is a MAP3K upstream of SEK1 and has been implicated in the induction of stress-induced signaling. Here, we show that ATO activates ASK1 in a dose- and time-dependent manner in an APL cell line. ASK1 activation is preceded by ATO-induced ROS accumulation, which is significantly reduced with N-acetyl-L-cysteine antioxidant co-treatment. Murine embryonic fibroblasts (MEFs) from ASK1 deficient mice are less susceptible to ATO-induced apoptosis and growth inhibition. Moreover, they exhibit markedly lower ATO-induced JNK activity compared to wild type cells. One model of ASK1 regulation suggests that ASK1 is kept in an inactive form by reduced thioredoxin-1 (Trx1). During oxidative stress, Trx1 is oxidized and releases ASK1 for activation. Immunoprecipitation of ASK1 followed by immuoblotting for Trx1 in APL cells shows a strong basal association that is lost with ATO treatment. Furthermore, the activity of thioredoxin reductase 1 (TrxR1), an enzyme that converts oxidized Trx1 into reduced Trx1, is significantly decreased following ATO treatment. This suggests that ATO activates ASK1 signaling by ROS-mediated oxidation of Trx1 and by inhibiting the restoration of reduced Trx1 by decreasing TrxR1 activity. In addition, we show that inhibition of TrxR1 with the TrxR1 inhibitor Au(III)Cl sensitizes APL cells to ATO-induced apoptosis. This suggests that regulation of ASK1 is dependent on Trx1 redox states. Overall, our results suggest that targeting Trx1 may enhance ASK1 signaling and ATO-induced apoptosis in a novel combination therapy.

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 4890. doi:1538-7445.AM2012-4890
Abstract 5226: Potential anti-tumor effect of a small molecule dipeptidyl peptidase inhibitor, 4175, in colorectal cancer
Authors: Zhang Jiping , MacFarlane Alexander W. , Jones Barry , Bachovchin William , Cambpell Kerry , Borghaei Hossein
Published: August 2012

Introduction: Cetuximab is an effective therapeutic agent in a number of malignancies. Current data indicates that about 30% of colorectal cancer patients bearing mutated K-ras do not benefit from this agent. A possible mechanism of the antitumor effect of cetuximab is mediated through antibody-dependent cell-mediated cytotoxicity (ADCC). The present study is aimed to investigate the potential activity of Ari-4175, a broad -spectrum inibitor of prolyl peptidases and a potent immune stimulator in the treatment of K-ras mutant colorectal cancer xenografts as a single agent or in combination with cetuximab. Methods: The effect of Ari-4175 alone or in combination with cetuximab was evaluated both in vitro and in vivo. In vitro, the proliferation of K-ras mutant colon cancer cell lines DLD-1 and HCT-116 was detected after three days of culture in the medium containing various concentrations of Ari-4175 or cetuximab. In vivo, nude mice bearing DLD-1 or HCT-116 xenograft tumors were randomly divided into four groups, control, Ari-4175 alone, cetuximab alone and Ari-4175 plus cetuximab. Ari-4175 was administered orally at 100 ug, q.d or b.i.d and cetuximab was injected i.p at 200 ug per week. Tumor measurements were conducted twice a week. Peripheral blood was collected from the mice before the treatment or after 7 to 14 days of the treatment. CD16 expression on NK cells was monitored by flow cytometry. Results: Ari-4175 (10 nM ∼ 200 uM) alone or in combination with cetuximab did not show significant cytotoxicity on either DLD-1 or HCT-116 in cell culture. However, the growth of both DLD-1 and HCT-116 tumors were significantly blocked by the application of Ari-4175 in a dose-dependent manner. The combination of Ari-4175 with cetuximab lead to a further decrease in tumor size although not statistically significant, probably due to lower number of animals. Cetuximab alone did not show any therapeutic effect on HCT-116 xenograft but did have moderate efficacy on DLD-1 tumors. Treatment with Ari-4175 also increased the level of CD16 on mouse NK cells. Conclusion: The prolyl peptidase inhibitor, Ari-4175, showed anti-tumor effect in K-ras mutant colorectal cancer xengrafts when given alone or in combination with cetuximab. The therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevating expression of CD16 (FcγRIIIA) on NK cells. Our study provides the basis of testing Ari-4175 in a clinical trial.

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 5226. doi:1538-7445.AM2012-5226
Abstract 5401: The influences of morphine on dendritic cell-mediated immunity
Authors: Chang Ming-Cheng , Chen Yu-Li , Huang Ching-Ting , Chiang Ying-Cheng , Huang Chia-Yen , Cheng Wen-Fang , Chen Tzer-Ming
Published: August 2012

Morphine is a widely-used drug for analgesics and drug abuse. Previous studies have also demonstrated that the widely used as an anesthetic agent as well as adjuvant for the treatment of cancer pain and neuropathic pain, will bring harmful effects on specific immune system. Furthermore, the suppressed immune function may lead to postoperative infection and postoperative dissemination of carcinoma. Our research team has confirmed that morphine could promote tumor growth in naïve immunocompromised mice in our previous project, and morphine could suppress the proliferative ability of T lymphocytes even erased the tumor protection effects enhanced by tumor vaccines in vivo. However, these apoptotic phenomena could not explain the complete reasons that morphine induced tumor progression. The antigen processing and presenting activity enhanced by antigen presenting cells is the main cause in tumor development, especially in dendritic cells. The tumorgenesis is always associated with the low antigen presentation activity, and it results the poor recognization by cytotoxic T cells even causes the immuno-escape responses. In the present study, we confirmed that the efficiency of bone marrow monocytes differentiate into dendritic cells was significantly decreased after morphine stimulation. Under high dose morphine treatment, more than 30 % of differentiation efficiency was eliminated in 6 days incubation. Besides, the expression of co-stimulation factor CD80 and CD86 were both decrease after morphine treatment. Furthermore, cytokine expression including IL-6 and TNF-α were both inhibited, however, only IL-10 was slightly increase after morphine stimulation. Besides, the antigen processing and presenting activity of ex-vivo bone marrow-derived dendritic cells were reduced after morphine stimulation. These results suggested that morphine might reduce the process of dendritic cells maturation. These results provided the complete molecular mechanism and the correlation between morphine and immunity.

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 5401. doi:1538-7445.AM2012-5401
Abstract 5439: Inhibition of growth and induction of differentiation of colon cancer cells by extracts from okra (Abelmoschus esculentus) and drumstick (Moringa oleifera)
Authors: Lea Michael A. , Akinpelu Taofeek , Amin Ritesh , Yarlagadda Kiranmai , Enugala Ramadevi , Dayal Bishambar , desBordes Charles
Published: August 2012

In previous studies we have observed that several polyphenolic molecules can inhibit growth and induce the synthesis of differentiation markers in colon cancer cells. In the present work we have sought to determine if similar activity can be observed with methanolic and ethanolic extracts from okra and drumstick. In okra, phenolic molecules and antioxidant activity were associated primarily with the seeds, whereas in drumstick the seeds had lower concentrations of phenolics and antioxidant activity than skin, pulp and seed coat. In studies with okra extracts we have concentrated on the effects of seed extracts because they were generally most inhibitory for cell proliferation as judged by protein yield, thymidine incorporation into DNA and tetrazolium salt reduction. With extracts from drumstick the greatest inhibition of growth was generally with seed coat extracts but anomalous results were obtained in assays of tetrazolium salt reduction. Inhibition was greater at low concentrations but at high concentrations the apparent effect was reversed. Studies in the absence of cells showed that a component of the drumstick seed-coat extract reacted directly to reduce the tetrazolium salt. Comparison with other parts of the drumstick indicated that this reduction was much greater with the seed coat extract. Small effects on colon cancer cell differentiation have been seen with extracts of okra seed and with pulp and seed extract from drumstick as judged by induction of alkaline phosphatase activity. In the case of okra seed extracts this effect was additive with the action of butyrate. Okra and drumstick have had a role in traditional medicine and the present data are encouraging for further studies on potential cancer chemopreventive action.

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 5439. doi:1538-7445.AM2012-5439
Abstract 5456: Potential role of nitric oxide in chromium-induced lung carcinogenesis
Authors: Forbes Thomas A. , Hopkins Lauren , Schneider Brent , Lazarus Lindsay , Leitenberg David , Constant Stephanie , Schwartz Arnold , Patierno Steven , Ceryak Susan
Published: August 2012

Certain hexavalent chromium [Cr(VI)] compounds are well established human respiratory toxins and carcinogens of occupational and environmental relevance. Our recent studies have shown that intranasal (IN) exposure of Balb/c mice to particulate zinc Cr(VI) compounds leads to pronounced innate inflammation in the lung, which we postulate plays a significant role in pulmonary tumorigenesis. Nitric oxide (NO) has been shown to be induced via inflammatory response mediators, and has been implicated in the progression of different cancers, including lung. Moreover, NO-induced tumor invasiveness has been correlated with enhanced matrix metalloproteinase (MMP) expression in lung tumor cell lines. Of particular relevance to the present study is the finding that in vitro exposure of human lung cells to Cr(VI) in culture led to increased NO production. The aim of the present study was to explore the role of NO in chromium-induced lung tumorigenesis. BALB/c mice received weekly IN delivery of either saline or 10 ug particulate basic zinc chromate, which is an intermediately water soluble chromate typically encountered in mining/chromate production facilities and which is also present as an environmental atmospheric contaminant in urban areas surrounding ferrochrome production facilities. After 9 weeks, immune cells, cytokines, NO, MMPs and pathologic features of lung injury and inflammation were measured in airway lavage fluid and lung tissue, at both 24h after the final Cr(VI) dose, as well as 1 week later. As previously shown, repetitive Cr(VI) exposure induced a neutrophilic inflammatory airway response 24h after treatment. Neutrophils were subsequently replaced by increasing numbers of macrophages 1 week after treatment. Peribronchiolar inflammation was observed in chromate-exposed mice, and was accompanied by a 100-fold increase in pro-MMP9 release into the airways. Notably, airway NO was significantly increased ∼ 1.9 fold in Cr(VI)-exposed mice as compared to their saline-treated counterparts at both time points following final exposure. Moreover, immunoreactivity of induced nitric oxide synthase (iNOS) was markedly increased in airways exposed to Cr(VI), with staining localized to infiltrating immune cells. In conclusion, repetitive exposure to particulate chromate induces an inflammatory environment in the lung, accompanied by enhanced NO production, which we postulate may promote Cr(VI) carcinogenesis. Supported by NIH grants CA107972 and ES017334 to SC and ES017307 to SRP.

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 5456. doi:1538-7445.AM2012-5456
Abstract 558: Bortezomib induction of the unfolded protein response mediates Epstein-Barr virus lytic activation but is separable from bortezomib-induced cytotoxicity
Authors: Shirley Courtney , Kalu Nene , Shamay Meir , Ambinder Richard F.
Published: August 2012

Epstein-Barr virus (EBV) is associated with many human cancers. Several therapeutic strategies involving the pharmacologic activation of the EBV lytic cycle for tumor killing have been described (1-2). We previously identified bortezomib, a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma, as a potent activator of EBV lytic gene expression. The mechanism of action of bortezomib as either a viral lytic activator or an anticancer drug remains poorly understood. However, induction of the unfolded protein response (UPR) has emerged as a central theme in both areas of investigation (3). In order to further evaluate the role of the UPR in lytic activation, we treated lymphoid and epithelial tumor cell lines with bortezomib and assessed induction of the UPR and EBV lytic gene expression. We found dose-dependent parallel induction of UPR and EBV lytic infection across cell lines. However, an EBV-immortalized lymphoblastoid cell line was relatively resistant to both bortezomib-induced UPR and induction of EBV lytic gene expression, but not resistant to bortezomib-induced cell killing. To further investigate, we assessed induction of the UPR by thapsigargin which leads to depletion of Ca2+ in the ER. Thapsigargin induced the UPR and EBV lytic gene expression across all the cell lines tested. Blocking ER stress and UPR activation, by cycloheximide treatment or by BiP knockdown, diminished EBV lytic gene expression but had no effect on cellular toxicity. Additionally, regulated knockdown of UPR associated transcription factors (XBP1(s), c-Jun) blocked lytic activation by both agents. Taken together, these results suggest that induction of the UPR by bortezomib is tightly linked to EBV lytic activation but may be separable from the cytotoxic effects of bortezomib. References: 1. Fu DX, Tanhehco Y, Chen J, Foss CA, Fox JJ, Chong JM, Hobbs RF, Fukayama M, Sgouros G, Kowalski J, Pomper MG, Ambinder RF. Bortezomib-induced enzyme-targeted radiation therapy in herpesvirus-associated tumors. Nat Med. 2008; 14(10):1118-22. 2. Feng WH, Hong G, Delecluse HJ, Kenney SC. Lytic induction therapy for Epstein-Barr virus-positive B-cell lymphomas. J Virol. 2004; 78(4):1893-902. 3. Shirley CM, Chen J, Shamay M, Li H, Zahnow CA, Hayward SD, Ambinder RF. Bortezomib induction of C/EBPα mediates Epstein-Barr virus lytic activation in Burkitt lymphoma. Blood. 2011; 117(23):6297-303.

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 558. doi:1538-7445.AM2012-558
Abstract 5598: Interaction between BRAF inhibitor PLX-4720 and CDK inhibitors can sensitize melanoma cells with BRAF V600E mutation
Authors: Tortelli Tharcísio Citrângulo , Chammas Roger , Chellappan Srikumar
Published: August 2012

BRAF V600E mutation happens in 60% of all melanomas cases and this mutation is responsible to poor prognosis of the disease. BRAF is part of the MAPK signaling pathway and the V600E mutation of BRAF confers full activation of this survival pathway. Several clinical trials are being conducted using mutated BRAF as a target but so far, all this trials works during a certain moment but soon, melanoma cells becomes resistant to treatment by activating some survival pathways that can continues the signal initialized in the MAPK pathway. Our objective is to evaluate if the combination of BRAF inhibitors and CDKs inhibitors can suppress the acquired resistance of V600E melanoma cells to BRAF inhibitors. Two melanoma cell lines were used in this study. The SKMel 28 cell line, which has BRAF V600E mutation, and the SKMel 02, which is wild type to BRAF. Olomoucine and Roscovitine were the CDKs inhibitors used in this study, while PLX-4720 was BRAF inhibitor. Western blot and Real time PCR were used to verify some survival pathways, like the MAP3K8 and the PRKD3 pathway, that are overexpressed after BRAF inhibition and MTT assay was used to verify cell viability with both treatments combined. The combination of Olomoucine and PLX-4720 or Roscovitine and PLX-4720 could sensitize the BRAF V600E mutated melanoma cell line SKMel 28, but not the BRAF wild type melanoma cell line SKMel 02. Two survival pathways (MAP3K8 and PRKD3) which are activated after BRAF inhibition by PLX-4720 were downregulated in the presence of the CDKs inhibitors in the SKMel 28 melanoma cell line. Also, the retinoblastoma protein was not phosphorylated when the SKMel28 melanoma cell line was treated with the BRAF inhibitor together with the CDKs. The treatment with the BRAF inhibitor and the CDKs inhibitors can sensitize BRAF V600E melanoma cells by decreasing cell viability, downregulation of survival pathways induced by the BRAF inhibitor and preventing Rb phosphorylation. This strategy may overcome the acquired resistance of BRAF-mutated melanoma after treatment with its inhibitors.

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 5598. doi:1538-7445.AM2012-5598
Abstract LB-217: Lycopene and gene expression in benign prostate: a phase II randomized trial
Authors: Gann Peter H. , Dai Yang , Giangreco Angeline Antonio , Deaton Ryan , van Breemen Richard , Lu Yi , Rueter Erika Enk , Nonn Larisa
Published: August 2012

Previous research indicates that lycopene and associated compounds in tomato foods could have cancer chemopreventive properties in the prostate. Pre-clinical and clinical studies provide support for mechanisms involving androgen or IGF-1 regulation, oxidative stress response, inflammation and DNA repair. We undertook a 6-month repeat biopsy trial in men with HGPIN, randomly assigned to consume placebo or LycoMato® capsules, a tomato oleoresin containing 30 mg/day of lycopene. Benign epithelium from fixed prostate biopsy sections (pre- and post-treatment) was laser capture microdissected and RNA was extracted. We reverse transcribed RNA and pre-amplified for 92 target and 4 housekeeping (HK) genes. Pre-amped RNA was loaded unto custom Taqman® Low Density Arrays for qPCR quantitation. For each gene, Ct values were standardized to the mean HK gene values and fold-change (RV, relative value) in expression between baseline and follow-up was determined. Evaluable data was obtained from 16 lycopene subjects and 22 placebo controls. Serum lycopene increased by 83.3% on average in the active group and declined by 35.0% in the placebo group, although changes varied considerably across subjects. Individual gene comparisons by assigned group revealed statistically significant relative downregulation of DDB1, SOD3, and CXCL12 in the lycopene group. Expression changes in GCLC a rate-limiting enzyme in glutathione synthesis and an NRF2 oxidative stress response gene - were positively correlated with serum lycopene changes (Spearman R = 0.42, P = 0.009). Ongoing gene set analysis, by sum of Wilcoxon signed-rank and permutation tests, thus far suggest non-significant trends for treatment effects in the androgen, DNA repair and oxidative stress response gene groups. Initial results from unsupervised hierarchical clustering and principal components analysis for 34 genes with the highest variance showed evidence for classification by treatment group. Among all subjects, baseline serum lycopene was inversely correlated with baseline expression of AMACR, XRCC1, ERCC3, and OGG1 (R −0.32 to −0.38, P < .05). Follow-up studies on protein expression of key targets using immunohistochemistry are underway. The results from this small but unique trial demonstrate the feasibility of this approach and so far indicate that long-term lycopene status may be associated with down-regulation of DNA repair genes in benign prostate and that a 6-month intervention could cause changes in expression of genes and gene sets selected a priori.

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 LB-217. doi:1538-7445.AM2012-LB-217
Abstract LB-295: Targeted therapy of human osteosarcoma cell lines
Authors: Yu Yan , Ibrahim Nuha , Walsh William R. , Yang Jia Lin
Published: August 2012

A <20% survival rate for metastatic and recurrent osteosarcoma reflects the inadequacy of available therapies. We aimed to [1] investigate the therapeutic effect of a multikinase inhibitor (sorafenib, gift from Bayer) alone or as a radiosensitizor in human osteosarcoma cell lines, [2] establish a 143B orthotopic mouse model of human osteosarcoma with lung metastasis to identify ras down stream signaling pathways, and [3] assess effect of blocking specific pathway on 143B invasion using a MEK/ERK inhibitor (U0126). Osteosarcoma cell lines, 143B (HOS cell line with k-ras oncogene transformation), HOS and U-2 OS were used in an in vitro experiments. The 143B was also used to set up an orthotopic osteosarcoma mouse model. Clonogenic assay was used to assess the anti-cell growth and anti-colony formation effects of sorafenib and/or radiotherapy (Therapax 3 System) respectively. Immunohistochemistry was used to measure ras down stream signaling factors from both local tumor and lung secondaries of the mouse model. A Matrigel assay was used to assess 143B invasion under interference. IC50s for sorafenib (µg/ml) and x-ray (Gy) were 14.98 and 2.72 (143B), 6.52 and 1.48 (HOS) and 7.72 and 1.49 (U-2 OS) respectively. Ras transformed 143B was relatively insensitive to sorafenib monotherapy. Sorafenib can enhance x-ray treatment in HOS (5-26%) and U-2 OS (4-26%), but not in 143B. The 143B was then used to be injected into the left tibia of 15 nude mice and showed tumor mass at both local area and lung. Detection of ras down stream signaling factors, we found that total MEK, Akt, p38 and phosphorylated MEK (p-MEK), but not p-Akt and p-p38 were positive in both local tumors and lung secondaries. Leiomyosarcoma controls expressed p-Akt and p-MEK, but not p-p38. The 143B cells treated with U0126 had significantly lower in vitro invasion ability compared with controls. Our results indicated that sorafenib may enhance radiotherapy in vitro in some of the osteosarcoma cell lines without overexpression of k-ras gene. The Ras/Raf/MEK/ERK, may play an important role in osteosarcoma lung metastasis, and the targeting MEK/ERK by its specific inhibitor may have a potential use in the effective treatment of osteosarcoma.

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 LB-295. doi:1538-7445.AM2012-LB-295
Abstract LB-425: An NF-κB pathway mediated positive feedback loop amplifies Ras activity to pathological levels in mice
Authors: Ji Baoan , Daniluk Jaroslaw , Liu Yan , Deng Defeng , Huang Haojie , Wang Huamin , Logsdon Craig D.
Published: August 2012

Elevated Ras activity is critical for Ras induced tumorigenesis. However, the underlying mechanisms that lead to pathological levels of Ras activity are unclear. Here, we found that stimulation of Ras signaling by typical inflammatory stimuli was transient and had no long term sequelae in wild-type mice. In contrast, these stimuli generated prolonged Ras signaling and led to chronic inflammation and precancerous lesions (PanINs) in mice expressing endogenous levels of oncogenic K-Ras. The effects of inflammatory stimuli on oncogenic Ras expressing mice were disrupted by deleting IKK2 or inhibiting Cox-2. Likewise, the expression of active IKK2 or Cox-2, or treatments with LPS generated chronic inflammation and PanINs only in mice expressing oncogenic Ras. The data support that in the presence of oncogenic Ras, inflammatory stimuli trigger an NF-κB mediated positive feedback mechanism involving Cox-2 that amplifies Ras activity to pathological levels. Because a large portion of the adult human population possesses Ras mutations in tissues including colon, pancreas, and lung, disruption of this positive feedback loop may be an important strategy for cancer prevention.

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 LB-425. doi:1538-7445.AM2012-LB-425
Abstract LB-46: Advocacy & Action
Authors: McIntyre Katherine E.
Published: August 2012

These powerful core statements communicate our purpose and express the heart and soul of all we do, and why we do it. Mission Rooted in God's love; we treat illness and promote wellness for all people. Vision Our vision is to set the standards of excellence in delivery of health care throughout the regions we serve. Values The following values are represented by the six brush strokes preceding our name in the logo. They serve as a reminder to ourselves and our community that our values precede-literally and figuratively-everything we do. - Compassion: Showing empathy and concern for everyone and responding with kindness, and sensitivity. - Quality: Optimizing talents, skills and abilities to achieve excellence in meeting and exceeding our patients’ expectations - Integrity: Adhering without compromise to high moral principles of honest, loyalty, sincerity and fairness - Courtesy: Demonstrating polite, cooperative and respectful behavior; showing consideration and care for each person - Accountability: Using material good wisely; being conscious of the environment; being accountable for prudent use of our talents and financial resources. -Team Work: Working together to accomplish task and goals; recognizing the interdependence of one another and cache person's unique gifts. Navigators Three patient navigators are employed at Lewis Cancer & Research Pavilion. The LCRP also employs patient resource navigators (social workers).

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 LB-46. doi:1538-7445.AM2012-LB-46
Magnesium: Novel Applications in Cardiovascular Disease – A Review of the Literature
Authors: Kupetsky-Rincon Erine A. , Uitto Jouni
Published: August 2012

Magnesium is an ubiquitous element and its formulation determines its efficacy and administration. It is used for gastrointestinal and obstetric disease and recently cardiovascular and neurological indications have also been explored. The role of serum/dietary magnesium intake on cardiovascular disease, carotid intima-media thickness (CIMT), hypertension (HTN) and cholesterol synthesis has been investigated. Despite differences in patient populations, some observational and interventional studies have suggested that low serum/dietary magnesium is associated with higher CIMT and more cardiovascular risk factors. A few clinical and basic science interventional studies have also shown the benefits of magnesium administration in cardiovascular disease prevention and as a neuroprotective agent. Low magnesium levels have been implicated in inflammation and endothelial dysfunction. Hypomagnesemia results in increased C-reactive protein and cytokine exaggeration, increased nuclear factor kappa B and platelet dysfunction, which can lead to thrombosis. Magnesium appears to play a vital function in cardiovascular stability and health, but an optimal dose and formulation has not been defined. Potentially promising avenues include the combination of magnesium with a statin to reduce cholesterol, C-reactive protein and CIMT, and its early use to reduce stroke morbidity and mortality. Understanding the role of magnesium in inflammation and mineralization and how it has the potential for playing a role in modulating cardiovascular and neurological disease can be a new frontier in medicine.
Adolescent Male Chimpanzees at Ngogo, Kibale National Park, Uganda Have Decided Dominance Relationships
Authors: Sherrow Hogan M.
Published: August 2012

Dominance relationships are common among primates, and are usually the result of resource competition. Adult male chimpanzees have pronounced dominance relationships, and can be ranked relative to one another in dominance hierarchies. Adult male chimpanzees achieve, and maintain, high rank through a combination of physical size, strength and political ability. Dominance in male chimpanzees has very real benefits as high-ranking males have priority access to resources and potential mates, and father more offspring than do low-ranking conspecifics. Previous research has suggested that adolescent male chimpanzees do not have dominance relationships with each other. Here, I report the first evidence of decided dominance relationships and a linear dominance hierarchy in adolescent male chimpanzees from an unusually large community of wild chimpanzees at Ngogo, Kibale National Park, Uganda.
Circulation
Editors' Picks
Authors:   The Editors
Published: August 2012

The following articles are being highlighted as part of
Circulation's
Topic Review series. This series will summarize the most important manuscripts, as selected by the editors, published in
Circulation
and the
Circulation
subspecialty journals. The studies included in this article represent the most read manuscripts published on the topic of cardiovascular surgery within the last year.
A Uniform Space–Time Gridding Algorithm for Comparison of Satellite Data Products: Characterization and Sensitivity Study
Authors: Smith Nadia , Menzel W. Paul , Weisz Elisabeth , Heidinger Andrew K. , Baum Bryan A.
Published: August 2012

To overcome the complexities associated with combining or comparing multisensor data, a statistical gridding algorithm is introduced for projecting data from their unique instrument domain to a uniform space–time domain. The algorithm has two components: 1) a spatial gridding phase in which geophysical properties are filtered on the basis of a set of criteria (e.g., time of day or viewing angle) and then aggregated into nearest-neighbor clusters as defined by equal-angle grid cells and 2) a temporal gridding phase in which daily statistics are calculated per grid cell from which longer time-aggregate statistics are derived. The sensitivity of the gridding algorithm is demonstrated using a month (1–31 August 2009) of level 2 Aqua/Moderate Resolution Imaging Spectroradiometer (MODIS) cloud-top pressure (CTP) retrievals as an example. Algorithm sensitivity is tested for grid size, number of days in the definition of a time average, viewing angle, and minimum number of observations per grid cell per day. The average CTP for high-level clouds from a number of different polar-orbiting instruments are compared on a 1° × 1° global grid. With the data projected onto a single grid, differences in CTP retrieval algorithms are highlighted. The authors conclude that this gridding algorithm greatly facilitates the intercomparison of CTP (or any other geophysical parameter) and algorithms in a dynamic environment. Its simplicity lends transparency to understanding the behavior of a given parameter and makes it useful for both research and operational use.
Comparison of PARASOL Observations with Polarized Reflectances Simulated Using Different Ice Habit Mixtures
Authors: Cole Benjamin H. , Yang Ping , Baum Bryan A. , Riedi Jerome , C.-Labonnote Laurent , Thieuleux Francois , Platnick Steven
Published: August 2012

Insufficient knowledge of the habit distribution and the degree of surface roughness of ice crystals within ice clouds is a source of uncertainty in the forward light scattering and radiative transfer simulations of ice clouds used in downstream applications. The Moderate Resolution Imaging Spectroradiometer (MODIS) collection-5 ice microphysical model presumes a mixture of various ice crystal shapes with smooth facets, except for the compact aggregate of columns for which a severely rough condition is assumed. When compared with Polarization and Anisotropy of Reflectances for Atmospheric Sciences coupled with Observations from a Lidar (PARASOL) polarized reflection data, simulations of polarized reflectance using smooth particles show a poor fit to the measurements, whereas very rough-faceted particles provide an improved fit to the polarized reflectance. In this study a new microphysical model based on a mixture of nine different ice crystal habits with severely roughened facets is developed. Simulated polarized reflectance using the new ice habit distribution is calculated using a vector adding–doubling radiative transfer model, and the simulations closely agree with the polarized reflectance observed by PARASOL. The new general habit mixture is also tested using a spherical albedo differences analysis, and surface roughening is found to improve the consistency of multiangular observations. These results are consistent with previous studies that have used polarized reflection data. It is suggested that an ice model incorporating an ensemble of different habits with severely roughened surfaces would potentially be an adequate choice for global ice cloud retrievals.
The Relationship between Total Cloud Lightning Behavior and Radar-Derived Thunderstorm Structure
Authors: Metzger Eric , Nuss Wendell A.
Published: August 2012

Total lightning detection systems have been in development since the mid-1980s and deployed in several areas around the world. Previous studies on total lightning found intra- and intercloud lightning (IC) activity tends to fluctuate significantly during the lifetime of thunderstorms and have indicated that lightning jumps or rapid changes in lightning flash rates are closely linked to changes in the vertical integrated liquid (VIL) reading on the National Weather Service’s Weather Surveillance Radar-1988 Doppler (WSR-88D) systems. This study examines the total lightning and its relationship to WSR-88D signatures used operationally to determine thunderstorm severity to highlight the potential benefit of a combined forecast approach. Lightning and thunderstorm data from the Dallas–Fort Worth, Texas, and Tucson, Arizona, areas from 2006 to 2009, were used to relate total lightning behavior and radar interrogation techniques. The results indicate that lightning jumps can be classified into severe wind, hail, or mixed-type jumps based on the behavior of various radar-based parameters. In 25 of 34 hail-type jumps and in 18 of 20 wind-type jumps, a characteristic change in cloud-to-ground (CG) versus IC lightning flash rates occurred prior to the report of severe weather. For hail-type jumps, IC flash rates increased, while CG flash rates were steady or decreased. For wind-type jumps, CG flash rates increased, while IC flash rates either increased (12 of 18) or were steady or decreased (6 of 18). Although not every lightning jump resulted in a severe weather report, the characteristic behavior in flash rates adds information to radar-based approaches for nowcasting the severe weather type.
A Multigrid Wave Forecasting Model: A New Paradigm in Operational Wave Forecasting
Authors: Chawla Arun , Tolman Hendrik L. , Gerald Vera , Spindler Deanna , Spindler Todd , Alves Jose-Henrique G. M. , Cao Degui , Hanson Jeffrey L. , Devaliere Eve-Marie
Published: August 2012

A new operational wave forecasting system has been implemented at the National Centers for Environmental Prediction (NCEP) using the third public release of WAVEWATCH III. The new system uses a mosaic of grids with two-way nesting in a single model. This global system replaces a previous operational wave modeling suite (based on the second release of WAVEWATCH III). The new forecast system consists of nine grids at different resolutions to provide the National Weather Service (NWS) and NCEP centers with model guidance of suitable resolution for all areas where they have the responsibility of providing gridded forecast products. New features introduced in WAVEWATCH III, such as two-way nesting between grids and carving out selected areas of the computational domain, have allowed the operational model to increase spatial resolution and extend the global domain closer to the North Pole, while at the same time optimizing the computational cost. A spectral partitioning algorithm has been implemented to separate individual sea states from the overall spectrum, thus providing additional products for multiple sea states. Field output data are now packed in version 2 of the gridded binary (GRIB2) format and apart from the standard mean wave parameters, they also include parameters of partitioned wave spectra. The partitioning is currently limited to three fields: the wind-wave component, and primary and secondary swells. The modeling system has been validated against data using a multiyear hindcast database as well as archived forecasts. A new software tool developed by the U.S. Army Corps of Engineers (USACE) is used to extend the analysis from overall error estimates to separate skill scores for wind seas and swells.
Black Male Perspectives on Their Educational Experiences in High School
Authors: Caton Marcia Theresa
Published: August 2012

This study examines the impact of the zero-tolerance policies on Black males’ educational experiences and outcomes. Individual interviews were conducted with Black males who dropped out of high school. Using counter-storytelling within a critical race theory framework, Black males discussed the influence of the zero-tolerance policies on their school experiences. These men’s narratives affirm that these policies created an inhospitable school environment and poor student–teacher relationship. Furthermore, school personnel’s use of the most punitive measures of the policies, suspension and expulsion of students, led to their school failure.
Culturally Relevant Science Teaching in Middle School
Authors: Laughter Judson C. , Adams Amelia D.
Published: August 2012

To respond to calls for more research on culturally relevant science teaching, we present findings from one middle school science teacher’s practices in an effort to contribute to this research. We describe how a discussion lab centered on Derrick Bell’s (1992) short story The Space Traders was purposively included in a lesson on scientific bias to engage middle school students in thinking about bias in larger societal contexts and in their own lives. We review literature in the growing field of culturally relevant science teaching as building on Ladson-Billings’s (1995a, 1995b, 2006) conception of culturally relevant pedagogy. We then describe the context and method of our study and present findings drawn from multiple data sources. We close with a discussion aimed at both practicing teachers and teacher educators.
The Importance of Jean Piaget
Authors: Erneling Christina E.
Published: August 2012

Jean Piaget, along with Sigmund Freud and B. F. Skinner, is one of the most influential thinkers in psychology. His influence on developmental and cognitive psychology, pedagogy and the so-called cognitive revolution is without doubt. The contributors to the book under review aim to show his past, contemporary as well as future relevance to important areas of psychology. I argue that they fail because they use Piaget’s own terminology, instead of explaining his ideas and relevance in a way accessible to someone not already familiar with or sceptical about his assumptions and ideas. Thus, the book neither meets the authors’ own stated goals, nor provides an accessible exposition of Piaget for the uninitiated or sceptical reader. A companion book like this one should help give answers to questions which someone unfamiliar with or sceptical of, but curious about, Piaget’s work would ask.