bluuebunny/crossref_metadata_2025 huggingface dataset:
Constitutive Activation of Extracellular Signal-Regulated Kinase Predisposes Diffuse Large B-Cell Lymphoma Cell Lines to CD40-Mediated Cell Death
Authors: Hollmann C. Annette , Owens Trevor , Nalbantoglu Josephine , Hudson Thomas J. , Sladek Robert
Published: April 2006

CD40 promotes survival, proliferation, and differentiation of normal B cells but can cause activation-induced cell death in malignant B lymphocytes. CD40 ligand and anti-CD40 antibodies have been used successfully to induce apoptosis in lymphoma lines both in vitro and in xenograft tumor models. Although this makes CD40 an attractive target for antitumor therapies, the response of malignant B cells to CD40 signaling is variable, and CD40 stimulation can enhance proliferation and can increase chemoresistance in some cell lines. It would therefore be useful to identify markers that predict whether a specific cell line or tumor will undergo apoptosis when stimulated with CD40 and to identify targets downstream of CD40 that affect only the apoptotic arm of CD40 signaling. We have analyzed gene expression patterns in CD40-sensitive and CD40-resistant diffuse large B-cell lymphoma (DLBCL) cell lines to identify signaling pathways that are involved in CD40-mediated apoptosis. CD40-resistant lines expressed pre-B-cell markers, including RAG and VPREB, whereas CD40-sensitive cells resembled mature B cells and expressed higher levels of transcripts encoding several members of the CD40 signaling pathway, including LCK and VAV. In addition, CD40-sensitive DLBCL cell lines also displayed constitutive activation of extracellular signal-regulated kinase (ERK) and failed to undergo apoptosis when ERK phosphorylation was inhibited. In contrast, CD40-resistant lines showed no constitutive activation of ERK and no increase in ERK activity in response to CD40 stimulation. Our results suggest that constitutive activation of ERK may be required for death signaling by CD40. (Cancer Res 2006; 66(77):3550-7)
Onset of Abnormal Blood and Lymphatic Vessel Function and Interstitial Hypertension in Early Stages of Carcinogenesis
Authors: Hagendoorn Jeroen , Tong Ricky , Fukumura Dai , Lin Qingcong , Lobo Jennifer , Padera Timothy P. , Xu Lei , Kucherlapati Raju , Jain Rakesh K.
Published: April 2006

Recent improvements in diagnostic methods have opened avenues for detection and treatment of (pre)malignant lesions at early stages. However, due to the lack of spontaneous tumor models that both mimic human carcinogenesis and allow direct optical imaging of the vasculature, little is known about the function of blood and lymphatic vessels during the early stages of cancer development. Here, we used a spontaneous carcinogenesis model in the skin of DNA polymerase η–deficient mice and found that interstitial fluid pressure was already elevated in the hyperplastic/dysplastic stage. This was accompanied by angiogenic blood vasculature that exhibited altered permeability, vessel compression, and decreased α-smooth muscle actin–positive perivascular cell coverage. In addition, the lymphatic vessels in hyperplastic/dysplastic lesions were partly compressed and nonfunctional. These novel insights may aid early detection and treatment strategies for cancer. (Cancer Res 2006; 66(7): 3360-4)
ERBB2-Mediated Transcriptional Up-regulation of the α5β1 Integrin Fibronectin Receptor Promotes Tumor Cell Survival Under Adverse Conditions
Authors: Spangenberg Christian , Lausch Ekkehart U. , Trost Tatjana M. , Prawitt Dirk , May Andreas , Keppler Romy , Fees Stephan A. , Reutzel Dirk , Bell Carolin , Schmitt Steffen , Schiffer Ilka B. , Weber Achim , Brenner Walburgis , Hermes Matthias , Sahin Ugur , Türeci Özlem , Koelbl Heinz , Hengstler Jan G. , Zabel Bernhard U.
Published: April 2006

Oncogenic activation of the receptor tyrosine kinase ERBB2 is a key event in the development of a number of epithelial malignancies. In these tumors, high levels of ERBB2 are strongly associated with metastatic disease and poor prognosis. Paradoxically, an inherent cellular response to hypermitogenic signaling by ERBB2 and other oncogenes seems to be growth arrest, rather than proliferation. Molecular characterization of this yet undefined antiproliferative state in independent cell lines overexpressing either wild-type ERBB2 or the mutationally activated receptor unveiled a dramatic induction of the α5β1 integrin fibronectin receptor. α5 Integrin up-regulation is mainly a transcriptional response mediated by the hypoxia-inducible transcription factors (HIF), leading to a massive increase in membrane-resident receptor molecules and enhanced fibronectin adhesiveness of the respective cells. Functionally, ERBB2-dependent ligation of fibronectin results in improved survival of mammary adenocarcinoma cells under adverse conditions, like serum withdrawal, hypoxia, and chemotherapy. HIF-1α is an independent predictor of poor overall survival in patients with breast cancer. In particular, HIF-1α overexpression correlates significantly with early local relapse and distant metastasis, a phenotype also highly characteristic of ERBB2-positive tumors. As HIF-1α is known to be stabilized by ERBB2 signaling under normoxic conditions, we propose that α5 integrin is a major effector in this regulatory circuit and may represent the molecular basis for the HIF-1α-dependent aggressiveness observed in ERBB2-overexpressing breast carcinomas. Hypermitogenic ERBB2 signaling and tumor hypoxia may act synergistically to favor the establishment of chemoresistant dormant micrometastatic cells frequently observed in patients with breast cancer. This new insight could be the basis for additional approaches complementing current cancer therapy. (Cancer Res 2006; 66(7): 3715-25)
Rational Design of the Microtubule-Targeting Anti–Breast Cancer Drug EM015
Authors: Aneja Ritu , Lopus Manu , Zhou Jun , Vangapandu Surya N. , Ghaleb Amr , Yao Joyce , Nettles James H. , Zhou Binfei , Gupta Meenakshi , Panda Dulal , Chandra Ramesh , Joshi Harish C.
Published: April 2006

We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, π-π, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti–breast cancer agent and displays a 20-fold lower IC50 against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]-dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic. (Cancer Res 2006; 66(7): 3782-91)
5-Amino-4-Imidazolecarboxamide Riboside Potentiates Both Transport of Reduced Folates and Antifolates by the Human Reduced Folate Carrier and Their Subsequent Metabolism
Authors: McGuire John J. , Haile William H. , Yeh Chen-Chen
Published: April 2006

Transport is required before reduced folates and anticancer antifolates [e.g., methotrexate (MTX)] exert their physiologic functions or cytotoxic effects. The folate/antifolate transporter with the widest tissue distribution and greatest activity is the reduced folate carrier (RFC). There is little evidence that RFC-mediated influx is posttranscriptionally regulated. We show that [3H]MTX influx in CCRF-CEM human childhood T-leukemia cells is potentiated up to 6-fold by exogenous 5-amino-4-imidazolecarboxamide riboside (AICAr) in a AICAr and MTX concentration–dependent manner. Metabolism to more biologically active polyglutamate forms is also potentiated for MTX and other antifolates. That potentiation of influx by AICAr is mediated by effects on the RFC is supported by analyses ±AICAr showing (a) similarity and magnitude of kinetic constants for [3H]MTX influx; (b) similarity of inhibitory potency of known RFC substrates; (c) lack of potentiation in a CCRF-CEM subline that does not express the RFC; and (d) similarity of time and temperature dependence. Potentiation occurs rapidly and does not require new protein synthesis. Effects of specific inhibitors of folate metabolism and the time and sequence of AICAr incubation with cells suggest that both dihydrofolate reductase inhibition and metabolism of AICAr are essential for potentiation. Acute folate deficiency or incubation of CCRF-CEM with AICAr-related metabolites (e.g., adenosine) does not initiate potentiation. AICAr increases growth inhibitory potency of MTX and aminopterin against CCRF-CEM cells when both AICAr and antifolate are present for the first 24 hours of a 120-hour growth period. AICAr is the first small molecule that regulates RFC activity. (Cancer Res 2006; 66(7): 3836-44)
N-cadherin Gene Expression in Prostate Carcinoma Is Modulated by Integrin-Dependent Nuclear Translocation of Twist1
Authors: Alexander Nelson R. , Tran Nhan L. , Rekapally Harish , Summers Carol E. , Glackin Carlotta , Heimark Ronald L.
Published: April 2006

The gain of N-cadherin expression in carcinomas has been shown to be important in the regulation of cell migration, invasion, and survival. Here, we show that N-cadherin mRNA expression in PC-3 prostate carcinoma cells is dependent on β1 integrin–mediated cell adhesion to fibronectin and the basic helix-loop-helix transcription factor Twist1. Depletion of Twist1 mRNA by small interfering RNA resulted in decreased expression of both Twist1 and N-cadherin and the inhibition of cell migration. Whereas Twist1 gene expression was independent of β1 integrin–mediated adhesion, Twist1 protein failed to accumulate in the nuclei of cells cultured in anchorage-independent conditions. The increased nuclear accumulation of Twist1 following cell attachment was suppressed by treatment with an inhibitor of Rho kinase or a β1 integrin neutralizing antibody. The effect of Twist1 on induction of N-cadherin mRNA required an E-box cis-element located within the first intron (+2,627) of the N-cadherin gene. These data raise the possibility that integrin-mediated adhesion to interstitial matrix proteins during metastasis differentially regulates the nuclear/cytoplasmic translocation and DNA binding of Twist1, activating N-cadherin transcription. (Cancer Res 2006; 66(7): 3365-9)
A Genetically Engineered Anti-CD45 Single-Chain Antibody-Streptavidin Fusion Protein for Pretargeted Radioimmunotherapy of Hematologic Malignancies
Authors: Lin Yukang , Pagel John M. , Axworthy Donald , Pantelias Anastasia , Hedin Nathan , Press Oliver W.
Published: April 2006

Acute myelogenous leukemia (AML) currently kills the majority of afflicted patients despite combination chemotherapy and hematopoietic cell transplantation (HCT). Our group has documented the promise of radiolabeled anti-CD45 monoclonal antibodies (Ab) administered in the setting of allogeneic HCT for AML, but toxicity remains high, and cure rates are only 25% to 30% for relapsed AML. We now show the superiority of pretargeted radioimmunotherapy (PRIT) compared with conventional radioimmunotherapy using a recombinant tetravalent single-chain Ab-streptavidin (SA) fusion protein (scFv4SA) directed against human CD45, administered sequentially with a dendrimeric N-acetylgalactosamine–containing clearing agent and radiolabeled 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic (DOTA)-biotin. The scFv4SA construct was genetically engineered by fusing Fv fragments of the human CD45-specific BC8 Ab to a full-length genomic SA gene and was expressed as a soluble tetramer in the periplasmic space of Escherichia coli. The fusion protein was purified to >95% homogeneity at an overall yield of ∼50% using iminobiotin affinity chromatography. The immunoreactivity and avidity of the fusion protein were comparable with those of the intact BC8 Ab, and the scFv4SA construct bound an average of 3.9 biotin molecules out of four theoretically possible. Mouse lymphoma xenograft experiments showed minimal toxicity, excellent tumor-specific targeting of the fusion protein and radiolabeled DOTA-biotin in vivo, marked inhibition of tumor growth, and cured 100% of mice bearing CD45-expressing tumors. These promising results have prompted large-scale cGMP production of the BC8 fusion protein for clinical trials to be conducted in patients with hematologic malignancies. (Cancer Res 2006; 66(7): 3884-92)
The Influence of a Human Embryonic Stem Cell–Derived Microenvironment on Targeting of Human Solid Tumor Xenografts
Authors: Tzukerman Maty , Rosenberg Tzur , Reiter Irena , Ben-Eliezer Shoshana , Denkberg Galit , Coleman Raymond , Reiter Yoram , Skorecki Karl
Published: April 2006

The awareness of the important role that the surrounding tissue microenvironment and stromal response play in the process of tumorigenesis has grown as a result of in vivo models of tumor xenograft growth in immunocompromised mice. In the current study, we used human embryonic stem cells in order to study the interactions of tumor cells with the surrounding microenvironment of differentiated human cell tissues and structures. Several cancer cell types stably expressing an H2A-green fluorescence protein fusion protein, which allowed tracking of tumor cells, were injected into mature teratomas and developed into tumors. The salient findings were: (a) the observation of growth of tumor cells with high proliferative capacity within the differentiated microenvironment of the teratoma, (b) the identification of invasion by tumor cells into surrounding differentiated teratoma structures, and (c) the identification of blood vessels of human teratoma origin, growing adjacent to and within the cancer cell–derived tumor. Mouse embryonic stem cell–derived teratomas also supported cancer cell growth, but provided a less suitable model for human tumorigenesis studies. Anticancer immunotherapy treatment directed against A431 epidermoid carcinoma cell–related epitopes induced the complete regression of A431-derived tumor xenografts following direct i.m. injection in immunocompromised mice, as opposed to corresponding tumors growing within a human embryonic stem cell–derived microenvironment, wherein remnant foci of viable tumor cells were detected and resulted in tumor recurrence. We propose using this novel experimental model as a preclinical platform for investigating and manipulating the stromal response in tumor cell growth as an additional tool in cancer research. (Cancer Res 2006; 66(7): 3792-801)
Signal Transducer and Activator of Transcription 1 Activation in Endothelial Cells Is a Negative Regulator of Angiogenesis
Authors: Battle Traci E. , Lynch Rebecca A. , Frank David A.
Published: April 2006

To determine the role of the transcription factor signal transducer and activator of transcription (STAT) 1 on endothelial cell function, human umbilical vein endothelial cells (HUVEC) were treated with IFN-γ, a potent activator of STAT1. IFN-γ inhibited cell growth and tube formation of HUVECs. Although the potent proangiogenic protein vascular endothelial growth factor (VEGF) stimulated cell growth and tube formation, IFN-γ could suppress these effects of VEGF. Transfection of HUVECs with short interfering RNA targeting STAT1 abrogated IFN-γ–induced inhibition of HUVEC growth and tube formation, and suppressed the inhibition of VEGF-induced tube formation by IFN-γ, indicating that STAT1 is critical for this process. IFN-γ blocks the biological activity of VEGF through inhibition of genes necessary for the VEGF response, including angiopoietin-2, urokinase plasminogen activator, tissue inhibitor of matrix metalloproteinase-1, cyclooxygenase-2, and VEGF receptor 2. To extend these findings in vivo, the role of STAT1 in angiogenesis was examined in STAT1-deficient mice using the Matrigel in vivo angiogenesis assay. Substantial cellular infiltration and formation of vascular structures occurred in STAT1−/− mice compared with wild-type controls. These data indicate that STAT1 plays a key role in the inhibition of angiogenesis through its action within endothelial cells, and exploiting this process may be useful in treating cancers and vascular tumors. (Cancer Res 2006; 66(7): 3649-57)
Contributions of Human Tumor Xenografts to Anticancer Drug Development
Authors: Sausville Edward A. , Burger Angelika M.
Published: April 2006

Mouse models of cancer have consistently been used to qualify new anticancer drugs for study in human clinical trials. The most used models include transplantable murine tumors grown in syngeneic hosts and xenografts of human tumors grown in immunodeficient mice. For the latter systems, retrospective preclinical-clinical correlation studies are available, which suggest that improvements must be made to increase their value. Transgenic, knock-out, and knock-in mouse models and their intercrosses are more recent developments that mirror defined steps of human carcinogenesis. However, their value in predicting clinical results remains to date poorly defined. We take the position that properly used and interpreted human tumor xenografts grown in immunodeficient mice can be useful, although not absolutely predictive of behavior in the clinic, and continue to make contributions to critical clinical development choices. (cancer Res 2006;66(7):3351-4)
A Single Nucleotide Polymorphism Chip-Based Method for Combined Genetic and Epigenetic Profiling: Validation in Decitabine Therapy and Tumor/Normal Comparisons
Authors: Yuan Eric , Haghighi Fatemeh , White Susan , Costa Ramiro , McMinn Julie , Chun Kathy , Minden Mark , Tycko Benjamin
Published: April 2006

Progress on several unresolved issues in cancer epigenetics will benefit from rapid and standardized methods for profiling DNA methylation genome-wide. In the area of epigenetic therapy, the demethylating drug decitabine (5-aza-2′-deoxycytidine) is increasingly used to treat acute myelogenous leukemia and myelodysplastic syndrome, but the mechanisms of its anticancer activity have remained unclear. Given the clinical efficacy of decitabine and the uncertainties about its mode of action, it will be useful to optimize methods for following DNA methylation as a biochemical response in individual patients. Here, we describe a single nucleotide polymorphism (SNP) chip-based method (MSNP) for profiling DNA methylation. Using this procedure, the extent of demethylation in bone marrow aspirates from patients with leukemia receiving decitabine can be assessed genome-wide using commercially available (Affymetrix) SNP chips. We validated the accuracy of MSNP by comparing the results with combined bisulfite restriction analysis and by sequencing cloned PCR products from bisulfite-converted DNA. We further validated MSNP in a Wilms' tumor/normal kidney comparison, comparing the results with methylation-sensitive Southern blotting. MSNP simultaneously detects aberrations in DNA copy number and loss of heterozygosity, making it a generally useful approach for combined genetic and epigenetic profiling in tissue samples from cancer patients. (Cancer Res 2006; 66(7): 3443-51)
Cyclooxygenase 2 Rescues LNCaP Prostate Cancer Cells from Sanguinarine-Induced Apoptosis by a Mechanism Involving Inhibition of Nitric Oxide Synthase Activity
Authors: Huh Jacob , Liepins Andrejs , Zielonka Jacek , Andrekopoulos Christopher , Kalyanaraman Balaraman , Sorokin Andrey
Published: April 2006

Expression of cyclooxygenase-2 (Cox-2), an inducible enzyme responsible for the production of prostaglandins from arachidonic acid, is elevated in human prostate tumor samples. The aim of this study was to investigate whether expression of Cox-2 is effective against prostate cancer cell apoptosis triggered by sanguinarine, the quaternary benzophenanthridine alkaloid with antineoplastic properties. Sanguinarine effectively induced apoptosis in LNCaP human prostate cancer epithelial cells as assessed by caspase-3 activation assay, Annexin V staining assay, or by visual analysis for the apoptotic morphology changes. Sanguinarine-mediated apoptosis was associated with the increase of nitric oxide (NO) formation in prostate cancer cells as assessed by measurements of nitrites with Sievers nitric oxide analyzer as well as flow cytometry analysis using NO fluorescent sensor. Activation of NO synthase (NOS) activity was crucial for sanguinarine-induced cell death because NOS inhibitor L-NMMA efficiently protected cells from apoptosis. Adenovirus-mediated transfer of Cox-2 into LNCaP cells inhibited sanguinarine-induced apoptosis and prevented an increase in NO production. Surprisingly, NO donors failed to induce apoptosis in LNCaP cells, suggesting that constitutive NO generation is not sufficient for triggering apoptosis in these cells. Besides NO generation, NOS is also capable of producing superoxide radicals. Sanguinarine-induced production of superoxide radicals, and the addition of MnTBAP, a scavenger of superoxide radicals, efficiently inhibited sanguinarine-mediated apoptosis. These results suggest that Cox-2 expression rescues prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of NOS activity, and that coadministration of Cox-2 inhibitors with sanguinarine may be developed as a strategy for the management of prostate cancer. (Cancer Res 2006; 66(7): 3726-36)
Using Chemopreventive Agents to Enhance the Efficacy of Cancer Therapy
Authors: Sarkar Fazlul H. , Li Yiwei
Published: April 2006

Emerging evidence suggests that cancer preventative agents might be combined with chemotherapy or radiotherapy for the more effective treatment of cancer. Recent studies suggest that genistein and other dietary compounds that prevent cancer may enhance the efficacy of cancer therapeutics by modifying the activity of key cell proliferation and survival pathways, such as those controlled by Akt, nuclear factor-κB, and cyclooxygenase-2. In this article, we summarize the findings of recent investigations of chemopreventive agents in combination with cancer treatment regimens. (Cancer Res 2006; 66(7):3347-50)
Signal Transduction Induced by Opioids in Immune Cells: A Review
Authors: Martin-Kleiner Irena , Balog Tihomir , Gabrilovac Jelka
Published: April 2006

New data regarding signal transduction triggered by opioid ligands in immune cells are reviewed, and the signal transduction in neuronal cells is documented. Similar signaling pathways are induced by opioids in immune as well as neuronal cells. Opioids altered second messenger cAMP, intracellular calcium, and second messenger-induced kinases in immune cells. Met-enkephalin, preferentially δ-opioid, was bimodally regulated, while ĸ-opioids inhibited these second messengers. δ-, ĸ- and µ-opioids altered nitric oxide secretion, inducing cGMP as the second messenger in immune cells. Coupling of opioid agonists to opioid receptors activated mitogen-activated protein/extracellular signal-regulated protein kinases and various transcription factors in immune cells. Activator protein 1 (AP-1), c-fos, and nuclear factor-ĸB (NF-ĸB) are transcription factors shared by neuronal and immune cells. δ-Opioids activated AP-1, c-fos, activating transcription factor 2, Ikaros-1 and Ikaros-2 transcription factors in immune cells. Induction of ĸ-opioid receptor gene by retinoic acid resulted in increased binding of Sp1 transcription factor to the promoter of the ĸ-opioid receptor. µ-Opioids inhibited synthesis of common transcription factors AP-1, c-fos, NF-ĸB, and nuclear factor of activated T cells in activated or stimulated immune cells, whereas µ-opioids activated NF-ĸB, GATA-3, and Kruppel-like factor 7 transcription factors in non-stimulated immune cells.
Relation between Laterality and Immune Response after Acute Cerebral Ischemia
Authors: Koch H.J. , Uyanik G. , Bogdahn U. , Ickenstein G.W.
Published: April 2006

Objective: During the last 2 decades, right/left hemisphere dominance was supposed to affect the immune system differently. Experimental and clinical observations indicate that the left hemisphere plays a crucial role in the development of the immune system. The true relationship between immune response and acute ischemic stroke laterality remains to be elucidated. Methods: We studied acute right-handed stroke patients admitted to a single acute neurology department with a specialized stroke unit. Being part of our clinical protocol, blood samples were taken within the first 24 h after the onset of stroke symptoms. The medical record of each patient was reviewed, and demographic, clinical laboratory (key criteria: C-reactive protein, CRP, and white blood cell count, WBC) and neuroimaging information was retrieved. All data were presented descriptively, and bivariate test statistics, ANOVA (log-transformed data) or linear correlations were calculated. Results: Fifty-six of the 187 patients admitted to our Stroke Unit between October 2003 and March 2004 with different stroke subtypes according to the TOAST criteria were retrospectively evaluated in order to characterize the impact of stroke laterality on immunoregulatory response measured by CRP levels and WBC. Correlation analysis revealed that left-sided ischemic stroke yielded a significantly higher correlation between CRP levels and WBC. Following left-sided stroke, a more marked variability in CRP and WBC was found compared to patients with right-sided ischemic stroke, although ANOVA did not show significant differences between immune response values as a function of stroke subtypes. Conclusions: We identified an association between stroke laterality and immunoregulatory response in patients with acute ischemic stroke. Left-sided stroke may be considered as a direct risk factor for infectious disease or immune deficits and should attract special attention. However, these preliminary results need be confirmed by controlled studies.
Interactions between Angiotensin ll and Atrial Natriuretic Peptide in Renomedullary Interstitial Cells: The Role of Neutral Endopeptidase
Authors: Maric Christine , Zheng Wei , Walther Thomas
Published: April 2006

Background/Aims: Neutral endopeptidase (NEP) inhibition attenuates renal damage in the diabetic kidney, but little is known about the mechanisms of this renoprotective effect. Methods: We examined the interaction between angiotensin II (Ang II) and atrial natriuretic peptide (ANP) under low (5 mM) and high (30 mM) glucose conditions, on cell proliferation and extracellular matrix (ECM) synthesis in renomedullary interstitial cells (RMICs) derived from wild-type (WT) and NEP-deficient (NEP–) mice. Results: Under high glucose conditions, Ang II (10–6M) increased cell proliferation (control, 174.3 ± 16.9; Ang II, 846.3 ± 91.0 cpm/well) and ECM synthesis (control, 22.3 ± 3.1; Ang II, 79.0 ± 9.6 cpm/cell) in RMICs derived from WT and NEP– mice to a similar extent. ANP (10–7M) reduced Ang II-induced cell proliferation and ECM synthesis in RMICs derived from both strains, but more efficiently in RMICs derived from NEP–mice. The Ang II-induced cell proliferation and ECM synthesis was attenuated with AT1 receptor blockade, but more efficiently in RMICs-derived NEP– mice. Conclusions: This data shows that ANP and AT1 receptor blockade attenuate Ang II-induced RMIC proliferation and ECM synthesis more efficiently in the absence of NEP. These results support the concept that NEP inhibition is beneficial in attenuating abnormal cell growth and ECM metabolism associated with diabetic nephropathy.
Rescuing the Literary in Black Studies
Authors: Temple Christel N.
Published: April 2006

Maulana Karenga ends the “Creative Production” chapter in Introduction to Black Studieswith a justifiable, negative critique of literature's modern lapse into types of detachment and personal gratification that are antithetical to the Black studies enterprise. Scholars have embraced this negative critique of the possibilities of literature to contribute to the problem-solving activities of the discipline. Karenga's critique is required study for the discipline as he issues a call for discourse “to provoke and expand the discussion, not to close or avoid it.” This essay is a response, provoked by Karenga, that evaluates axiological and epistemological variables of the academy, the discipline of Black studies, and African culture that support the rescue of the literary in Black studies.
The Web of Managerial Accountability
Authors: Page Stephen
Published: April 2006

This article examines how government reinvention affects the accountability of public managers to different stakeholders by comparing the reinvention of federal welfare, education, and environmental programs. It maps the various accountability relationships surrounding public managers and investigates how reinvention has influenced each of them. The findings reveal no consistent pattern of change across accountability relationships but suggest three hypotheses about the impact of reinvention. The hypotheses suggest different ways that administrative reforms affect the politics of public management: They change the balance of relationships and mechanisms that different stakeholders use to hold program managers and staff to account. In the process, they increase some stakeholders' program influence and disempower others.
Democracy and Prostitution
Authors: Wagenaar Hendrik
Published: April 2006

This article discusses democratic deliberation as a core element of public administration in today's decentered world of governance. The juxtaposition of hierarchy and deliberation in policy networks is illustrated with the case of the legalization of brothels in the Netherlands. The case shows that despite distrust and conflict, the actors managed, through deliberative elements in negotiations, to attain the transformation of the prostitution sector into a regular business sector. However, the use of a deliberative implementation strategy did not preclude the emergence of negative, unintended consequences. The success or failure of the deliberative process is sensitive to its design, particularly the issue of who is included and excluded. A deliberative, collaborative approach to policy implementation has the potential to optimize social and cognitive capital. This is seen as a precondition for the constant, painful redesign of policies in the face of conflict and contingency that characterize successful policy implementation.
Accountability and the Evil of Administrative Ethics
Authors: Dubnick Melvin J. , Justice Jonathan B.
Published: April 2006

Scholars of administrative ethics have recently been attentive to the problem of so-called administrative evil. The authors argue that evil can be understood as a socially constructed category of agents and acts specific to particular circumstances and moral communities, and the authors apply a framework of accountability to reflect the dynamics of that constructed reality. Selected examples of efforts to hold evil actors accountable or otherwise to account for evil acts illustrate a paradox: Responses to so-called evil may themselves be labeled evil in hindsight or by members of other contemporaneous communities. In light of this paradox and attendant ethical dilemmas, the authors argue that conventional ethical and behavioral prescriptions are necessary but insufficient protections against catastrophic mis-, mal-, or nonfeasance in and by organizations.
Beyond Guanxi: Network Contingencies in Taiwanese Business Groups
Authors: Chung Chi-Nien
Published: April 2006

Business groups consisting of legally independent affiliates with institutionalized relationships with each other exist in almost every market economy. While the groups are important and pervasive, little attention has been paid to the processes by which business groups emerge and grow. Reasons for this gap include a) a deficiency of the top-down, macro perspective of many business group studies, and b) the overemphasis of Guanxi networks in the literature of business organizations in East Asia. Personal relationships ( Guanxi) are treated as the necessary and sufficient condition for the entrepreneurship and evolution of business groups. In an attempt to refine the Guanxi perspective, the author uses case studies of five major Taiwanese business groups to propose a set of contingency factors. The suggestion offered in this paper is that entrepreneurs’ attributes and contextual factors are inseparable from the functions of the Guanxi network in the entrepreneurial process. Tracing the movements of these groups over the past four decades, it appears that group diversification evolves in a path-dependent fashion as opposed to a Guanxi-driven, idiosyncratic pattern as suggested by the Guanxi perspective. The influences of Guanxi for group diversification were clear in the early stages when markets were tightly controlled and the personalistic networks became the core capabilities underlining diversification. However, as groups grew and institutions developed, the significance of political Guanxi diminished and the decision-making of diversification strategy became hinged mainly upon the resources firm accumulated overtime.
Organizational Characteristics as Predictors of Nurses’ Psychological Work Reactions
Authors: Tummers Gladys E. R. , van Merode Godefridus G. , Landeweerd Jan A.
Published: April 2006

The current study aims to examine effects of organizational characteristics (decision authority and environmental uncertainty) on nurses’ psychological work reactions (job satisfaction and intrinsic work motivation; burnout and health complaints). In this context, we were primarily interested in the congruence between decision authority and environmental uncertainty. The contingency approach of organizations was used as a leading framework. In order to investigate these relationships, questionnaires were administered to 1188 nurses working in general hospitals in the Netherlands. Because the standardization of tasks is expected to be different between intensive care units (ICUs) and non-ICUs, and consequently, this difference might influence the effects of organizational characteristics on psychological work reactions, the relationships were investigated separately for each type of unit. Correlation and hierarchical regression analysis were used to analyse the data. From the results of these analyses, it appeared that decision authority has a positive effect on intrinsic work motivation in both types of unit. In addition to this additive effect, the congruence between decision authority and environmental uncertainty was confirmed, but only in ICUs. It appeared that high environmental uncertainty would enhance the positive effect of decision authority on intrinsic work motivation. Furthermore, the congruence between decision authority and environmental uncertainty in the prediction of burnout and psychosomatic health complaints was not confirmed: high decision authority appeared not to buffer the negative effect of environmental uncertainty on burnout and health complaints. The results are discussed as well as the limitations of the study. Suggestions for further research are also given.
Nitrogen mineralization and nitrate leaching of a sandy soil amended with different organic wastes
Authors: Burgos Pilar , Madejón Engracia , Cabrera Francisco
Published: April 2006

Organic wastes can be recycled as a source of plant nutrients, enhancing crop production by improving soil quality. However, the study of the dynamic of soil nutrient, especially the N dynamic, after soil application of any organic material is vital for assessing a correct and effective use of the material, minimizing the losses of nitrate in leachates and avoiding the negative environmental effects that it may cause in groundwater. To estimate the effect of three organic materials, a municipal solid waste compost (MWC), a non-composted paper mill sludge (PS), and an agroforest compost (AC) on the N dynamic of a sandy soil two experiments were carried out: an incubation experiment and a column experiment. The incubation experiment was conducted to estimate the N mineralization rate of the different soil-amendment mixtures. The soil was mixed with the organic amendments at a rate equivalent to 50 000 kg ha-1 and incubated during 40 weeks at constant moisture content (70% of its water-holding capacity) and temperature (28°C) under aerobic conditions. Organic amendment-soil samples showed an immobilization of N during the first weeks, which was more noticeable and longer in the case of PS-treated soil compared to the other two amendments due to its high C/N ratio. After this immobilization stage, a positive mineralization was observed for all treatment, especially in MWC treated soil. Contemporaneously a 1-year column (19 cm diameter and 60 cm height) experiment was carried out to estimate the nitrate losses from the soil amended with the same organic materials. Amendments were mixed with the top soil (0-15 cm) at a rate equivalent to 50 000 kg ha-1. The columns were periodically irrigated simulating rainfall in the area of study, receiving in total 415 mm of water, and the water draining was collected during the experimental period and analysed for NO3-N. At the end of the experimental period NO3-N content in soil columns at three depths (0-20, 20-35 and 35-50 cm) was determined. The nitrate concentration in drainage water confirmed the results obtained in the incubation experiment: nitrate leaching was higher in soil treated with MWC due to its higher N-mineralization rate. Nevertheless, the nitrate losses represented a low amount compared with the total nitrogen added to soil. No clear signs of water-draining contamination were observed during the first year after the application of AC and PS; however, the nitrate leaching in soil treated with MWC slightly exceeded the limit allowed for the Drinking Water Directive 98/83/CE.
Leaching of heavy metals in acid mine drainage
Authors: Saria Lana , Shimaoka Takayuki , Miyawaki Kentaro
Published: April 2006

Acid mine drainage is one of the most serious environmental problems that the coal and metal mining industry is currently facing. The generation of low pH drainage enhances the dissolution of heavy metals in water. The samples used in this research originated from three pits at mine dumps. In a study reported in this paper, three types of tests; namely static test, kinetic test and column test were conducted to estimate acid generation and acid neutralization reaction rates, and to predict the solubility of metals and their release rates. Static test showed that all samples had a pH of net acid generation (NAG pH) < 4, a net acid producing potential (NAPP) > 10 kg H2SO4tonne-1, and a S-content > 3%, which can be classified as a high acid-forming capacity. Simulated runoff in the column tests was equivalent to 5-year average rainfall in Indonesia, the resultant leachates showed acidic behaviour (pH < 3.5). Based on the results, it was found that high mobilization of heavy metals (Cr, Cu, Zn, Cd and Pb) takes place under strong acidic conditions (pH ≅ 2).
Evaluation of Bangkok sewage sludge for possible agricultural use
Authors: Pasda Nuanjun , Panichsakpatana Supamard , Limtong Pitayakon , Oliver Robert , Montange Denis
Published: April 2006

Bangkok (Thailand) covers more than 1 500 km2 and has 10 million inhabitants. The disposal of wastewater is creating huge problems of pollution. The estimated amount of sewage sludge was estimated to be around 108 tonnes dry matter (DM) per day in 2005. In order to find a lasting way of disposal for this sewage sludge, the suitability of the sludge produced from three waste-water treatment plants for use as fertilizing material was investigated. Monthly samplings and analysis of sewage sludge from each plant showed that the composition of sludge varied according to the area of collection and period of sampling, and there was no link to rainfall cycle. Plant nutrient content was high (i.e. total N from 19 to 38 g kg-1 DM) whereas organic matter content was low. The concentrations of heavy metals varied between sludge samples, and were sometimes higher than the EU or US regulations for sewage sludge use in agriculture. Faecal coliforms were present in the sludge from one of the plants, indicating a possible contamination by night soil. In order to decrease this potentially pathogenic population the sewage sludge should be heated by composting. As the C/N ratio of sewage sludge was low (around 6) some organic by-products with high carbon content could be added as structural material to enhance the composting.
Design Concept for the Development of Cylinder Drives based on Electrorheological Fluids
Authors: Zaun M.
Published: April 2006

This article deals with the practical use of electrorheological fluids (ERFs). At the Institute for Fluid Power Drives and Control (IFAS), a test rig has already been in use for several years and different applications have been investigated with it. During these investigations, information about the various influences on the ER effect, in terms of yield stress and current density, could be gathered. Due to the improvement of the ERF itself and the associated components, it is now possible to build up cylinder drives with improved forces and dynamic behavior. Nevertheless, there is still a lack of design rules and design aids for applications based on ERFs till today. After introducing some of the applications developed at IFAS, this article presents the latest measurements of valves based on ERFs. Knowing the influence of geometric parameters on the ER effect, a mathematical model has been adapted to the fluid used in recent measurements. It is also shown that a modular design of the cylinder drives makes the setup of the simulation model possible and enables the application engineer to carry out an accurate measurement.
Cable Vibration Control using Magnetorheological Dampers
Authors: Duan Y. F. , Ni Y. Q. , Ko J. M.
Published: April 2006

As the world's first implementation of magnetorheological (MR) smart damping technique in bridge structures, a total of 312 semi-active MR dampers (RD-1005, Lord Corporation) have recently been installed for rain–wind-induced cable vibration control on the cable-stayed Dongting Lake Bridge, China. This project has undergone several stages of in situ experiments and tests: (i) modal tests of undamped cables, (ii) forced vibration tests of MR-damped trial cables, (iii) monitoring of MR-damped and undamped cable responses under rain–wind excitations, (iv) comparative tests using different damper setups, (v) full installation, and (vi) field measurements and real-time control tests after the installation. After outlining the above six stages of the whole project and addressing the experience and lessons learned from both open-loop control and closed-loop control practices, this study focuses on the design considerations of implementing MR dampers for cable vibration control, taking into account the effects of the damper stiffness, damper mass, stiffness of damper support, nonlinearity of the damper, and sag and inclination of the cable. The research efforts make it possible to develop elaborate MR dampers specific for application to bridge stay cables.
Promoting Student Interest in Mental Health Nursing
Authors: Stuhlmiller Cynthia M.
Published: April 2006

Factors related to undergraduate nursing education are among the issues inhibiting interest in mental health nursing as a field of practice. To gain more understanding about views about mental health nursing, a survey was conducted with undergraduate nursing students at a major university in Australia after implementation of a mental health nursing course. The data provide information about student beliefs, concerns, and how mental health nursing might be promoted.
A Faith-Based Integrated Substance Abuse and HIV Prevention Program for Rural African American Adolescents
Authors: Brown Emma J. , Wells Sean
Published: April 2006

The purpose of this daylong workshop was to reach consensus about a prevention program to decrease risk and increase resiliency behaviors associated with substance abuse and HIV among rural adolescents in faith-based settings. The process and outcomes of the workshop are described. Workshop participants validated and prioritized risk and resiliency factors associated with substance abuse and HIV infection and used these to decide between potential prevention programs. A substance abuse (All Stars) program and an HIV (Be Proud! Be Responsible!) curriculum were selected and integrated. Consensus was reached that the implementation team should consist of adults and adolescents.
Evidence-Based Multidisciplinary Strategies for Working With Children Who Set Fires
Authors: Sharp Daryl L. , Blaakman Susan W. , Cole Elizabeth C. , Cole Robert E.
Published: April 2006

In 1999, the National Association of State Fire Marshals received a grant from the Office of Juvenile Justice and Delinquency Prevention, which culminated in the development of nationwide workshops designed to help communities intervene with children who play with and/or set fires. The purpose of this article is to describe the content of these multidisciplinary workshops including a comprehensive overview of fireplay and firesetting among youth in the United States. Strategies for assessing and intervening with these children and their families within a community-based framework are discussed, and implications for nursing practice and research are highlighted.
Using the PRECEDE Model to Plan Men's Health Programs in a Managed Care Setting
Authors: Meador Margaret George , Linnan Laura A.
Published: April 2006

Managed care organizations represent an important venue for delivering health promotion programs. However, most health plans do not employ public health strategies that match peoples’ needs and preferences to effective behavior change techniques. This article focuses on the planning efforts by Blue Cross and Blue Shield of North Carolina (BCBSNC) to address the problem of underutilization of preventive health care services among adult male members—an issue that has received comparatively little attention in the health behavior arena. BCBSNC planners used the PRECEDE planning process to define issues relevant to the target population and determine appropriate intervention strategies. Increasing perceived susceptibility and severity to disease, perceived benefits of screening, physician recommendation for screening, and health knowledge/awareness emerged as intervention priorities. The PRECEDE planning process yielded important evidence-based information and strategies to address men's underuse of preventive services and led BCBSNC to adopt new systems for planning interventions to promote the health of its members.
All or Nothing... or Just a Hat? Farmers’ Sun Protection Behaviors
Authors: Silk Kami J. , Parrott Roxanne L.
Published: April 2006

Farmers have an increased risk for developing skin cancers and thus comprise an important audience for messages that address sun protection practices. This project examines sun protection behaviors of farmers from southeastern Georgia and uses those measured behaviors to conduct a cluster analysis. Farmers (N = 480) were clustered into three groups using six variables that measured their frequency of sun protective and purchasing behaviors. The three groups were characterized as either engaging heavily in sun protective behaviors, engaging in none of the recommended sun protective behaviors, or only wearing hats as a sun protective behavior. Practitioners seeking to develop health message interventions that target farming populations should consider the current behaviors of subgroups of farmers when developing audience segments to tailor messages aimed at increasing sun protective behaviors. Practical recommendations for message content targeted toward the subgroups of farmers are provided.