bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic and Functional Significance of Thromboxane Synthase Gene Overexpression in Invasive Bladder Cancer
Authors: Moussa Omar , Yordy John S. , Abol-Enein Hassan , Sinha Debajyoti , Bissada Nabil K. , Halushka Perry V. , Ghoneim Mohamed A. , Watson Dennis K.
Published: December 2005

Thromboxane synthase (TXAS) is one of the enzymes downstream from cyclooxygenase-2 and catalyzes the synthesis of thromboxane A2 (TXA2). TXAS was among the genes we identified based on its overexpression in invasive bladder tumors. TXAS is overexpressed in common forms of bladder tumors: 69 of 97 (71.1%) transitional cell carcinoma (TCC), 38 of 53 (71.6%) squamous cell carcinoma, and 5 of 11 (45.5%) adenocarcinoma relative to nontumor tissue. Overall, 112 of 161 (69.5%) invasive tumors exhibited elevated expression. Significantly, patients with tumors having >4-fold levels of TXAS expression showed significant statistical evidence of lower overall survival expressed by the estimated hazard ratio of 2.74 with P = 0.009 in Cox's regression analysis. TXAS mRNA expression was found to be an independent prognostic marker for patients with bladder cancer. Treatment of bladder cancer cell lines (T24 and TCC-SUP) with TXAS inhibitors and TXA2 (TP) receptor antagonists reduced cell growth, migration, and invasion, whereas TP agonists stimulated cell migration and invasion. The positive correlation between elevated TXAS expression and shorter patient survival supports a potential role for TXAS-regulated pathways in tumor invasion and metastases and suggests that modulation of the TXAS pathway may offer a novel therapeutic approach. (Cancer Res 2005; 65(24): 11581-7)
Development of Ewing's Sarcoma from Primary Bone Marrow–Derived Mesenchymal Progenitor Cells
Authors: Riggi Nicolò , Cironi Luisa , Provero Paolo , Suvà Mario-Luca , Kaloulis Konstantinos , Garcia-Echeverria Carlos , Hoffmann Francesco , Trumpp Andreas , Stamenkovic Ivan
Published: December 2005

Ewing's sarcoma is a member of Ewing's family tumors (EFTs) and the second most common solid bone and soft tissue malignancy of children and young adults. It is associated in 85% of cases with the t(11;22)(q24:q12) chromosomal translocation that generates fusion of the 5′ segment of the EWS gene with the 3′ segment of the ETS family gene FLI-1. The EWS-FLI-1 fusion protein behaves as an aberrant transcriptional activator and is believed to contribute to EFT development. However, EWS-FLI-1 induces growth arrest and apoptosis in normal fibroblasts, and primary cells that are permissive for its putative oncogenic properties have not been discovered, hampering basic understanding of EFT biology. Here, we show that EWS-FLI-1 alone can transform primary bone marrow–derived mesenchymal progenitor cells and generate tumors that display hallmarks of Ewing's sarcoma, including a small round cell phenotype, expression of EFT-associated markers, insulin like growth factor-I dependence, and induction or repression of numerous EWS-FLI-1 target genes. These observations provide the first identification of candidate primary cells from which EFTs originate and suggest that EWS-FLI-1 expression may constitute the initiating event in EFT pathogenesis. (Cancer Res 2005; 65(24): 11459-68)
Gene Expression Profiles Associated with Treatment Response in Oligodendrogliomas
Authors: French Pim J. , Swagemakers Sigrid M.A. , Nagel Jord H.A. , Kouwenhoven Mathilde C.M. , Brouwer Eric , van der Spek Peter , Luider Theo M. , Kros Johan M. , van den Bent Martin J. , Sillevis Smitt Peter A.
Published: December 2005

Oligodendrogliomas are a specific subtype of brain tumor of which the majority responds favorably to chemotherapy. In this study, we made use of expression profiling to identify chemosensitive oligodendroglial tumors. Correlation of expression profiles to loss of heterozygosity on 1p and 19q, common chromosomal aberrations associated with response to treatment, identified 376, 64, and 60 differentially expressed probe sets associated with loss of 1p, 19q or 1p, and 19q, respectively. Correlation of expression profiles to the tumors' response to treatment identified 16 differentially expressed probe sets. Because transcripts associated with chemotherapeutic response were identified independent of common chromosomal aberrations, expression profiling may be used as an alternative approach to the tumors' 1p status to identify chemosensitive oligodendroglial tumors. Finally, we correlated expression profiles to survival of the patient after diagnosis and identified 103 differentially expressed probe sets. The observation that many genes are differentially expressed between long and short survivors indicates that the genetic background of the tumor is an important factor in determining the prognosis of the patient. Furthermore, these transcripts can help identify patient subgroups that are associated with favorable prognosis. Our study is the first to correlate gene expression with chromosomal aberrations and clinical performance (response to treatment and survival) in oligodendrogliomas. The differentially expressed transcripts can help identify patient subgroups with good prognosis and those that will benefit from chemotherapeutic treatments. (Cancer Res 2005; 65(24): 11335-44)
Hypoxia-Induced Down-regulation of BRCA1 Expression by E2Fs
Authors: Bindra Ranjit S. , Gibson Shannon L. , Meng Alice , Westermark Ulrica , Jasin Maria , Pierce Andrew J. , Bristow Robert G. , Classon Marie K. , Glazer Peter M.
Published: December 2005

Decreased BRCA1 expression in the absence of genetic mutation is observed frequently in sporadic cancers of the breast and other sites, although little is known regarding the mechanisms by which the expression of this gene can be repressed. Here, we show that activating and repressive E2Fs simultaneously bind the BRCA1 promoter at two adjacent E2F sites in vivo, and that hypoxia induces a dynamic redistribution of promoter occupancy by these factors resulting in the transcriptional repression of BRCA1 expression. Functionally, we show that hypoxia is associated with impaired homologous recombination, whereas the nonhomologous end-joining (NHEJ) repair pathway is unaffected under these conditions. Repression of BRCA1 expression by hypoxia represents an intriguing mechanism of functional BRCA1 inactivation in the absence of genetic mutation. We propose that hypoxia-induced decreases in BRCA1 expression and consequent suppression of homologous recombination may lead to genetic instability by shifting the balance between the high-fidelity homologous recombination pathway and the error-prone NHEJ pathway of DNA repair. Furthermore, these findings provide a novel link between E2Fs and the transcriptional response to hypoxia and provide insight into the mechanisms by which the tumor microenvironment can contribute to genetic instability in cancer. (Cancer Res 2005; 65(24): 11597-604)
BRCA1 Regulates RAD51 Function in Response to DNA Damage and Suppresses Spontaneous Sister Chromatid Replication Slippage: Implications for Sister Chromatid Cohesion, Genome Stability, and Carcinogenesis
Authors: Cousineau Isabelle , Abaji Christine , Belmaaza Abdellah
Published: December 2005

The breast/ovarian cancer susceptibility proteins BRCA1 and BRCA2 maintain genome stability, at least in part, through a functional role in DNA damage repair. They both colocalize with RAD51 at sites of DNA damage/replication and activate RAD51-mediated homologous recombination repair of DNA double-strand breaks (DSB). Whereas BRCA2 interacts directly with and regulates RAD51, the role of BRCA1 in this process is unclear. However, BRCA1 may regulate RAD51 in response to DNA damage or through its ability to interact with and regulate MRE11/RAD50/NBS1 (MRN) during the processing of DSBs into single-strand DNA (ssDNA) ends, prerequisite substrates for RAD51, or both. To test these hypotheses, we measured the effect of BRCA1 on the competition between RAD51-mediated homologous recombination (gene conversion and crossover) versus RAD51-independent homologous recombination [single-strand annealing (SSA)] for ssDNA at a site-specific chromosomal DSB within a DNA repeat, a substrate for both homologous recombination pathways. Expression of wild-type BRCA1 in BRCA1-deficient human recombination reporter cell lines promoted both gene conversion and SSA but greatly enhanced gene conversion. In addition, BRCA1 also suppressed both spontaneous gene conversion and deletion events, which can arise from either crossover or sister chromatid replication slippage (SCRS), a RAD51-independent process. BRCA1 does not seem to block crossover. From these results, we conclude that (a) BRCA1 regulates RAD51 function in response to the type of DNA damage and (b) BRCA1 suppresses SCRS, suggesting a role for this protein in sister chromatid cohesion/alignment. Loss of such control in response to estrogen-induced DNA damage after BRCA1 inactivation may be a key initial event that triggers genome instability and carcinogenesis. (Cancer Res 2005; 65(24): 11384-91)
Bortezomib Sensitizes Pancreatic Cancer Cells to Endoplasmic Reticulum Stress-Mediated Apoptosis
Authors: Nawrocki Steffan T. , Carew Jennifer S. , Pino Maria S. , Highshaw Ralph A. , Dunner Kenneth , Huang Peng , Abbruzzese James L. , McConkey David J.
Published: December 2005

Bortezomib (PS-341, Velcade) is a potent and selective inhibitor of the proteasome that is currently under investigation for the treatment of solid malignancies. We have shown previously that bortezomib has activity in pancreatic cancer models and that the drug induces endoplasmic reticulum (ER) stress but also suppresses the unfolded protein response (UPR). Because the UPR is an important cytoprotective mechanism, we hypothesized that bortezomib would sensitize pancreatic cancer cells to ER stress-mediated apoptosis. Here, we show that bortezomib promotes apoptosis triggered by classic ER stress inducers (tunicamycin and thapsigargin) via a c-Jun NH2-terminal kinase (JNK)–dependent mechanism. We also show that cisplatin stimulates ER stress and interacts with bortezomib to increase ER dilation, intracellular Ca2+ levels, and cell death. Importantly, combined therapy with bortezomib plus cisplatin induced JNK activation and apoptosis in orthotopic pancreatic tumors resulting in a reduction in tumor burden. Taken together, our data establish that bortezomib sensitizes pancreatic cancer cells to ER stress-induced apoptosis and show that bortezomib strongly enhances the anticancer activity of cisplatin. (Cancer Res 2005; 65(24): 11658-66)
TRAIL Receptor-Selective Mutants Signal to Apoptosis via TRAIL-R1 in Primary Lymphoid Malignancies
Authors: MacFarlane Marion , Kohlhaas Susan L. , Sutcliffe Michael J. , Dyer Martin J.S. , Cohen Gerald M.
Published: December 2005

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) and its agonistic antibodies, which are currently in early clinical trials for treating various malignancies, induce apoptosis through triggering of either TRAIL-R1 or TRAIL-R2. Based on studies using agonistic monoclonal antibodies, we recently proposed that primary chronic lymphocytic leukemic cells seem to signal apoptosis primarily through TRAIL-R1. We have now synthesized mutant forms of TRAIL specific for TRAIL-R1 or TRAIL-R2. The selectivity of these mutants to induce apoptosis in cell lines is due to selective binding to their cognate receptors resulting in apoptosis via formation of a death-inducing signaling complex. Using these mutants, we now unequivocally show that primary cells from patients with chronic lymphocytic leukemia and mantle cell lymphoma signal to apoptosis almost exclusively through TRAIL-R1. Thus, no significant therapeutic benefit can be anticipated from treating such patients with agents currently in clinical trials that signal predominantly through TRAIL-R2, such as HGS-ETR2 or Apo2L/TRAIL. Our study highlights the necessity to determine whether primary cells from a particular tumor signal via TRAIL-R1 or TRAIL-R2. Such information will provide a rational approach to optimize TRAIL therapy. (Cancer Res 2005; 65(24): 11265-70)
Loss of Imprinting ofIGF2: A Common Epigenetic Modifier of Intestinal Tumor Risk
Authors: Kaneda Atsushi , Feinberg Andrew P.
Published: December 2005

Epigenetic alterations in cancer occur at least as commonly as genetic mutations, but epigenetic alterations could occur secondarily to the tumor process itself. To establish a causal role of epigenetic changes, investigators have turned to genetically engineered mouse models. Here, we review a recent study showing that a mouse model of loss of imprinting (LOI) of the insulin-like growth factor II gene (Igf2), which shows aberrant activation of the normally silent maternal allele, modifies the risk of intestinal neoplasia caused by mutations of the adenomatous polyposis coli (Apc) gene. This increased risk corresponds to the apparent increased risk of colorectal cancer in patients with LOI of IGF2. The model suggests that preexisting epigenetic alterations in normal cells increase tumor risk by expanding the target cell population and/or modulating the effect of subsequent genetic alterations on these cells, providing a novel idea for cancer risk management. (Cancer Res 2005; 65(24): 11236-40)
Loss of Phosphatase and Tensin Homologue Increases Transforming Growth Factor β–Mediated Invasion with Enhanced SMAD3 Transcriptional Activity
Authors: Hjelmeland Anita B. , Hjelmeland Mark D. , Shi Qing , Hart Janet L. , Bigner Darell D. , Wang Xiao-Fan , Kontos Christopher D. , Rich Jeremy N.
Published: December 2005

In normal epithelial tissues, the multifunctional cytokine transforming growth factor-β (TGF-β) acts as a tumor suppressor through growth inhibition and induction of differentiation whereas in advanced cancers, TGF-β promotes tumor progression through induction of tumor invasion, neoangiogenesis, and immunosuppression. The molecular mechanisms through which TGF-β shifts from a tumor suppressor to a tumor enhancer are poorly understood. We now show a role for the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) in repressing the protumorigenic effects of TGF-β. The TGF-β effector SMAD3 inducibly interacts with PTEN on TGF-β treatment under endogenous conditions. RNA interference (RNAi) suppression of PTEN expression enhances SMAD3 transcriptional activity and TGF-β–mediated induction of SMAD3 target genes whereas reconstitution of PTEN in a null cancer cell line represses the expression of TGF-β–regulated target genes. Targeting PTEN expression through RNAi in a PTEN wild-type cell line increases TGF-β–mediated invasion but does not affect TGF-β–mediated growth inhibition. Reconstitution of PTEN expression in a PTEN-null cell line blocks TGF-β–induced invasion but does not modulate TGF-β–mediated growth regulation. These effects are distinct from Akt and Forkhead family members that also interact with SMAD3 to regulate apoptosis or proliferation, respectively. Pharmacologic inhibitors targeting TGF-β receptors and phosphatidylinositol 3-kinase signaling downstream from PTEN cooperate to block TGF-β–mediated invasion. Thus, the loss of PTEN expression in human cancers may contribute to a role for TGF-β as a tumor enhancer with specific effects on cellular motility and invasion. (Cancer Res 2005; 65(24): 11276-81)
Glutathione-Related Systems and Modulation of Extracellular Signal–Regulated Kinases Are Involved in the Resistance of AGS Adenocarcinoma Gastric Cells to Diallyl Disulfide–Induced Apoptosis
Authors: Filomeni Giuseppe , Aquilano Katia , Rotilio Giuseppe , Ciriolo Maria R.
Published: December 2005

We have previously characterized the cytotoxic action of diallyl disulfide (DADS) on neuroblastoma cells, and we have shown the crucial role of an early and massive reactive oxygen species production in the induction of c-Jun NH2-terminal kinase–mediated apoptotic pathway. In the present work, we report that DADS is ineffective in inducing apoptosis in a human adenocarcinoma gastric cell line (AGS). In particular, we show that AGS cells are able to recover from the p53/p21-mediated cell cycle arrest in the G2-M phase upon DADS treatment without committing cells to death. This event is most likely due to a peculiar surviving pathway of these cells involving: (a) the formation of mixed disulfides between reduced glutathione (GSH) and protein thiols, (b) a higher and inducible glutathione peroxidase activity, and/or (c) an efficient modulation of the phospho-active levels of the extracellular signal–regulated kinases 1 and 2 (ERK 1/2). Moreover, by increasing glutathione peroxidase expression or GSH concentrations, cell cycle arrest is fully abolished; the apoptotic death is induced by either decreasing the availability of intracellular GSH or inhibiting the reactivation of ERK 1/2. Altogether, our data show that ERK 1/2 participates in the active proliferation of AGS cells and that an efficient reactive oxygen species buffering system makes these cells resistant to DADS-mediated detrimental effects. (Cancer Res 2005; 65(24): 11735-42)
Akt Phosphorylates and Regulates Pdcd4 Tumor Suppressor Protein
Authors: Palamarchuk Alexey , Efanov Alexey , Maximov Vadim , Aqeilan Rami I. , Croce Carlo M. , Pekarsky Yuri
Published: December 2005

Programmed cell death 4 (Pdcd4) is a tumor suppressor protein that interacts with eukaryotic initiation factor 4A and inhibits protein synthesis. Pdcd4 also suppresses the transactivation of activator protein-1 (AP-1)–responsive promoters by c-Jun. The Akt (protein kinase B) serine/threonine kinase is a key mediator of phosphoinositide 3-kinase pathway involved in the regulation of cell proliferation, survival, and growth. Because Pdcd4 has two putative Akt phosphorylation sites at Ser67 and Ser457, we investigated whether Akt phosphorylates and regulates Pdcd4. Our results show that Akt specifically phosphorylates Ser67 and Ser457 residues of Pdcd4 in vitro and in vivo. We further show that phosphorylation of Pdcd4 by Akt causes nuclear translocation of Pdcd4. Using luciferase assay, we show that phosphorylation of Pdcd4 by Akt also causes a significant decrease of the ability of Pdcd4 to interfere with the transactivation of AP-1–responsive promoter by c-Jun. (Cancer Res 2005; 65(24): 11282-6)
Endothelial EphrinB2 Is Controlled by Microenvironmental Determinants and Associates Context-Dependently With CD31
Authors: Korff Thomas , Dandekar Gudrun , Pfaff Dennis , Füller Tim , Goettsch Winfried , Morawietz Henning , Schaffner Florence , Augustin Hellmut G.
Published: December 2005

Objective—

The EphB ligand ephrinB2 has been identified as a critical determinant of arterial endothelial differentiation and as a positive regulator of invading endothelial cells during angiogenesis. This study was aimed at identifying determinants of endothelial cell ephrinB2 expression.

Methods and Results—

Arteriovenous asymmetrical endothelial cell ephrinB2 expression in vivo is lost on transfer into culture with aortic endothelial cells becoming partially ephrinB2-negative and saphenous vein endothelial cells becoming partially ephrinB2-positive. Contact with smooth muscle cells and angiogenic stimulation by vascular endothelial growth factor lead to an increased endothelial cell ephrinB2 expression. Quiescent, smooth muscle-contacting endothelial cells express ephrinB2 uniformly on their luminal surface. In contrast, monolayer endothelial cells translocate ephrinB2 to interendothelial cell junctions, which is strongly enhanced by EphB4-Fc-mediated receptor body activation. Junctional ephrinB2 colocalizes and coimmunoprecipitates with CD31.

Conclusions—

This study identifies distinct regulatory mechanisms of endothelial ephrinB2 expression and cellular distribution in quiescent and activated endothelial cells. The data demonstrate that endothelial cell ephrinB2 expression is controlled by microenvironmental determinants rather than being an intrinsic endothelial cell differentiation marker.
ABCA1 and ABCG1 Synergize to Mediate Cholesterol Export to ApoA-I
Authors: Gelissen Ingrid C. , Harris Matthew , Rye Kerry-Anne , Quinn Carmel , Brown Andrew J. , Kockx Maaike , Cartland Sian , Packianathan Mathana , Kritharides Leonard , Jessup Wendy
Published: December 2005

Objective—

To study the acceptor specificity for human ABCG1 (hABCG1)-mediated cholesterol efflux.

Methods and Results—

Cells overexpressing hABCG1 were created in Chinese Hamster Ovary (CHO-K1) cells and characterized in terms of lipid composition. hABCG1 expressed in these cells formed homodimers and was mostly present intracellularly. Cholesterol efflux from hABCG1 cells to HDL
2
and HDL
3
was increased but not to lipid-free apolipoproteins. A range of phospholipid containing acceptors apart from high-density lipoprotein (HDL) subclasses were also efficient in mediating ABCG1-dependent export of cholesterol. Importantly, a buoyant phospholipid-containing fraction generated from incubation of lipid-free apoA-I with macrophages was nearly as efficient as HDL
2
. The capacity of acceptors to induce ABCG1-mediated efflux was strongly correlated with their total phospholipid content, suggesting that acceptor phospholipids drive ABCG1-mediated efflux. Most importantly, acceptors for ABCG1-mediated cholesterol export could be generated from incubation of cells with lipid-free apoA-I through the action of ABCA1 alone.

Conclusions—

These results indicate a synergistic relationship between ABCA1 and ABCG1 in peripheral tissues, where ABCA1 lipidates any lipid-poor/free apoA-I to generate nascent or pre–β-HDL. These particles in turn may serve as substrates for ABCG1-mediated cholesterol export.
Antioxidants Inhibit the Ability of Lysophosphatidylcholine to Regulate Proteoglycan Synthesis
Authors: Chang Mary Y. , Han Chang-Yeop , Wight Thomas N. , Chait Alan
Published: December 2005

Objective—

We previously have shown that lysophosphatidylcholine (lysoPC) regulates proteoglycan synthesis by vascular smooth muscle cells (SMCs). Given the accumulating evidence for reactive oxygen species (ROS) as mediators of a variety of effects of lysoPC, the present study evaluates the potential role of ROS as intermediate molecules in the regulation of proteoglycan synthesis by lysoPC.

Methods and Results—

LysoPC (10 μmol/L) was found to stimulate rapid and sustained generation of ROS by SMC, as indicated using a fluorescent probe for measuring intracellular oxidants and fluorescence-activated cell sorting. This was not associated with cytotoxicity, as evaluated by fluorescence microscopy using MitoTracker Red or propidium iodide, cell number, cell protein, or lactate dehydrogenase release. Pretreatment with catalase or superoxide dismutase, specific scavengers of hydrogen peroxide and superoxide, respectively, blocked the ability of lysoPC to stimulate both accumulation of ROS and proteoglycan synthesis. Most importantly, these enzymatic antioxidants prevented lysoPC from stimulating the synthesis of proteoglycans with enhanced lipoprotein-binding properties, as quantified by a gel shift binding assay.

Conclusions—

These findings strongly suggest that ROS are key mediators in the ability of lysoPC to regulate proteoglycan synthesis and that these effects can be inhibited by antioxidants.
Effects of Rosiglitazone on Lipids, Adipokines, and Inflammatory Markers in Nondiabetic Patients With Low High-Density Lipoprotein Cholesterol and Metabolic Syndrome
Authors: Samaha Frederick F. , Szapary Philippe O. , Iqbal Nayyar , Williams Monica M. , Bloedon LeAnne T. , Kochar Arshneel , Wolfe Megan L. , Rader Daniel J.
Published: December 2005

Background—

PPAR-γ agonists improve insulin sensitivity and glycemic control in type 2 diabetes and may reduce atherosclerosis progression. Thus, PPAR-γ agonists may be an effective therapy for metabolic syndrome. However, the full spectrum of potentially antiatherogenic mechanisms of PPAR-γ agonists have not been fully tested in nondiabetic patients with metabolic syndrome.

Methods and Results—

We performed a prospective, double-blinded, placebo-controlled study of 60 nondiabetic subjects with low high-density lipoprotein cholesterol (HDL-C) level and metabolic syndrome to rosiglitazone 8 mg daily or placebo for 12 weeks. We found no significant effect of rosiglitazone on HDL-C (+5.5% versus +5.8%,
P
=0.89), and an increase in total cholesterol (+8% versus −1%;
P
=0.03). Nevertheless, rosiglitazone significantly increased adiponectin (+168% versus +25%;
P
<0.001), and lowered resistin (−6% versus +4%;
P
=0.009), C-reactive protein (−32% versus +36%,
P
=0.002), interleukin (IL)-6 (−22% versus +4%,
P
<0.001), and soluble tumor-necrosis factor-α receptor-2 (−5% versus +7%,
P
<0.001).

Conclusions—

These findings suggest that rosiglitazone, presumably through its PPAR-γ agonist properties, has direct effects on inflammatory markers and adipokines in the absence of favorable lipid effects. These findings may help explain the mechanism underlying the possible antiatherosclerotic effects of rosiglitazone.
Elevated Concentrations of Nonesterified Fatty Acids Increase Monocyte Expression of CD11b and Adhesion to Endothelial Cells
Authors: Zhang Wei-Yang , Schwartz Eric , Wang Yingjie , Attrep Jeanne , Li Zhi , Reaven Peter
Published: December 2005

Objective—

Monocyte proinflammatory activity has been demonstrated in obesity, insulin resistance, and type 2 diabetes, metabolic conditions that are frequently associated with elevated levels of nonesterified fatty acids (NEFA). We therefore tested the hypothesis that NEFA may induce monocyte inflammation.

Methods and Results—

Monocytes exposed to NEFA for 2 days demonstrated a dose-related increase in intracellular reactive oxygen species (ROS) formation and adhesion to endothelial cells. All of these effects were inhibited by the coaddition of antioxidants such as glutathione or butylated hydroxytoluene, by inhibition of ROS generation by NADPH oxidase inhibitors, and by inhibition of protein kinase C, a recognized stimulator of NAPDH oxidase. Monocytes exposed to NEFA also demonstrated a significant increase in CD11b message expression. Stimulation of monocyte adhesion to endothelial cells by NEFA was inhibited by addition of neutralizing antibodies to either CD11b or CD18. Finally, surface expression of CD11b increased significantly on monocytes as measured by flow cytometry, after their incubation with NEFA.

Conclusion—

These studies indicate that elevated concentrations of NEFA may enhance integrin facilitated monocyte adhesion to endothelial cells and these effects appear mediated, in part, through activation of NADPH oxidase and oxidative stress.
Compartmentalized Phosphodiesterase-2 Activity Blunts β-Adrenergic Cardiac Inotropy via an NO/cGMP-Dependent Pathway
Authors: Mongillo Marco , Tocchetti Carlo G. , Terrin Anna , Lissandron Valentina , Cheung York-Fong , Dostmann Wolfgang R. , Pozzan Tullio , Kass David A. , Paolocci Nazareno , Houslay Miles D. , Zaccolo Manuela
Published: December 2005

β-Adrenergic signaling via cAMP generation and PKA activation mediates the positive inotropic effect of catecholamines on heart cells. Given the large diversity of protein kinase A targets within cardiac cells, a precisely regulated and confined activity of such signaling pathway is essential for specificity of response. Phosphodiesterases (PDEs) are the only route for degrading cAMP and are thus poised to regulate intracellular cAMP gradients. Their spatial confinement to discrete compartments and functional coupling to individual receptors provides an efficient way to control local [cAMP]
i
in a stimulus-specific manner. By performing real-time imaging of cyclic nucleotides in living ventriculocytes we identify a prominent role of PDE2 in selectively shaping the cAMP response to catecholamines via a pathway involving β
3
-adrenergic receptors, NO generation and cGMP production. In cardiac myocytes, PDE2, being tightly coupled to the pool of adenylyl cyclases activated by β-adrenergic receptor stimulation, coordinates cGMP and cAMP signaling in a novel feedback control loop of the β-adrenergic pathway. In this, activation of β
3
-adrenergic receptors counteracts cAMP generation obtained via stimulation of β
1
/β
2
-adrenoceptors. Our study illustrates the key role of compartmentalized PDE2 in the control of catecholamine-generated cAMP and furthers our understanding of localized cAMP signaling.
Functional TRPM7 Channels Accumulate at the Plasma Membrane in Response to Fluid Flow
Authors: Oancea Elena , Wolfe Joshua T. , Clapham David E.
Published: December 2005

Many cells are constantly exposed to fluid mechanical forces generated by flowing blood, and wall shear stresses modulate aspects of their structure and function. However, the mechanisms for mechanotransduction of flow are not well understood. Here we report that TRPM7, which is both an ion channel and a functional kinase, is translocated within cells in response to laminar flow. After exposure of cells to physiological values of laminar fluid flow, the number of TRPM7 molecules localized at or near the plasma membrane increased up to 2-fold, in less than 100 seconds. This increase in membrane-localized GFP-TRPM7, as seen by total internal reflection fluorescence microscopy, closely correlated with increases in TRPM7 current. Both endogenous and heterologously expressed TRPM7 was found in tubulovesicular structures that were translocated to the region of the plasma membrane on induction of shear stress. In vascular smooth muscle cells, but not in several types of endothelial cells, fluid flow increased endogenous native TRPM7 current amplitude. We hypothesize that TRPM7 plays a role in pathological response to vessel wall injury.
Twenty-Four-Hour Observations of the Marine Boundary Layer Using Shipborne NOAA High-Resolution Doppler Lidar
Authors: Wulfmeyer Volker , Janjić Tijana
Published: December 2005

Shipborne observations obtained with the NOAA high-resolution Doppler lidar (HRDL) during the 1999 Nauru (Nauru99) campaign were used to study the structure of the marine boundary layer (MBL) in the tropical Pacific Ocean. During a day with weak mesoscale activity, diurnal variability of the height of the convective MBL was observed using HRDL backscatter data. The observed diurnal variation in the MBL height had an amplitude of about 250 m. Relations between the MBL height and in situ measurements of sea surface temperature as well as latent and sensible heat fluxes were examined. Good correlation was found with the sea surface temperature. The correlation with the latent heat flux was lower, and practically no correlation between the MBL height and the sensible heat and buoyancy fluxes could be detected. Horizontal wind profiles were measured using a velocity–azimuth display scan of HRDL velocity data. Strong wind shear at the top of the MBL was observed in most cases. Comparison of these results with GPS radiosonde data shows discrepancies in the wind intensity and direction, which may be due to different observation times and locations as well as due to multipath effects at the ship’s platform. Vertical wind profiles corrected for ship’s motion were used to derive vertical velocity variance and skewness profiles. Motion compensation had a significant effect on their shape. Normalized by the convective velocity scale and by the top of the mixed layer zi, the variance varied between 0.45 and 0.65 at 0.4z/zi and decreased to 0.2 at 1.0z/zi. The skewness ranged between 0.3 and 0.8 in the MBL and showed in almost all cases a maximum between 1.0z/zi and 1.1z/zi. These profiles revealed the existence of another turbulent layer above the MBL, which was probably driven by wind shear and cloud condensation processes.
Use of Real-Time Multisensor Data to Assess the Relationship of Normalized Corn Yield with Monthly Rainfall and Heat Stress across the Central United States
Authors: Westcott Nancy E. , Hollinger Steven E. , Kunkel Kenneth E.
Published: December 2005

This study evaluated the suitability of rain estimates based on the National Weather Service (NWS) Weather Surveillance Radar-1988 Doppler (WSR-88D) network to estimate yield response to rainfall on a county scale and to provide real-time information related to crop stress resulting from deficient or excessive precipitation throughout the summer. The relationship between normalized corn yield and rainfall was examined for nine states in the central United States for 1997–99 and 2001–02. Monthly rainfall estimates were computed employing multisensor precipitation estimate (MPE) data from the National Centers for Environmental Prediction and quality-controlled (QC_Coop) and real-time (RT_Coop) NWS cooperative gauge data. In-season MPE rain estimates were found to be of comparable quality to the postseason QC_Coop estimates for predicting county corn yields. Both MPE and QC_Coop estimates were better related to corn yield than were RT_Coop estimates, presumably because of the lower density of RT_Coop gauges. Large corn yields typically resulted when May rain was less than 125 mm and July rain was greater than 50 mm. Low yields often occurred when July rainfall was less than 100 mm. For moderate July rains (50–100 mm), positive and negative normalized yields resulted. Parameterization of heat stress (number of July days > 32.2°C) improved the correlation between rainfall and normalized corn yield, particularly for years with the poorest yield-vs-rain relationship (1998 and 1999). For the combined analysis years, the multiple regression correlation coefficient was 0.56, incorporating May and July rainfall and July heat stress and explaining 31% of the variance of normalized corn yield. Results show that MPE rainfall estimates provide timely yield projections within the growing season.
Effects of Cloud Microphysics on Tropical Atmospheric Hydrologic Processes and Intraseasonal Variability
Authors: Lau K. M. , Wu H. T. , Sud Y. C. , Walker G. K.
Published: December 2005

The sensitivity of tropical atmospheric hydrologic processes to cloud microphysics is investigated using the NASA Goddard Earth Observing System (GEOS) general circulation model (GCM). Results show that a faster autoconversion rate leads to (a) enhanced deep convection in the climatological convective zones anchored to tropical land regions; (b) more warm rain, but less cloud over oceanic regions; and (c) an increased convective-to-stratiform rain ratio over the entire Tropics. Fewer clouds enhance longwave cooling and reduce shortwave heating in the upper troposphere, while more warm rain produces more condensation heating in the lower troposphere. This vertical differential heating destabilizes the tropical atmosphere, producing a positive feedback resulting in more rain and an enhanced atmospheric water cycle over the Tropics. The feedback is maintained via secondary circulations between convective tower and anvil regions (cold rain), and adjacent middle-to-low cloud (warm rain) regions. The lower cell is capped by horizontal divergence and maximum cloud detrainment near the freezing–melting (0°C) level, with rising motion (relative to the vertical mean) in the warm rain region connected to sinking motion in the cold rain region. The upper cell is found above the 0°C level, with induced subsidence in the warm rain and dry regions, coupled to forced ascent in the deep convection region.

It is that warm rain plays an important role in regulating the time scales of convective cycles, and in altering the tropical large-scale circulation through radiative–dynamic interactions. Reduced cloud–radiation feedback due to a faster autoconversion rate results in intermittent but more energetic eastward propagating Madden–Julian oscillations (MJOs). Conversely, a slower autoconversion rate, with increased cloud radiation produces MJOs with more realistic westward-propagating transients embedded in eastward-propagating supercloud clusters. The implications of the present results on climate change and water cycle dynamics research are discussed.
Recent Stratospheric Climate Trends as Evidenced in Radiosonde Data: Global Structure and Tropospheric Linkages
Authors: Thompson David W. J. , Solomon Susan
Published: December 2005

The global structure of recent stratospheric climate trends is examined in radiosonde data. In contrast to conclusions published in previous assessments of stratospheric temperature trends, it is demonstrated that in the annual mean the tropical stratosphere has cooled substantially over the past few decades. The cooling of the tropical stratosphere is apparent in both nighttime and adjusted radiosonde data, and seems to be robust to changes in radiosonde instrumentation. The meridional structure of the annual-mean stratospheric trends is not consistent with our current understanding of radiative transfer and constituent trends but is consistent with increased upwelling in the tropical stratosphere.

The annual-mean cooling of the tropical stratosphere is juxtaposed against seasonally varying trends in the extratropical stratosphere dominated by the well-known springtime cooling at polar latitudes. The polar stratospheric trends are accompanied by similarly signed trends at tropospheric levels in the Southern Hemisphere but not in the Northern Hemisphere.
The Thinning of Arctic Sea Ice, 1988–2003: Have We Passed a Tipping Point?
Authors: Lindsay R. W. , Zhang J.
Published: December 2005

Recent observations of summer Arctic sea ice over the satellite era show that record or near-record lows for the ice extent occurred in the years 2002–05. To determine the physical processes contributing to these changes in the Arctic pack ice, model results from a regional coupled ice–ocean model have been analyzed. Since 1988 the thickness of the simulated basinwide ice thinned by 1.31 m or 43%. The thinning is greatest along the coast in the sector from the Chukchi Sea to the Beaufort Sea to Greenland.

It is hypothesized that the thinning since 1988 is due to preconditioning, a trigger, and positive feedbacks: 1) the fall, winter, and spring air temperatures over the Arctic Ocean have gradually increased over the last 50 yr, leading to reduced thickness of first-year ice at the start of summer; 2) a temporary shift, starting in 1989, of two principal climate indexes (the Arctic Oscillation and Pacific Decadal Oscillation) caused a flushing of some of the older, thicker ice out of the basin and an increase in the summer open water extent; and 3) the increasing amounts of summer open water allow for increasing absorption of solar radiation, which melts the ice, warms the water, and promotes creation of thinner first-year ice, ice that often entirely melts by the end of the subsequent summer.

Internal thermodynamic changes related to the positive ice–albedo feedback, not external forcing, dominate the thinning processes over the last 16 yr. This feedback continues to drive the thinning after the climate indexes return to near-normal conditions in the late 1990s. The late 1980s and early 1990s could be considered a tipping point during which the ice–ocean system began to enter a new era of thinning ice and increasing summer open water because of positive feedbacks. It remains to be seen if this era will persist or if a sustained cooling period can reverse the processes.
Estimating the Vertical Structure of Intense Mediterranean Precipitation Using Two X-Band Weather Radar Systems
Authors: Berne A. , Delrieu G. , Andrieu H.
Published: December 2005

The present study aims at a preliminary approach of multiradar compositing applied to the estimation of the vertical structure of precipitation—an important issue for radar rainfall measurement and prediction. During the HYDROMET Integrated Radar Experiment (HIRE’98), the vertical profile of reflectivity was measured, on the one hand, with an X-band vertically pointing radar system, and, on the other hand, with an X-band RHI scanning protocol radar. The analysis of the raw data highlights the effects of calibration and attenuation problems affecting the measurements of both radar systems. Once the two radar systems have been intercalibrated, various attenuation correction techniques are applied. The comparison of raw, intercalibrated, and corrected radar measurements for the two radar systems stresses the importance of calibration and attenuation correction. The applied corrections improve the consistency of the vertical profile of reflectivity that is measured by the two radar systems. However, a significant uncertainty remains when strong radar signal attenuations occur.
The Concept of a Microwave Radar with an Asymmetric Knifelike Beam for the Remote Sensing of Ocean Waves
Authors: Karaev V. Yu , Kanevsky M. B. , Balandina G. N. , Challenor P. , Gommenginger C. , Srokosz M.
Published: December 2005

The features of near-nadir probing of the ocean surface from a satellite are investigated, and a new configuration of a microwave radar for the surface slopes measurement is proposed. Numerical modeling is used to examine the feasibility of a spaceborne implementation, to devise a measuring technique, and to develop a data processing algorithm.

It is shown that the radar with a knifelike beam (1° × 25°–30°) can be used to measure the variance of surface wave slopes. Using range selection and a new processing procedure to synthesize data, it is possible to achieve the spatial resolution required to study wave processes on the ocean surface from satellites. A new approach to wind speed retrieval at and near nadir is also discussed.
Quality Control of Pre-1948 Cooperative Observer Network Data
Authors: Kunkel Kenneth E. , Easterling David R. , Hubbard Kenneth , Redmond Kelly , Andsager Karen , Kruk Michael C. , Spinar Michael L.
Published: December 2005

A recent comprehensive effort to digitize U.S. daily temperature and precipitation data observed prior to 1948 has resulted in a major enhancement in the computer database of the records of the National Weather Service’s cooperative observer network. Previous digitization efforts had been selective, concentrating on state or regional areas. Special quality control procedures were applied to these data to enhance their value for climatological analysis. The procedures involved a two-step process. In the first step, each individual temperature and precipitation data value was evaluated against a set of objective screening criteria to flag outliers. These criteria included extreme limits and spatial comparisons with nearby stations. The following data were automatically flagged: 1) all precipitation values exceeding 254 mm (10 in.) and 2) all temperature values whose anomaly from the monthly mean for that station exceeded five standard deviations. Additional values were flagged based on differences with nearby stations; in this case, metrics were used to rank outliers so that the limited resources were concentrated on those values most likely to be invalid. In the second step, each outlier was manually assessed by climatologists and assigned one of the four following flags: valid, plausible, questionable, or invalid. In excess of 22 400 values were manually assessed, of which about 48% were judged to be invalid. Although additional manual assessment of outliers might further improve the quality of the database, the procedures applied in this study appear to have been successful in identifying the most flagrant errors.
Vertical Distribution of the Mirror Image Returns Observed by TRMM PR and Estimated for a 35-GHz Radar
Authors: Li Ji , Nakamura Kenji
Published: December 2005

The vertical distribution of Tropical Rainfall Measuring Mission (TRMM) precipitation radar (PR)-observed precipitation reflectivity and their mirror image (MI) reflectivity are outlined in this paper. The purpose of this study is to investigate the possibility and the limitation of the MI method, which can be used to estimate rain attenuation. Because the MI returns are attenuated much more greatly than the direct image returns, and also because the MI return is affected by the surface reflection and surface scattering, the MI returns are much smaller and more complex than the direct image (DI) returns. However, because the MI returns might be contaminated by the surface or contributed by bistatic scattering near the surface, there are many strong mirror returns between the surface and below surface at 1 km. The ratio of detectable MI return pixels to detected DI return pixels depends on rain rate, target height, and storm height. In addition, differences also exist between the convective and stratiform rain. The reason for this might be because the difference of the surface cross section and the difference of the storm height between the two types of rainfall. Furthermore, the direct and the mirror returns for a 35-GHz radar are also estimated. The virtue of the MI method of the Ka-band radar may reside in expanding the dynamic range of the MI method from 4–30 to 0.6–30 mm h−1.
The impact of trust on strategic resource acquisition through interorganizational networks:Towards a conceptual model
Authors: De Wever Sigrid , Martens Rudy , Vandenbempt Koen
Published: December 2005

In this article, we build a conceptual framework that models the influence of social capital as a multidimensional concept on strategic resource acquisition through interorganizational networks. Interorganizational networks are considered as effective when they allow for the acquisition of strategicresources. Our conceptual framework reflects that network effectiveness is dependent on the structural and the relational dimension of social capital. The main focus is on how the relational dimension of social capital – in this article conceptualized as trust – in interorganizational networks can directly and indirectly influence the acquisition of strategic resources through those networks. Based on the network literature, social capital literature and the literature on trust, we seek to develop propositions that detail the relationships among trust, interorganizational network characteristics, strategic resource acquisition/network effectiveness and performance. Basically, we argue 1) that different types of trust will have a different impact on network effectiveness, 2) that the level of trust will influence network effectiveness, and 3) that the interaction between trust and other variables, such as structural dimension variables, are fundamental for analyzing network effectiveness.
Making sense of the collapse of Barings Bank
Authors: Brown Andrew D.
Published: December 2005

We may usefully interrogate individual texts in order to expose them as exercises in power that serve hegemonic and legitimation functions. To illustrate this argument I analyse the account of the collapse of Barings Bank given in the Report of the Board of Banking Supervision, and juxtapose this with other versions of the events given by investigative journalists, Nicholas Leeson, and management scholars.The Report, I suggest, promulgates a public discourse myth designed to mitigate public anxieties, and is an explicit attempt to maintain and reproduce the legitimacy of the Bank of England, the City of London, and existing regulatory structures.
Determinants of objective and subjective success of men and women
Authors: Lortie-Lussier Monique , Rinfret Natalie
Published: December 2005

The objective of the study reported here was to determine whether a set of individual variables predicted both the objective and subjective career success of 156 women and 218 men managers in the Quebec public service. Hierarchical regressions performed separately for each gender revealed that few variables predicted both dimensions of success. Human capital was found to be the most important predictor of objective success, salary and position level, regardless of gender. Men’s advancement to senior management positions was facilitated by age, family situation and mentoring, while that of women was facilitated by selfrated interpersonal skills. Age and self-rated interpersonal skills were the only predictors of subjective success, career satisfaction and job satisfaction, for both genders. Ambition negatively predicted career satisfaction for both genders. Findings are discussed from the perspective of current notions of career success in organizations.