bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood pressure and ageing
Authors: Pinto Elisabete 
Published: February 2007

Abstract
Isolated systolic hypertension, an elevation in systolic but not diastolic pressure, is the most prevalent type of hypertension in those aged 50 or over, occurring either de novo or as a development after a long period of systolic-diastolic hypertension with or without treatment. The increase in blood pressure with age is mostly associated with structural changes in the arteries and especially with large artery stiffness. It is known from various studies that rising blood pressure is associated with increased cardiovascular risk. In the elderly, the most powerful predictor of risk is increased pulse pressure due to decreased diastolic and increased systolic blood pressure. All evidence indicates that treating the elderly hypertensive patient will reduce the risk of cardiovascular events. However, there is no evidence yet for the very elderly. This population is particularly susceptible to side effects of treatments and the reduction of blood pressure, although reducing the risk of cardiovascular events such as stroke, may result in increased mortality.
Mice Lacking bi-1 Gene Show Accelerated Liver Regeneration
Authors: Bailly-Maitre Béatrice , Bard-Chapeau Emilie , Luciano Fréderic , Droin Nathalie , Bruey Jean-Marie , Faustin Benjamin , Kress Christina , Zapata Juan M. , Reed John C. 
Published: February 2007

Abstract
The liver has enormous regenerative capacity such that, after partial hepatectomy, hepatocytes rapidly replicate to restore liver mass, thus providing a context for studying in vivo mechanisms of cell growth regulation. Bax inhibitor-1 (BI-1) is an evolutionarily conserved endoplasmic reticulum (ER) protein that suppresses cell death. Interestingly, the BI-1 protein has been shown to regulate Ca2+ handling by the ER similar to antiapoptotic Bcl-2 family proteins. Effects on cell cycle entry by Bcl-2 family proteins have been described, prompting us to explore whether bi-1–deficient mice display alterations in the in vivo regulation of cell cycle entry using a model of liver regeneration. Accordingly, we compared bi-1+/+ and bi-1−/− mice subjected to partial hepatectomy with respect to the kinetics of liver regeneration and molecular events associated with hepatocyte proliferation. We found that bi-1 deficiency accelerates liver regeneration after partial hepatectomy. Regenerating hepatocytes in bi-1−/− mice enter cell cycle faster, as documented by more rapid incorporation of deoxynucleotides, associated with earlier increases in cyclin D1, cyclin D3, cyclin-dependent kinase (Cdk) 2, and Cdk4 protein levels, more rapid hyperphosphorylation of retinoblastoma protein, and faster degradation of p27Kip1. Dephosphorylation and nuclear translocation of nuclear factor of activated T cells 1 (NFAT1), a substrate of the Ca2+-sensitive phosphatase calcineurin, were also accelerated following partial hepatectomy in BI-1–deficient hepatocytes. These findings therefore reveal additional similarities between BI-1 and Bcl-2 family proteins, showing a role for BI-1 in regulating cell proliferation in vivo, in addition to its previously described actions as a regulator of cell survival. [Cancer Res 2007;67(4):1442–50]
Gefitinib Reverses TRAIL Resistance in Human Bladder Cancer Cell Lines via Inhibition of AKT-Mediated X-Linked Inhibitor of Apoptosis Protein Expression
Authors: Shrader Marissa , Pino Maria Simona , Lashinger Laura , Bar-Eli Menashe , Adam Liana , Dinney Colin P.N. , McConkey David J. 
Published: February 2007

Abstract
In a previous study, we found that the small-molecule epidermal growth factor receptor (EGFR) inhibitor gefitinib (ZD1839, Iressa) blocked cell proliferation at biologically relevant concentrations in approximately one third (6 of 17) of human bladder cancer cell lines examined. Here, we studied the effects of gefitinib on apoptosis in a representative subset of the same panel of cells. The drug had modest effects on DNA fragmentation as a single agent at concentrations that produced strong growth inhibition (≤1 μmol/L) and also failed to promote apoptosis induced by conventional chemotherapeutic agents (gemcitabine and paclitaxel). However, gefitinib did interact with recombinant human tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) to induce high levels of apoptosis in gefitinib-responsive but not gefitinib-unresponsive lines. The molecular mechanisms involved down-regulation of active AKT and X-linked inhibitor of apoptosis protein (XIAP) expression and were mimicked by chemical inhibitors of the phosphatidylinositol 3-kinase/AKT pathway but not of the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase/ERK pathway. Furthermore, direct small interfering RNA–mediated knockdown of AKT resulted in down-regulation of XIAP and TRAIL sensitization, and knockdown of XIAP itself was sufficient to reverse TRAIL resistance. Together, our results show that EGFR pathway activation limits TRAIL-induced apoptosis via an AKT- and XIAP-dependent mechanism in EGFR-dependent human bladder cancer cells, providing the conceptual framework for a further evaluation of the combination in relevant preclinical in vivo models. [Cancer Res 2007;67(4):1430–5]
PEA-15 Inhibits Tumor Cell Invasion by Binding to Extracellular Signal-Regulated Kinase 1/2
Authors: Glading Angela , Koziol James A. , Krueger Joseph , Ginsberg Mark H. 
Published: February 2007

Abstract
Phosphoprotein enriched in astrocytes of 15 kDa (PEA-15) binds to extracellular signal-regulated kinase 1 and 2 (ERK1/2) mitogen-activated protein (MAP) kinases to alter ERK1/2 cellular localization and target preferences and binds to adaptors in the extrinsic cell death pathway to block apoptosis. Here, we report that PEA-15 protein expression is inversely correlated with the invasive behavior of breast cancer in an immunohistochemical analysis of a breast cancer progression tissue microarray. Short hairpin RNA–mediated inhibition of PEA-15 expression increased the invasion of PEA-15–expressing tumor cells in vitro, suggesting a causative role for PEA-15 in the inhibition of invasion. This causative role was confirmed by the finding that the enforced expression of PEA-15 in invasive tumor cells reduced invasion. The effect of PEA-15 on tumor invasion is mediated by its interaction with ERK1/2 as shown by the following: (a) PEA-15 mutants that fail to bind ERK1/2 did not inhibit invasion; (b) overexpression of ERK1 or activated MAP/ERK kinase (MEK) reversed the inhibitory effect of PEA-15; (c) when an inhibitor of ERK1/2 activation reduced invasion, PEA-15 expression did not significantly reduce invasion further. Furthermore, we find that the effect of PEA-15 on invasion seems to relate to the nuclear localization of activated ERK1/2. PEA-15 inhibits invasion by keeping ERK out of the nucleus, as a PEA-15 mutant that cannot prevent ERK nuclear localization was not able to inhibit invasion. In addition, membrane-localized ERK1, which sequesters endogenous ERK1 to prevent its nuclear localization, also inhibited invasion. These results reveal that PEA-15 regulates cancer cell invasion via its ability to bind ERK1/2 and indicate that nuclear entry of ERK1/2 is important in tumor behavior. [Cancer Res 2007;67(4):1536–44]
Smad4 Regulates Claudin-1 Expression in a Transforming Growth Factor-β–Independent Manner in Colon Cancer Cells
Authors: Shiou Sheng-Ru , Singh Amar B. , Moorthy Krishnan , Datta Pran K. , Washington M. Kay , Beauchamp R. Daniel , Dhawan Punita 
Published: February 2007

Abstract
We have recently reported that the expression of a tight junction protein, claudin-1, is increased during colon carcinogenesis and particularly metastatic colorectal cancer. Manipulation of claudin-1 levels in colon cancer cells showed a positive correlation between claudin-1 expression and tumor growth and metastasis. However, the mechanisms underlying the increased claudin-1 expression in colorectal cancer remains unknown. The tumor suppressor Smad4 is a central intracellular signal transduction component of the transforming growth factor-β (TGF-β) family of cytokines. Loss of Smad4 protein expression is correlated with poor prognosis and is frequently observed in invasive and metastatic colorectal carcinoma. In the present study, we report an inverse relationship between Smad4 and claudin-1 expression in human colorectal carcinoma tumor samples and in human colon cancer cell lines. We found that the expression of Smad4 in Smad4-deficient but claudin-1–positive SW480 or HT29 colon cancer cell lines down-regulates claudin-1 expression through transcriptional repression by modulating β-catenin/T-cell factor/lymphocyte enhancer factor activity. Furthermore, this Smad4-dependent inhibition of claudin-1 expression is independent of TGF-β signaling because Smad4 expression alone is insufficient to restore TGF-β signaling in the SW480 cells, and the selective TGF-β receptor kinase inhibitor LY364947 did not prevent the Smad4 suppression of claudin-1 protein expression in either SW480 or HT29 cells. Taken together, these findings suggest a novel mechanism underlying Smad4 tumor–suppressive function through regulation of a potential metastatic modulator, claudin-1, in a TGF-β–independent manner. [Cancer Res 2007;67(4):1571–9]
An Emerging Role for Endothelial Nitric Oxide Synthase in Chronic Inflammation and Cancer
Authors: Ying Lei , Hofseth Lorne J. 
Published: February 2007

Abstract
Nitric oxide (NO) is a free radical that is involved in carcinogenesis. Recent literature indicates that endothelial NO synthase (eNOS) can modulate cancer-related events (angiogenesis, apoptosis, cell cycle, invasion, and metastasis). We review the literature linking eNOS to carcinogenesis to encourage future research assessing the role of eNOS in cancer prevention and treatment. [Cancer Res 2007;67(4):1407–10]
Possible Role of Semaphorin 3F, a Candidate Tumor Suppressor Gene at 3p21.3, in p53-Regulated Tumor Angiogenesis Suppression
Authors: Futamura Manabu , Kamino Hiroki , Miyamoto Yuji , Kitamura Noriaki , Nakamura Yasuyuki , Ohnishi Shiho , Masuda Yoshiko , Arakawa Hirofumi 
Published: February 2007

Abstract
Although the regulation of tumor angiogenesis is believed to be one of the core functions of p53, the mechanism still remains to be elucidated. Here, we report that semaphorin 3F (SEMA3F), an axon guidance molecule, is involved in p53-regulated antiangiogenesis. The expression level of SEMA3F mRNA was increased by both exogenous and endogenous p53. Chromatin immunoprecipitation assay indicated that a potent p53-binding sequence in intron 1 of SEMA3F interacts with p53 and that it has a p53-responsive transcriptional activity. Overexpression of SEMA3F inhibited in vitro cell growth of the lung cancer cell line H1299. In nude mice assay, the size of the H1299 tumors expressing SEMA3F was much smaller, and they showed lesser number of blood vessels as compared with the control tumors. Moreover, tumors derived from the p53-knockdown colorectal cancer cell line LS174T displayed a remarkable enhancement of tumor vessel formation as compared with control tumors containing normal levels of p53. The expression levels of SEMA3F and neuropilin-2 (NRP2), the functional receptor for SEMA3F, in p53-knockdown LS174T tumors were lower than those in the control tumors. Adenovirus-mediated SEMA3F gene transfer induced the remarkable in vitro growth suppression of the stable transformant of H1299 cells, which express high levels of NRP2. These results suggest that p53 negatively regulates tumor vessel formation and cell growth via the SEMA3F-NRP2 pathway. [Cancer Res 2007;67(4):1451–9]
Thrombospondin-1 Peptide ABT-510 Combined with Valproic Acid Is an Effective Antiangiogenesis Strategy in Neuroblastoma
Authors: Yang Qiwei , Tian Yufeng , Liu Shuqing , Zeine Rana , Chlenski Alexandre , Salwen Helen R. , Henkin Jack , Cohn Susan L. 
Published: February 2007

Abstract
In the pediatric cancer neuroblastoma, clinically aggressive disease is associated with increased levels of angiogenesis stimulators and high vascular index. We and others have hypothesized that blocking angiogenesis may be effective treatment for this pediatric malignancy. However, little is known about the efficacy of antiangiogenic agents in pediatric malignancies. Recently, promising results have been reported in an adult phase I study of ABT-510, a peptide derivative of the natural angiogenic inhibitor thrombospondin-1. Histone deacetylase inhibitors, such as valproic acid (VPA), have also been shown to have antiangiogenic activity in several cancer models. In this study, we evaluated the effects of ABT-510 and VPA on neuroblastoma tumor growth and angiogenesis. Although only VPA was capable of blocking the proliferation of neuroblastoma cells and inducing neuroblastoma cell apoptosis in vitro, treatment with VPA or ABT-510 alone significantly suppressed the growth of neuroblastoma xenografts established from two different MYCN-amplified cell lines. Combination therapy more effectively inhibited the growth of small neuroblastoma xenografts than single-agent treatment, and in animals with large xenografts, total cessation of tumor growth was achieved with this treatment approach. The microvascular density was significantly reduced in the xenografts treated with combination therapy compared with controls or tumors treated with single agents. In addition, the number of structurally abnormal vessels was reduced, suggesting that these agents may “normalize” the tumor vasculature. Our results indicate that ABT-510 combined with VPA may be an effective antiangiogenic treatment strategy for children with high-risk neuroblastoma. [Cancer Res 2007;67(4):1716–24]
Endothelin-1 and Endothelin-3 Promote Invasive Behavior via Hypoxia-Inducible Factor-1α in Human Melanoma Cells
Authors: Spinella Francesca , Rosanò Laura , Di Castro Valeriana , Decandia Samantha , Nicotra Maria Rita , Natali Pier Giorgio , Bagnato Anna 
Published: February 2007

Abstract
Endothelin (ET) B receptor (ETBR), which is overexpressed in human cutaneous melanomas, promotes tumorigenesis upon activation by ET-1 or ET-3, thus representing a potential novel therapeutic target. Hypoxia-inducible factor-1α (HIF-1α) is the transcriptional factor that conveys signaling elicited by hypoxia and growth factor receptors. Here, we investigated the interplay between ET axis and hypoxia in primary and metastatic melanoma cell lines. We report that under normoxic conditions, ETBR activation by ET-1/ET-3 enhances vascular endothelial growth factor (VEGF) up-regulation, cyclooxygenase (COX)-1/COX-2 protein expression and COX-2 promoter activity, prostaglandin E2 (PGE2) production, and do so to a greater extent under hypoxia. Moreover, COX-1/COX-2 inhibitors block ET-induced PGE2 and VEGF secretion, matrix metalloproteinase (MMP) activation, and cell invasion, indicating that both enzymes function as downstream mediators of ET-induced invasive properties. The ETBR selective antagonist BQ788 or transfection with ETBR small interfering RNA (siRNA) block the ET-mediated effects. ETs also increase HIF-1α expression under both normoxic and hypoxic conditions and its silencing by siRNA desensitizes COX-2 transcriptional activity, PGE2 and VEGF production, and MMP activation in response to ET-3, implicating, for the first time, HIF-1α/COX as downstream targets of ETBR signaling leading to invasiveness. In melanoma xenografts, specific ETBR antagonist suppresses tumor growth, neovascularization, and invasiveness-related factors. Collectively, these results identify a new mechanism whereby ET-1/ET-3/ETBR axis can promote and interact with the HIF-1α–dependent machinery to amplify the COX-mediated invasive behavior of melanoma. New therapeutic strategies using specific ETBR antagonist could provide an improved approach to the treatment of melanoma by inhibiting tumor growth and progression. [Cancer Res 2007;67(4):1725–34]
TSC1 Sets the Rate of Ribosome Export and Protein Synthesis through Nucleophosmin Translation
Authors: Pelletier Corey L. , Maggi Leonard B. , Brady Suzanne N. , Scheidenhelm Danielle K. , Gutmann David H. , Weber Jason D. 
Published: February 2007

AbstractNucleophosmin (B23) is a nucleolar phosphoprotein that has been implicated in numerous cellular processes. In particular, nucleophosmin interacts with nucleolar components of newly synthesized ribosomes to promote ribosome nuclear export. Nucleophosmin is a classic mitogen-induced protein, with changes in its expression correlating with growth factor stimulation. In this study, we examined the underlying mechanism of nucleophosmin induction and showed that hyperproliferative signals emanating from oncogenic H-RasV12 cause tremendous increases in nucleophosmin protein expression. Nucleophosmin protein accumulation was dependent on mammalian target of rapamycin (mTOR) activation, as rapamycin completely prevented nucleophosmin induction. Consistent with this finding, genetic ablation of Tsc1, a major upstream inhibitor of mTOR, resulted in nucleophosmin protein induction through increased translation of existing nucleophosmin mRNAs. Increases in nucleophosmin protein accumulation were suppressed by reintroduction of TSC1. Induction of nucleophosmin through Tsc1 loss resulted in a greater pool of actively translating ribosomes in the cytoplasm, higher overall rates of protein synthesis, and increased cell proliferation, all of which were dependent on efficient nucleophosmin nuclear export. Nucleophosmin protein accumulation in the absence of Tsc1 promoted the nuclear export of maturing ribosome subunits, providing a mechanistic link between TSC1/mTOR signaling, nucleophosmin-mediated nuclear export of ribosome subunits, protein synthesis levels, and cell growth. [Cancer Res 2007;67(4):1609–17]
Adenoviral Transduction ofMRP-1/CD9andKAI1/CD82Inhibits Lymph Node Metastasis in Orthotopic Lung Cancer Model
Authors: Takeda Takayuki , Hattori Noboru , Tokuhara Takahiro , Nishimura Yoshihiro , Yokoyama Mitsuhiro , Miyake Masayuki 
Published: February 2007

AbstractConventional therapies still remain less effective for metastasis of lung cancer, thus leading to a poor prognosis for this disorder. Although the processes involved in metastasis have not yet been clearly elucidated, our previous studies have shown that higher expression levels of MRP-1/CD9 and KAI1/CD82 in cancer cells are significantly correlated with less metastatic potency. To determine whether the gene transfer of these tetraspanins into lung tumor cells may be a useful strategy to regulate metastasis, we adopted an orthotopic lung cancer model produced by the intrapulmonary implantation of Lewis lung carcinoma (LLC) cells and evaluated the metastatic growth in the mediastinal lymph nodes using two different methods of gene delivery as follows: (a) the implantation of LLC cells preinfected with adenovirus encoding either MRP-1/CD9 cDNA, KAI1/CD82 cDNA, or LacZ gene into the mouse lung and (b) the intratracheal administration of these adenoviruses into the mice orthotopically preimplanted with LLC cells. In both cases, we found that the delivery of either MRP-1/CD9 or KAI1/CD82 cDNA dramatically reduced the metastases to the mediastinal lymph nodes in comparison with those of LacZ gene delivery, without affecting the primary tumor growth at the implanted site. These results reemphasize the important role of MRP-1/CD9 and KAI1/CD82 in the suppression of the metastatic process and also show the feasibility of gene therapy when using these tetraspanins for lung cancer to prevent metastasis to the regional lymph nodes. This strategy may therefore be clinically applicable as a prophylactic treatment to suppress the occurrence of lymph node metastasis. [Cancer Res 2007;67(4):1744–9]
Adaptation of Energy Metabolism in Breast Cancer Brain Metastases
Authors: Chen Emily I. , Hewel Johannes , Krueger Joseph S. , Tiraby Claire , Weber Martin R. , Kralli Anastasia , Becker Katja , Yates John R. , Felding-Habermann Brunhilde 
Published: February 2007

Abstract
Brain metastases are among the most feared complications in breast cancer, as no therapy exists that prevents or eliminates breast cancer spreading to the brain. New therapeutic strategies depend on specific knowledge of tumor cell properties that allow breast cancer cell growth within the brain tissue. To provide information in this direction, we established a human breast cancer cell model for brain metastasis based on circulating tumor cells from a breast cancer patient and variants of these cells derived from bone or brain lesions in immunodeficient mice. The brain-derived cells showed an increased potential for brain metastasis in vivo and exhibited a unique protein expression profile identified by large-scale proteomic analysis. This protein profile is consistent with either a selection of predisposed cells or bioenergetic adaptation of the tumor cells to the unique energy metabolism of the brain. Increased expression of enzymes involved in glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation pathways suggests that the brain metastatic cells derive energy from glucose oxidation. The cells further showed enhanced activation of the pentose phosphate pathway and the glutathione system, which can minimize production of reactive oxygen species resulting from an enhanced oxidative metabolism. These changes promoted resistance of brain metastatic cells to drugs that affect the cellular redox balance. Importantly, the metabolic alterations are associated with strongly enhanced tumor cell survival and proliferation in the brain microenvironment. Thus, our data support the hypothesis that predisposition or adaptation of the tumor cell energy metabolism is a key element in breast cancer brain metastasis, and raise the possibility of targeting the functional differentiation in breast cancer brain lesions as a novel therapeutic strategy. [Cancer Res 2007;67(4):1472–86]
Heat Shock Protein 90 and ErbB2 in the Cardiac Response to Doxorubicin Injury
Authors: Gabrielson Kathleen , Bedja Djahida , Pin Scott , Tsao Allison , Gama Lucio , Yuan Bibo , Muratore Nicole 
Published: February 2007

Abstract
A major drawback to doxorubicin as a cancer-treating drug is cardiac toxicity. To understand the mechanism of doxorubicin cardiac toxicity and the potent synergic effect seen when doxorubicin is combined with anti-ErbB2 (trastuzumab), we developed an in vivo rat model that exhibits progressive dose-dependent cardiac damage and loss of cardiac function after doxorubicin treatment. The hearts of these animals respond to doxorubicin damage by increasing levels of ErbB2 and the ErbB family ligand, neuregulin 1β, and by activating the downstream Akt signaling pathway. These increases in ErbB2 protein levels are not due to increased ErbB2 mRNA, however, suggesting post-transcriptional mechanisms for regulating this protein in the heart. Accordingly, levels of heat shock protein 90 (HSP90), a known ErbB2 protein stabilizer and chaperone, are increased by doxorubicin treatment, and coimmunoprecipitation reveals binding of HSP90 to ErbB2. Isolated cardiomyocytes are more susceptible to doxorubicin after treatment with HSP90 inhibitor, 17-(allylamino)-17-demethoxygeldanamycin, suggesting that the HSP90 is protective during doxorubicin treatment. Thus, our results provide one plausible mechanism for the susceptibility of the heart to anti-ErbB2 therapy post-doxorubicin therapy in subclinical and clinical conditions. Additionally, these results suggest that further testing is needed for HSP90 inhibitors under various conditions in the heart. [Cancer Res 2007;67(4):1436–41]