tbuckley/cabot-search huggingface dataset:
Abstract 1039: A Proprotein Convertase Regulates Integrin - MMP Cooperation In VSMCs
Authors: Philipp Stawowy, Heike Meyborg, Bernadette Baumann, Dietger Stibenz, Eckart Fleck, Kristof Graf
Journal: Circulation (2007)

ECM remodeling is a key feature in atherosclerosis and restenosis. Integrins link the cytoskeleton with the ECM and regulate adhesion/migration. MMPs are the major degrading enzymes important for cell motility. Binding of the MMP-2 zymogen to alpha v beta 3 is necessary for its full activation, thereby coordinating cell motility with membrane-associated proteolysis. The alpha v integrin chain is synthesized as a proprotein that is endoproteolytically activated by furin. Furin is the prototype proprotein convertase, highly expressed in human atherosclerotic lesions. The aim of this study was to investigate the role of furin in integrin -MMP coordination and cooperation in VSMCs. Methods and Results: Treatment of VSMCs with either the furin inhibitor dec-CMK (50 umol/L) or an MMP-inhibitor (GM6001; 25 umol/L) significantly inhibited VSMC Matrigel invasion (p&lt;0.05 vs. controls). Immunoblotting demonstrated that dec-CMK inhibited alpha v endoproteolytic activation, but this did not affect alpha v membrane expression assessed by FACS analysis. Zymography revealed that in dec-CMK or TSR1265 (10 umol/L; an inhibitor of MMP-2 binding to alpha v beta 3) treated cells, maturation of the intermediate 68 kDa MMP-2 to its fully active 62 kDa form was significantly decreased (p&lt;0.05 vs. controls). Furthermore, dec-CMK significantly inhibited binding of FITC-conjugated pro-MMP-2 to the cell surface of VSMCs. Immunfluorescence and 3D in gel zymography demonstrated that inhibition of endoproteolytic cleavage of the alpha v integrin inhibits actin rearrangement and focal contact formation upon integrin stimulation (matrix adhesion or PMA treatment), as well as membrane-associated proteolysis. Conclusion: Our study demonstrates that endoproteolytic cleavage of alpha v integrin by furin regulates not only integrin activation, but also affects MMP-2 maturation. Endoproteolytic activation of alpha v is required for cytoskeleton rearrangement upon integrin stimulation and focal contact formation, as well as the coordination and cooperation of integrins and MMPs. Therefore furin-convertase may be a novel target in atherosclerosis and restenosis.
Abstract 10251: Achieved Dose of Beta-Blocker but not Achieved Heart Rate Predicts Clinical Outcomes in Heart Failure Patients With Atrial Fibrillation
Authors: Naoko Kato, Koichiro Kinugawa, Teruhiko Imamura, Hironori Muraoka, Shun Minatsuki, Toshiro Inaba, Hisataka Maki, Masaru Hatano, Atsushi Yao, Issei Komuro, Ryozo Nagai
Journal: Circulation (2013)

Background:  Little is known whether achieved heart rate is a surrogate maker during titration of β-blocker in heart failure (HF) with atrial fibrillation (AF). The purpose of this study was to clarify surrogate markers when titrating β-blocker among HF patients having reduced ejection fraction (HFrEF, EF   Methods:  Of consecutive HFrEF patients who were hospitalized for HF at our hospital between 2002 and 2010, patients prescribed β-blocker on a de novo basis were retrospectively examined. Left ventricular EF and BNP was assessed 6 month after the titration of β-blocker. Median duration of follow-up was 36 month. Primary endpoint was hospitalization for HF and/or all-cause death.   Results:  Of 253 patients who were enrolled in the study, 56 patients (21%) had AF. There were no significant differences in age and gender between HFrEF patients with and without AF (64.2±12.6 vs. 61.9±14.5 years; male 25% vs. 24%). During the follow-up, 36% and 28% in HFrEF patients with and without AF had the adverse events respectively (p=0.42). Multivariate Cox regression analysis showed that plasma levels of B-type natriuretic peptide (BNP), LVEF, and achieved heart rate were independent predictors for adverse outcomes in HFrEF without AF, whereas BNP levels and achieved fixed dose of β-blocker predicted the outcomes in HFrEF with AF (all, p   Conclusions:  Achieved heart rate is a predictor for cardiac events in only HFrEF patients without AF. The new scoring systems can stratify the prognosis in HFrEF with and without AF.
Effects of 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and selenium (1,4-Phenylenebis(methylene)selenocyanate, p-XSC, or selenium-enriched yeast) on tumorgenesis and antioxidant levels in A/J mouse lung
Authors: John P. Richie, Wayne A. Kleinman, Dhimant Desai, Shantu Amin, Karam El-Bayoumy
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

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Tobacco smoke contains an abundance of oxidants and free radicals, which, in addition to carcinogens such as polycyclic aromatic hydrocarbons and tobacco specific nitrosamines (TSNAs), are thought to play a role in lung carcinogenesis and be responsible for the observed depletion of blood antioxidants in smokers. Results from epidemiological, clinical intervention and laboratory studies indicate a protective role for selenium against several cancers including lung cancer. In one trial, Se-enriched yeast (Se-yeast) protected against lung cancer in individuals with low baseline levels of plasma Se. We hypothesize that one mechanism for Se chemoprevention is inhibition of oxidative damage to critical macromolecules by inducing antioxidant enzymes and/or levels of antioxidants especially in target organs. To test this, we determined (1) if antioxidants in the lung are depleted in NNK treated mice in relation to tumor formation and (2) whether Se (p-XSC or Se-yeast) is effective at preventing these changes. A/J mice (5 wk old) were fed either control or experimental (containing 10 ppm p-XSC or Se-yeast) diets and, beginning at wk 7, received NNK (3 μmol in 0.1 ml cottonseed oil) by gavage once weekly for 8 wk. Mice were sacrificed 26 wk after NNK initiation and lungs were analyzed for tumor multiplicity and antioxidant content. p-XSC significantly reduced NNK-induced tumor burden by 74% (10.4 ± 6.0 vs 2.7 ± 1.5 tumors/mouse, P<0.001) and decreased tumor incidence from 96% to 68% (P<0.01), whereas Se- yeast had no effect. P-XSC was nearly 10-fold more effective at enhancing lung Se than was Se-yeast (P<0.01). Decreases in ascorbate levels ranging from 15% to 25% were observed in NNK-treated mice (P<0.05). In mice administered both NNK and p-XSC, ascorbate levels were increased 45% over NNK-treated alone (P<0.01), whereas p-XSC alone had no effect. Glutathione (GSH) levels in lung were unchanged in NNK-treated mice but were increased 72-75% in mice treated with a both NNK and p-XSC (P<0.01) and 42% in mice treated with p-XSC alone. Cyst(e)ine (Cys + cysteine) levels were decreased 18% in NNK-treated mice (P<0.02), but were increased about 2-fold in mice treated with either NNK and p-XSC in combination or with p-XSC alone (P<0.001). Se-yeast had no effect on antioxidant levels in either control or NNK-treated mice. These results demonstrate that NNK-induced tumorigenesis is associated with decreased ascorbate levels and indicate that inhibition of lung carcinogenesis by p-XSC is correlated with increased antioxidant levels. Altogether, these findings support the hypothesis that Se, in the form of p-XSC, inhibits tumor formation, in part, by protecting against oxidative damage, possibly through induction of lung GSH. Supported by NIH grants CA70972 and CA17613.
Formulated oligomeric polyphenols (oligonol) from grape seeds inhibit phorbol ester-induced tumor promotion and COX-2 expression in mouse skin: nuclear factor-κB and CCAAT/enhancer binding protein as potential targets.
Authors: Joydeb K. Kundu, Young K. Shin, Young Joon Surh
Journal: Cancer Research (2006)

5743   Multiple lines of evidence suggest that plant polyphenols are effective in preventing degenerative diseases including cancer. The present study was aimed at evaluating the anti-tumor promoting activity of oligonol, a formulation of catechin oligomers derived from the grape seed extract, in mouse skin  in vivo . The chemopreventive activity of oligonol was evaluated in a 7,12-dimethylbenz[a]anthracene (DMBA)-initiated and 12- O -tetradecanoylphorbol-13-acetate (TPA)-promoted mouse skin carcinogenesis model. Oligonol, when topically applied on the dorsal skin of female ICR mice 30 min prior to each TPA (10 nmole) application, dose-dependently inhibited papilloma formation. The incidence and burden of squamous cell carcinoma formation were also reduced by oligonol pretreatment. While only 53% of mice treated with DMBA and TPA survived at 40 week, all animals given oligonol (10 mg/mouse) were alive. Immunohistochemical analysis of papilloma sections revealed the reduced expression of proliferating cell nuclear antigen (PCNA) and cytosolic level of an oncoprotein β-catenin in oligonol pretreated mice. Because of a causal link between chronic inflammation and cancer, anti-inflammatory components present in our daily diet are anticipated to exert chemopreventive effects. One of the biochemical changes causally linked to inflammation-associated cancer is the inappropriate induction of cyclooxygenase-2 (COX-2). Topical application of oligonol significantly inhibited TPA-induced COX-2 expression. COX-2 gene expression is known to be regulated by a distinct set of transcription factors. Oligonol blunted TPA-induced nuclear translocation and DNA binding of NF-κB by preventing phosphorylation and subsequent degradation of IκBα. Oligonol also suppressed TPA-induced DNA binding of CCAAT/enhancer binding protein (C/EBP) and expression of C/EBPβ in mouse skin, while the activation of activator protein-1 (AP-1) remained unaffected. In addition, oligonol diminished the phosphorylation and/or catalytic activities of extracellular signal-regulated protein kinase (ERK) and p38 MAP kinases. While ERK and p38 MAP kinases are known to regulate TPA-induced NF-κB activation and COX-2 expression, the role of these MAP kinases in regulating TPA-induced C/EBP acti vation in mouse skin had remained unknown. Topical application of a pharmacological inhibitor of p38 MAP kinase (SB203580), but not ERK (U0126), attenuated TPA-induced activation of C/EBP, suggesting the possible role of p38 MAP kinase in tumor promoter-induced C/EBP activation in mouse skin  in vivo . Taken together, the above findings suggest that oligonol suppresses mouse skin tumor promotion and TPA-induced expression of COX-2 and activation of NF-κB and C/EBP by blocking p38 MAP kinase signaling.
Ionizing radiation alters localization and phosphorylation of caveolin-1 in glioblastoma cells and blood-brain barrier endothelium.
Authors: Deedee K. Smart, C. Matthew Bradbury, C. Norman Coleman, David Gius
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

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Radiation is the primary treatment modality for glioblastomas, but the therapeutic benefit of ionizing radiation is limited by the ability of normal brain tissue to tolerate this treatment. This is due, in part, because radiation alters the structure and function of microvascular networks, and, in part, because of the radioresistant character of astrocytomas. Although intact cerebral microvasculature lacks caveolae, caveolin-1, the principle structural and functional component of caveolae, is detected predominantly in association with endothelia throughout the adult brain. Furthermore, ionizing radiation induces the upregulation of caveolae in cerebral microvessels and increases blood-brain barrier permeability. This evidence suggests that blood-brain barrier permeability induced by ionizing radiation may be mediated through cellular signaling pathways that involve caveolin-1. It has been established that caveolin-1 expression levels are altered in glioblastoma cells compared to non-transformed astrocytes, suggesting that caveolin-1 may participate in signaling that contributes to a transformed phenotype. Therefore, we hypothesized that ionizing radiation may affect caveolin-1 function within blood-brain barrier endothelium and glioblastoma cells. C3H mice at 6 weeks of age received 6 Gy of whole brain irradiation and were sacrificed at 24 hours, 48 hours, and 7 days after treatment. Immunohistochemical analysis of fixed, frozen brain sections using an antibody to caveolin-1 revealed alterations in the distribution of the protein at 24 and 48 hours post-irradiation, with a return to the distribution characteristic of unirradiated brain by 7 days after treatment. U251 glioblastoma cells were exposed to 2-20 Gy of ionizing radiation and collected at 6, 24, or 48 hours following irradiation. The cells were processed for immunocytochemistry and immunoblot analysis using antibodies to caveolin-1 and Tyr-14 phosphorylated caveolin-1. Although there was no demonstrated change in the total levels of caveolin-1 protein after irradiation, the expression of phosphorylated caveolin-1 was altered in a dose- and time-dependent manner. Microarray analyses using total RNA from unirradiated and irradiated mouse brain microvessels are underway. Taken together, these data suggest that caveolin-1 alters its protein-protein interactions with increased blood-brain barrier permeability in response to ionizing radiation. Furthermore, caveolin-1 may be a potential mediator of radiation-induced signaling in glioblastoma.
Abstract 77: Genomic characterization of aggressive subtype of neuroblastoma without MYCN amplification
Authors: Miki Ohira, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara
Journal: Cancer Research (2015)

Abstract Neuroblastoma is known to exhibit wide ranges of clinical behavior, from spontaneous regression to highly resistant to chemotherapy, and one of the challenges in the clinic is to develop adequate therapeutic strategies for the intermediate risk-type of patients (stage 3 or 4 without MYCN amplification) whose prognosis sometimes tends to be poor in long-time follow-up (10 years survival rate (SR) was 51% in our database, n = 161). To discover the key target genes or pathways for the unfavorable subset in this patient group, we have analyzed 44 primary tumors (dead:24, alive:20) without MYCN amplification nor ALK alteration by integrated genomic analyses such as array CGH, gene expression profiling and whole exome sequencing (SureSelect 50Mb, average read depth:157, x20 coverage:95%). We found 816 non-synonymous somatic single nucleotide variations (SNVs) in coding genes and alteration number in each tumor strongly associates with age at diagnosis (p&amp;lt;0.0001) and patient prognosis (p = 0.187). A novel ATRX mutation was identified in a tumor with 1p and 11q losses isolated from a male patient (age:93 months). Recurrent SNVs (n = 2 to n = 6) were found in 44 genes, 20 of those were involved only in the tumors from the patient with poor prognosis, in the 44 tumor set. Validation of these 20 SNVs is ongoing by using additional clinical samples. These features of genomic alterations could be useful for risk classification for each tumor and constructing new therapeutic strategies for aggressive neuroblastomas without MYCN amplification. Citation Format: Miki Ohira, Kenji Tatsuno, Shuichi Tsutsumi, Shogo Yamamoto, Yohko Nakamura, Takehiko Kamijo, Hiroyuki Aburatani, Akira Nakagawara. Genomic characterization of aggressive subtype of neuroblastoma without MYCN amplification. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 77. doi:10.1158/1538-7445.AM2015-77
Abstract 4664: Impact of TP53 mutations, single nucleotide variants and global methylation patterns on pre-menopausal breast cancer risk
Authors: Nardin Samuel, Mathieu Lemire, Ana Novokmet, Thomas J. Hudson, David Malkin
Journal: Cancer Research (2015)

Abstract INTRODUCTION: Li-Fraumeni Syndrome (LFS) is a cancer predisposition syndrome that confers a high lifetime risk of developing malignancies, including pre-menopausal breast cancer. Over 80% of LFS patients harbor germline mutations of the TP53 tumor suppressor gene. OBJECTIVE: We sought to determine if the spectrum of TP53 variants, as well as global methylation methylation patterns, correlates with the presence of TP53 mutations or influences cancer risk in pre-menopausal breast cancer patients. METHODS: Constitutional DNA was obtained from peripheral blood lymphocytes (PBL) of 10 patients with pre-menopausal breast cancer harboring germline TP53 mutations, 10 patients diagnosed with pre-menopausal breast cancer that are non-mutation carriers, 15 TP53 mutation carriers who do not have cancer, and 15 healthy female controls. Genome-wide methylation analysis of PBL-derived DNA was performed using the Illumina 450K array. Sanger sequencing of exons 2-11, and flanking intron regions of the TP53 gene was performed. RESULTS: The most commonly observed single nucleotide polymorphism (SNP) in TP53 across all samples was at c.215C&amp;gt;G (p.Pro72Arg) in exon 4 (rs1042522). We observed a G allele frequency of 66.0% in our study group. Three additional low-frequency variants in TP53 were observed: the exon 4: c.108G&amp;gt;A (p.Pro36Pro) variant was found in 2 patients, exon 6: c.639A&amp;gt;G (p.Arg213Arg) was found in 9 patients and intron 9: c.993+12T&amp;gt;C was found in 4 patients. Methylation patterns were not associated with a specific TP53 mutation or variant; however, distinct methylation patterns were observed in TP53 mutation carriers when compared to either TP53 wild-type healthy individuals or patients with early-onset breast cancer. DISCUSSION: This study represents an epigenome-wide analysis and targeted genetic survey of germline TP53 in early-onset, pre-menoupausal breast cancer. As a result of the mutation frequency observed, germline mutations in TP53 may need to be included in the genetic work-up of patients with early-onset breast cancer. Parallel studies of genome-wide methylation demonstrate these patterns may serve as an independent biomarker of early-onset breast cancer risk. Note: This abstract was not presented at the meeting. Citation Format: Nardin Samuel, Mathieu Lemire, Ana Novokmet, Thomas J. Hudson, David Malkin. Impact of TP53 mutations, single nucleotide variants and global methylation patterns on pre-menopausal breast cancer risk. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4664. doi:10.1158/1538-7445.AM2015-4664
The Antineoplastic Agent Bryostatin-1 Induces Proinflammatory Cytokine Production in Human Monocytes: Synergy With Interleukin-2 and Modulation of Interleukin-2Rγ Chain Expression
Authors: Maria Carla Bosco, Sandra Rottschafer, Lynn S. Taylor, John R. Ortaldo, Dan L. Longo, Igor Espinoza-Delgado
Journal: Blood (1997)
Abstract A113: Immunomodulatory properties of bromodomain inhibitors in pancreatic cancer cells
Authors: Ana S. Leal, Charlotte R. Williams, Michael B. Sporn, Karen T. Liby
Journal: Cancer Research (2015)

Abstract Bromodomain and extra terminal domain (BET) proteins function as epigenetic signaling factors that “read” chromatin modifications, controlling numerous genes involved in cell cycle, cell growth, inflammation and cancer. The BET inhibitors, JQ1 and I-BET-762, occupy selective pockets of bromodomains in BET proteins resulting in a release of the chromatin and consequent suppression of the transduction of targeted genes. Cell lines developed from a pancreatic carcinoma (Panc 1343) and ascites (PanAsc 2159) of LSL-KrasG12d/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC mouse model) were treated with several concentrations of JQ1 and I-BET-762. JQ1 and I-BET-762 have growth inhibitory properties, with IC50 (48 hr treatment) of 24.5 nM and 94.5 nM, and 1.8 μM and 1.2 μM in PanAsc 2159 and Panc 1343 cells, respectively. Several cytokines and chemokines, produced by tumor cells, stromal cells or inflammatory infiltrating cells, play important roles in promoting (GM-CSF, IL-6 and CCL2) or suppressing (CCL27, CCL4, IL17A or IL27) tumor progression. RT profiler PCR of PanAsc 2159 cells treated with 300 nM of JQ1 for 24 hr revealed the ability of this compound to upregulate CCL24, IL17a and IL-27 and downregulate CCL7, CXCL1, CCL2, IL16 and IL6. JQ1 and I-BET-762 reduced the protein and RNA levels of CCL2, IL6 and GM-CSF in Panc 1343 and PanAsc 2159 cells, and also in RAW macrophage-like cells stimulated with LPS. JQ1 and I-BET-762 also reduced the protein levels of secreted TNF-α in RAW cells stimulated with LPS. JQ1 and I-BET-762 appear to have immunomodulatory effects in pancreatic cancer cell lines derived from KPC mice, altering the levels of several chemokines and cytokines. These compounds also have a growth inhibitory effect in these cell lines. Exploring the effects of these compounds in KPC mice is ongoing. We thank James Bradner for the generous gift of JQ1. Citation Format: Ana S. Leal, Charlotte R. Williams, Michael B. Sporn, Karen T. Liby. Immunomodulatory properties of bromodomain inhibitors in pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr A113.
Exposure to fine airborne particulate matters induces hepatic fibrosis in murine models
Authors: Ze Zheng, Xuebao Zhang, Jiemei Wang, Aditya Dandekar, Hyunbae Kim, Yining Qiu, Xiaohua Xu, Yuqi Cui, Aixia Wang, Lung Chi Chen, Sanjay Rajagopalan, Qinghua Sun, Kezhong Zhang
Journal: Journal of Hepatology (2015)
Estimated Glomerular Filtration Rate Changes In Patients (Pts) With Chronic Myeloid Leukemia (CML) Treated With Tyrosine Kinase Inhibitors (TKI)
Authors: Musa Yilmaz, Hagop M. Kantarjian, Alfonso Quintas-Cardama, Susan O'Brien, Jan A. Burger, Alessandra Ferrajoli, Gautam Borthakur, Farhad Ravandi, Sherry Pierce, Elias Jabbour, Jorge E. Cortes
Journal: Blood (2013)
3H-1,2-dithiole-3-thione exerts a chemotherapeutic function by inhibiting TNFα-stimulated Twist expression in Hs578T cells
Authors: Yong Huang, Jose Russo, Thomas Sutter
Journal: Cancer Research (2007)

1447   Twist is a master regulator of morphogenesis in embryogenic development and plays an essential role in cancer metastasis by induction of an epithelial-mesenchymal-transition. It also promotes  in vivo  angiogenesis, chromosome instability and taxol resistance of breast cancer. Twist expression inhibits mammary cell differentiation, and suppresses apoptosis by disregulating p53. TNFα is a cytokine that can be secreted by tumor cells and their surrounding inflammatory cells, and may exert both pro- and anti-tumor development effects. TNFα activates Twist expression in normal mouse fibroblast cells through NF-κB signaling pathway. Here, we show that TNFα also stimulates Twist expression in human breast cancer cells. The breast cancer cell line Hs578T was grown in DMEM medium supplemented with 10% FBS. After treatment with 1ng/ml TNFα for 48h, total RNA was isolated for reverse transcription and real time PCR analysis. The ΔΔCt method was used to calculate the fold change. Twist1 mRNA level was significantly increased by about 6-fold after TNFα treatment. We have previously shown that the cancer chemopreventive agent 3 H -1,2-dithiole-3-thione (D3T) has anti-inflammatory effects. D3T blocks NF-κB nuclear translocation and DNA binding, and thus suppresses the lipopolysaccharide-mediated induction of iNOS. In this study we further demonstrate that D3T inhibits the upregulation of Twist1 expression induced by treatment with TNFα. The Hs578T cells were pretreated with vehicle (DMSO) or D3T (40μm) for 16h followed by 1ng/ml TNFα incubation for 48h. The level of Twist1 mRNA in the D3T-pretreated cells was decreased by 75% when compared to the level in DMSO-pretreated cells. We propose that TNFα can independently increase the expression of Twist in certain breast cancer cells and thus stimulate tumorigenesis and metastasis. This effect can be blocked by D3T. Therefore, the chemopreventive agent D3T may also exert a chemotherapeutic effect. (This work was supported by grants DAMD17-03-1-0229)