bluuebunny/crossref_metadata_2025 huggingface dataset:
Extensive Immunoglobulin Production Sensitizes Myeloma Cells for Proteasome Inhibition
Authors: Meister Silke , Schubert Ulrich , Neubert Kirsten , Herrmann Kai , Burger Renate , Gramatzki Martin , Hahn Sabine , Schreiber Sandra , Wilhelm Sabine , Herrmann Martin , Jäck Hans-Martin , Voll Reinhard E.
Published: February 2007

Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins. The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-κB (NF-κB) apparently contributes to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs), which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting human myeloma cell line JK-6L and murine μH-chain–transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor–treated cells. Hence, proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing clinical applications. [Cancer Res 2007;67(4):1783–92]
The α6β4 Integrin Can Regulate ErbB-3 Expression: Implications for α6β4 Signaling and Function
Authors: Folgiero Valentina , Bachelder Robin E. , Bon Giulia , Sacchi Ada , Falcioni Rita , Mercurio Arthur M.
Published: February 2007

The integrin α6β4 has been shown to facilitate key functions of carcinoma cells, including their ability to migrate, invade, and evade apoptosis. The mechanism involved seems to be a profound effect of α6β4 on specific signaling pathways, especially the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. An intimate relationship between α6β4 and growth factor receptors may explain this effect of α6β4 on signaling. Previously, we showed that α6β4 and ErbB-2 can function synergistically to activate the PI3K/Akt pathway. Given that ErbB-2 can activate PI3K only when it heterodimerizes with other members of the epidermal growth factor receptor family, these data imply that other receptors cooperate in this process. Here, we report that α6β4 can regulate the expression of ErbB-3 using several different models and that the consequent formation of an ErbB-2/ErbB-3 heterodimer promotes the α6β4-dependent activation of PI3K/Akt and the ability of this integrin to impede apoptosis of carcinoma cells. Our data also support the hypothesis that α6β4 can regulate ErbB-3 expression at the translational level as evidenced by the findings that α6β4 does not increase ErbB-3 mRNA significantly, and that this regulation is both rapamycin sensitive and dependent on eukaryotic translation initiation factor 4E. These findings provide one mechanism to account for the activation of PI3K by α6β4 and they also provide insight into the regulation of ErbB-3 in carcinoma cells. [Cancer Res 2007;67(4):1645–52]
Gene expression analysis of gallium-resistant and gallium-sensitive lymphoma cells reveals a role for metal-responsive transcription factor-1, metallothionein-2A, and zinc transporter-1 in modulating the antineoplastic activity of gallium nitrate
Authors: Yang Meiying , Kroft Steven H. , Chitambar Christopher R.
Published: February 2007

Several clinical trials have shown gallium nitrate to be an active agent in the treatment of lymphoma. Whereas gallium is known to target cellular iron homeostasis, the basis for lymphoma cell resistance to gallium is not known. Understanding mechanisms of resistance may suggest strategies to enhance the clinical efficacy of gallium. In the present study, we used a focused DNA microarray to compare the expression of genes related to metal metabolism in gallium-resistant and gallium-sensitive lymphoma cell lines developed by us. Gallium-resistant cells were found to display a marked increase in gene expression for metallothionein-2A and the zinc transporter ZnT-1. Cells exposed to gallium nitrate displayed an increase in the binding of metal-responsive transcription factor-1 to metal response element sequences involved in the transcriptional regulation of metallothionein and ZnT-1 genes. Gallium nitrate induced metallothionein-2A and ZnT-1 expression in cells. A role for metallothionein in modulating the antineoplastic activity of gallium was confirmed by showing that the induction of metallothionein expression by zinc provided partial protection against the cytotoxicity of gallium and by showing that the level of endogenous metallothionein in lymphoma cell lines correlated with their sensitivity to gallium nitrate. Immunohistochemical staining of lymphomatous tissues revealed metallothionein protein to be variably expressed in different lymphomas. Our studies show for the first time that gallium acts on pathways related to zinc metabolism and that metal-responsive transcription factor-1 activity and metallothionein expression contribute to the development of gallium drug resistance. Furthermore, the endogenous level of metallothionein in lymphoma may be an important determinant of clinical response to gallium nitrate. [Mol Cancer Ther 2007;6(2):633–43]
Docetaxel-induced apoptosis in melanoma cells is dependent on activation of caspase-2
Authors: Mhaidat Nizar M. , Wang Yufang , Kiejda Kelly A. , Zhang Xu Dong , Hersey Peter
Published: February 2007

Taxanes have a broad spectrum of activity against various human cancers, including melanoma. In this study, we have examined the molecular mechanism of docetaxel-induced apoptosis of human melanoma. We report that docetaxel induced varying degrees of apoptosis in a panel of melanoma cell lines but not in normal fibroblasts. Induction of apoptosis was caspase dependent and associated with changes in mitochondrial membrane potential that could be inhibited by overexpression of Bcl-2. Docetaxel induced changes in Bax that correlated with sensitivity to docetaxel-induced apoptosis. These changes in Bax were not inhibited by overexpression of Bcl-2. Kinetic studies of caspase-2 activation by Western blotting and fluorogenic assays revealed that activation of caspase-2 seemed to be the initiating event. Inhibition of caspase-2 with z-VDVAD-fmk or by small interfering RNA knockdown inhibited changes in Bax and mitochondrial membrane potential and events downstream of mitochondria. Activation of caspase-8 and Bid seemed to be a late event, and docetaxel was able to induce apoptosis in cells deficient in caspase-8 and Bid. p53 did not seem to be involved as a p53 null cell line was sensitive to docetaxel and an inhibitor of p53 did not inhibit apoptosis. Small interfering RNA knockdown of PUMA and Noxa also did not inhibit apoptosis. These results suggest that docetaxel induces apoptosis in melanoma cells by pathways that are dependent on activation of caspase-2, which initiates mitochondrial dependent apoptosis by direct or indirect activation of Bax. [Mol Cancer Ther 2007;6(2):752–61]
Hormonal Treatment of Idiopathic Short Stature
Authors: Reiter Edward O.
Published: February 2007

Background and Objective: The classification idiopathic short stature (ISS) represents a heterogeneous group of children who, as a group, are similar in height to patients with growth hormone (GH) deficiency, Turner syndrome, and short stature as a consequence of being born small for gestational age. GH therapy has been an effective treatment for enhancing height in children with ISS. Methods: A large body of literature – including data from KIGS (Pfizer International Growth Study Database) and the National Cooperative Growth Study database – shows that non-placebo-controlled GH treatment programs generally, though not uniformly, are associated with substantial increments in height gain. Placebo-controlled trials conducted in several countries report significant gains of 5 to 8 cm in final height. Conclusions: Long-term data are needed to assess the behavioral consequences, if any, of GH treatment for children with ISS. As the pool of children with ISS is potentially large, it would be highly desirable if clinical trials enabled accurate prediction of likely height gain and could result in greater individualization of treatment. The use of aromatase inhibitors to slow estrogen-mediated skeletal maturation is a new treatment modality, but it has only been minimally tested. The lower cost and ease of oral administration are attractive considerations, but long-term safety data are needed.
How Proinflammatory Cytokines May Impair Growth and Cause Muscle Wasting
Authors: Thissen Jean-Paul
Published: February 2007

Background: Cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, that are released in response to injury are thought to inhibit growth and cause muscle wasting, at least in part by inhibiting anabolic hormones such as insulin-like growth factor I (IGF-I). Because critical illness in humans is accompanied by high circulating concentrations of growth hormone (GH), which is the main stimulus for IGF-I production by the liver, resistance to GH is thought to contribute to the IGF-I decline observed in catabolic diseases. While TNF-α seems to cause GH resistance mainly through downregulation of liver GH receptor expression, IL-6 may inhibit the GH-stimulated Janus kinase and signal transducer and activator of transcription pathways by induction of suppressors of cytokine signaling proteins. Elevations in circulating IGF binding protein-1 levels, as observed in many catabolic situations, may play a role in the decline in muscle mass by decreasing the rate of protein synthesis in skeletal muscle. Furthermore, the increase in local muscle cytokines produced during inflammation makes the muscle GH-resistant and reduces its own IGF-I production. Finally, not only decreased IGF-I production by muscle, but also decreased muscle sensitivity to the anabolic effects of IGF-I, may contribute to muscle wasting observed in response to severe stress. Conclusions: Taken together, proinflammatory cytokines may contribute to the growth retardation and muscle wasting that occur after injury by impairing the GH/IGF-I axis at several levels.
ABCs of Natriuretic Peptides: Cardiac Aspects
Authors: Nir Amiram
Published: February 2007

Background: The natriuretic peptides are a family of structurally similar peptides. Atrial natriuretic peptide and B-type natriuretic peptide (BNP) are cardiac hormones secreted from the heart in response to cardiac chamber distention. Their biological actions include diuresis, natriuresis and vasodilatation, as well as suppression of the renin-angiotensin-aldosterone and endothelin systems. The hemodynamic actions of the secreted natriuretic peptide unload the heart in response to increased intravascular volume. Knowledge regarding the biological actions of the natriuretic peptides continues to evolve into clinical use. A synthetic BNP analogue has shown a beneficial short-term effect in acute decompensated heart failure, while plasma levels of natriuretic peptides have been shown to be elevated in patients with heart disease. Conclusions: BNP and the N-terminal segment of its prohormone, NT-pro-BNP, are very sensitive markers for many forms of heart disease. Future research will likely allow greater use of these peptides in the diagnosis and treatment of heart diseases in adults and children.
Novel Medical Approaches to the Treatment of Pituitary Tumors
Authors: van der Lely A.J.
Published: February 2007

Premise: Acromegaly should be treated by clinicians as not just a growth disorder, but also as a metabolic condition. That means developing a tailored approach that normalizes tissue-specific hormonal actions. All medical treatment regimens should have specific normal levels of hormones that might differ per patient. Unfortunately, the way to accomplish this has not yet been devised. Background: There have been no major breakthroughs in clinical neuroendocrinology, at least regarding pituitary tumors. Medical treatment of Cushing disease, prolactinomas, nonfunctioning pituitary tumors and thyroid-stimulating hormone-producing adenomas still relies on medications introduced 10 to 15 years ago. The only major breakthrough to impact current neuroendocrine treatment is in the field of acromegaly. This article presents a case history followed by a discussion of the mechanisms of the medical therapies for acromegaly.
Management of Glucocorticoid Replacement in Adult Growth Hormone Deficiency
Authors: Filipsson Helena , Johannsson Gudmundur
Published: February 2007

In multiple pituitary hormone deficiency, interactions occur among thyroxine, cortisol and growth hormone (GH). This review addresses the issues of endogenous cortisol production and exogenous cortisol replacement and discusses cortisol metabolism in the context of adult GH deficiency. In addition, we review the effect of GH on 11-β-hydroxysteroid dehydrogenase type 1, the current literature regarding the choice of glucocorticoid (GC) treatment and dose levels and dosing regimens. Recommendations for GC replacement therapy are also provided.
Positive Metabolic Impact of Treatment with Pegvisomant in an Acromegalic Patient
Authors: Grottoli Silvia , Gasco Valentina , Mainolfi Alessandra , De Giorgio Damiano , Ghigo Ezio
Published: February 2007

Background: Glucose intolerance and diabetes mellitus are important complications of acromegaly. Somatostatin analogues (SSAs) exert a dual effect on carbohydrate metabolism. Normalisation of the growth hormone/insulin-like growth factor I (GH/IGF-I) axis could improve metabolic balance, but inhibition of insulin secretion could worsen glucose tolerance. Case Description: We report a case of an acromegalic patient with diabetes mellitus that was resistant to SSA therapy. Results: Treatment with SSAs typically induces mild reductions in GH and IGF-I levels, but rarely results in normalisation of these parameters. In addition, glucose levels as well as glycosylated haemoglobin levels (HbA1c) show marked deterioration. In contrast, pegvisomant (PEG) treatment normalises IGF-I levels, and glucose, insulin and HbA1c levels gradually decrease. During SSA therapy, this patient required an increase in the dose and type of hypoglycaemic agents. During PEG treatment, however, hypoglycaemic drugs are often reduced. Conclusion: Patients with acromegaly whose disease is inadequately controlled by SSA therapy can achieve normalisation of IGF-I levels and full control of the disease, including strong improvement of glucose homeostasis despite marked reduction of antidiabetic therapy, when treated with the GH antagonist, PEG.
Potent arterial antithrombotic effect of direct factor-Xa inhibition with ZK-807834 administered to coronary artery disease patients
Authors: Zafar Urooj , Osende Julio , Shimbo Daichi , Palencia Stella , Crook Julia , Leadley Robert , Fuster Valentin , Chesebro James , Farkouh Michael
Published: February 2007

It was the objective of this study to evaluate the anti-thrombotic potency of direct factor-Xa inhibition with ZK-807834 in stable coronary patients, using an ex-vivo model of arterial thrombus formation. Tissue factor pathway is important in atherothrom-bosis. Direct factor-Xa blockade may more potently reduce thrombosis and prevent coronary events. Badimon Perfusion Chamber 5-minute quantitative studies have shown 40-55% arterial thrombus reduction with abciximab, 23% with Clopidogrel, but none with heparin. Coronary patients (n= 18, 59 ± 9 years, 55% males) were blindly randomized to four groups receiving 24-hour infusion of a low, medium or high dose of direct factor-Xa inhibitor ZK-807834, or placebo. Arterial thrombus formation was measured in Badimon Chamber at baseline, end-of-infusion [Eol], and four hours and eight hours after Eol, and factor-X activity, prothrombin time [PT] ratio and plasma drug levels were measured simultaneously. For the low-, medium- and high-dose ZK-807834 groups, mean percent-reduction in thrombus size from baseline to Eol were 29%, 34% and 68%, respectively (p<0.00l), and at 8-h post Eol were 11%, 19% and 27%, respectively (p<0.01). Mean PT-ratio prolongation showed a strong linear relationship (Pearson’s r=0.93) with ZK-807834 plasma concentration. Mean percent-reduction in factor-X activity from baseline was 13%, 42% and 58%, respectively. Placebo had no effect on thrombus size or factor-X activity. In conclusion, direct factor-Xa inhibition with ZK-807834 markedly reduces ex-vivo arterial thrombus formation and factor-X activity in a dose-dependent manner. Plasma levels of ZK-807834 show a strong linear correlation with PT ratio. This direct factor-Xa inhibitor may reduce the need for additional potent glycoprotein llbllla inhibition.
Platelet activation via PAR4 is involved in the initiation of thrombin generation and in clot elasticity development
Authors: Ramström Sofia , Bjerke Maria , Lindahl Tomas , Vretenbrant Karin
Published: February 2007

Thrombin is a pivotal enzyme formed in the coagulation cascade and an important and potent platelet activator. The two pro-tease-activated thrombin receptors on human platelets are denoted PARI and PAR4. The physiological relevance of PAR4 is still unclear, as both aggregation and secretion can be accomplished by PARI activation alone. In the present study we have investigated the role of PARs in platelet activation, blood coagulation, clot elasticity and fibrinolysis. Flow cytometry, free oscillation rheometry and thrombin generation measurements were used to analyze blood or platelet-rich plasma from healthy individuals. Maximum PARI activation with the peptide SFLLRN gave fewer fibrinogen-binding platelets with lower mean fluorescent intensity than maximum PAR4 activation with AYPGKF. Inhibition of any of the receptors prolonged clotting times. However, PARI is more important for fibrinolysis; inhibition of this receptor prolonged all the steps in the fibrinolytic process. Clot elasticity decreased significantly when the PAR4 receptor was inhibited. In the thrombin generation measurements, PAR4 inhibition delayed the thrombin generation start and peak, but did not affect the total amount of thrombin generated. PAR I inhibition had no significant impact on thrombin generation. We found that PAR4 is most likely activated by low concentrations of thrombin during the initial phase of thrombin generation and is of importance to the clotting time. Furthermore, we suggest that the PAR4 receptor may have a physiological role in the stabilisation of the coagulum.
Glycoprotein Ibα inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques
Authors: Penz Sandra , Reininger Armin , Toth Orsolya , Deckmyn Hans , Brandi Richard , Siess Wolfgang
Published: February 2007

Anti-platelet drugs are used to prevent intra-arterial thrombus formation after rupture of atherosclerotic plaques. Until now, the inhibitory effect of present and future anti-platelet drugs such as aspirin, ADP receptor P2Y1/P2Y12 antagonists and glycoprotein (GP) Ibα inhibitors on the interaction of platelets with human plaques is not known. To study those effects we obtained human atherosclerotic plaques by surgical endarterectomy. Plaques induced maximal platelet aggregation in hirudinized platelet-rich plasma (PRP) and blood that was effectively inhibited by aspirin, the P2Y1 antagonist MRS2179 and the P2Y12 antagonist AR-C69931 MX, but not by GPIbα blockade with the mAB 6B4. Inhibition of platelet aggregation by MRS2179 was 74 ± 37% and 68 ± 20%, by AR-C69931 MX 94 ± 7% and 80 ± 6%, and by aspirin 88 ± 19% and 64 ± 28%, in PRP and blood, respectively (mean ± SD; n6–12 with plaques from 6 patients). The combination of both ADP receptor antagonists completely inhibited plaque-induced platelet aggregation in hirudinized PRP and blood. Under arterial flow conditions (1,500s-1), blockade of platelet GPIbα– resulted in a strong decrease of plaque-stimulated platelet adhesion/aggregate formation of 77 ± 5% (mean ± SD; n=4). Furthermore, MRS2I79, AR-C6993IMX and their combination reduced plaque-dependent platelet aggregate formation by 35 ± 14%, 32 ± 13% and 58 ± 12% (mean ± SD; n=5), respectively. Aspirin was without significant effect. In conclusion, a GPIbα-blocking antibody, as well as P2Y1 and P2Y12 receptor antagonists, alone or in combination, reduce in contrast to aspirin human plaque-induced platelet thrombus formation under arterial flow. Although these new anti-platelet agents inhibit platelet thrombus formation after plaque rupture, more efficient platelet blockers are required.
Interaction of an annexin V homodimer (Diannexin) with phosphatidylserine on cell surfaces and consequent antithrombotic activity
Authors: Larkin Sandra , Emeis Jef , Allison Anthony , Kuypers Frans
Published: February 2007

Annexin V(AV), a protein with anticoagulant activity, exerts antithrombotic activity by binding to phosphatidylserine (PS), inhibiting activation of serine proteases important in blood coagulation. The potential use of this protein as an anticoagulant is limited as it rapidly passes from the blood into the kidneys due to its relatively small size (36 kDa). We used recombinant DNA technology to produce a homodimer of human AV (DAV, 73 kDa), which exceeds the renal filtration threshold, and has a 6.5-hour half-life in the rat circulation. Human red blood cells with externalized PS were used to show that DAV had a higher affinity for PS-exposing cells than AV. DAV labeling sensitively identifies PS-exposing cells, was found to be a potent inhibitor of the activity of the prothombinase complexes and inhibits the ability of secretory phospholipase A2 to hydrolyze phospholipids of PS-exposing cells, reducing the formation of mediators of blood coagulation and reperfusion injury. DAV exerts dose-dependent antithrombotic activity in ratveins. This combination of activities suggests that DAV is a valuable probe to measure PS exposure and may be efficacious as a novel drug in a wide range of clinical situations.
Signal transduction induced in endothelial cells by growth factor receptors involved in angiogenesis
Authors: Schweighofer Bernhard , Hofer Erhard
Published: February 2007

New vessel formation during development and in the adult is triggered by concerted signals of largely endothelial-specific receptors for ligands of the VEGF, angiopoietin and ephrin families. The signals and genes induced by these receptors operate in the context of additional signals transduced by non-endothelial specific growth factor receptors, inflammatory cytokine receptors as well as adhesion molecules. We summarize here available data on characteristic signaling of the VEGF receptor-2 and the current state of knowledge regarding the additional different receptor tyrosine kinases of the VEGF, Tie and Ephrin receptor families. Furthermore, the potential cross-talk with signals induced by other growth factors and inflammatory cytokines as well as the modulation by VE-cadherin is discussed.
Ubiquitylation within signaling pathways in- and outside of inflammation
Authors: Hochrainer Karin , Lipp Joachim
Published: February 2007

Ubiquitin is a highly conserved 76-amino-acid peptide that becomes covalently attached to lysine residues of target proteins. Since ubiquitin itself contains seven lysine residues, ubiquitin molecules can generate different types of polyubiquitin chains. Lys48-linked polyubiquitylation is well-known as posttrans-lational tag for targeting proteins for degradation by the 26S proteasome. Recent studies have revealed several new functions of ubiquitin, e.g. activation of protein kinases, control of gene transcription, DNA repair and replication, intracellular trafficking and virus budding. These functions are mainly mediated by Lys63 polyubiquitin chains or attachment of a single ubiquitin molecule to one or several lysine residues within the target protein. Importantly, protein ubiquitylation exhibits inducibility, reversibilty and recognition by specialized ubiquitin-binding domains, features similar to protein phosphorylation. In this review we comprehensively describe regulations of protein ubiquitylation and their impact on distinct signaling pathways.
Fluorescent proteins and fluorescence resonance energy transfer (FRET) as tools in signaling research
Authors: Birbach Andreas , Schmid Johannes
Published: February 2007

The advent of fluorescent proteins has revolutionized signaling research, shifting focus from biochemical assays to analysis of live cells, organized tissues and even entire organisms. Modern applications of fluorescent proteins go beyond their use as specific markers of cells or tissues, allowing the researcher to visualize intracellular translocations as well as biochemical reactions. In this mini-review, we summarize the properties of a variety of fluorescent proteins, their detection using fluorescence microscopy and flow analysis, as well as their basic and more advanced applications, including fluorescence resonance energy transfer (FRET) to study signaling dynamics.
Resolution of inflammation: Intracellular feedback loops in the endothelium
Authors: Winsauer Gabriele , de Martin Rainer
Published: February 2007

Timely termination of the inflammatory reaction is equally important as its elicitation, since a persistent or exaggerated response may lead to detrimental effects in the affected tissues and organs. Therefore, and in accordance with the complex and highly coordinated activation phase, negative regulatory mechanisms have evolved which function on multiple levels to ensure the appropriate termination of the inflammatory response. This review will focus on the mechanisms that are operative in endothelial cells to shut down the activity of specific signaling pathways and transcription factors that have been activated in response to pro-inflammatory mediators, and provide evidence that the stage for resolution is set already early in the activation phase of the inflammatory response. The elucidation of these feedback mechanisms is of importance for the understanding of acute versus chronic inflammation, and for novel strategies for therapeutic intervention.
Inflammatory profile of oxidized phospholipids
Authors: Bochkov Valery
Published: February 2007

Lipid oxidation products and in particular oxidized phospholipids (OxPL) are increasingly recognized as inducers of chronic inflammation characteristic of atherosclerosis. OxPL stimulate production of chemokines and adhesion of monocytes to endothelial cells. However, accumulating data suggest that, in addition to the proatherogenic and proinflammatory effects, OxPL can stimulate antiinflammatory and tissue-protective mechanisms. Thus, depending on the biological situation, OxPL can either stimulate or inhibit inflammation. In this review, the inflammatory properties of OxPL are discussed together with the underlying receptor, signalling and transcriptional mechanisms.
Plasma tissue factor antigen in localized prostate cancer: Distribution, clinical significance and correlation with haemostatic activation markers
Authors: Chun Felix , Amirkhosravi Ali , Friedrich Martin , Leuenroth Sven , Eifrig Barbara , Bokemeyer Carsten , Francis John , Langer Florian
Published: February 2007

Tissue factor (TF) is involved in cancer growth and metastasis, and haemostatic abnormalities are found in most patients with advanced malignancies, including prostate cancer (PC). Because anti-haemostatic agents are increasingly screened for their potential to prolong survival in tumor patients, a detailed characterization of haemostatic markers in selected cancer subtypes and clinical stages is warranted. In this study, we measured preoperative plasma TF antigen in a large cohort of patients with localized PC and correlated its levels with markers of coagulation and platelet activation, prostate-specific antigen (PSA), and his-topathological findings to explore its potential as a prognostic marker in this tumor entity. Out of 140 patients, 19% and 23% had plasma TF antigen levels of <40 pg/ml (low-TF) and >200 pg/ ml (high-TF), respectively, which was substantially higher than in 42 healthy male controls. Patients also had low-grade systemic coagulation activation as evidenced by elevated D-dimer, FI +2, and PAP plasma levels. Furthermore, similar to sP-selectin and sCD40L antigen, flow cytometric analysis of platelet-derived microparticles in plasma revealed significantly increased numbers in high-TF as compared to low-TF patients and controls. Whereas elevated D-dimer was associated with larger and less differentiated tumors, preoperative plasmaTF antigen levels (median [IQR]) were higher in patients with (161 pg/ml [100-236]) than in those without recurrent PC (105 pg/ml [52-182]), as indicated by a serum PSA of >0.1 ng/ml during ambulatory follow-up. In patients with localized PC, preoperative plasma TF antigen levels correlate with platelet activation in vivo and may indicate an increased risk for recurrent disease.
Prevention by NCX 4016, a nitric oxide-donating aspirin, but not by aspirin, of the acute endothelial dysfunction induced by exercise in patients with intermittent claudication
Authors: Migliacci Rino , Procacci Alessandra , De Monte Paola , Bonizzoni Erminio , Gresele Paolo
Published: February 2007

Ischemia/reperfusion damage evokes systemic inflammation and endothelial dysfunction in patients with intermittent claudication. We compared the effects of aspirin with those of a nitric oxide-donating aspirin in preventing the acute, systemic endothelial dysfunction provoked by exercise-induced ischemia of the lower limbs in patients with intermittent claudication. In a prospective, randomized, single-blind, parallel-groups trial among 44 patients with intermittent claudication we compared four weeks of aspirin (100 mg o.d.) with NCX 4016 (800 mg b.i.d.). Primary end point was the exercise-induced changes in brachial flow-mediated vasodilation (FMD) at day 28; secondary end points were effort-induced changes of markers of neutrophil (plasma elastase) and endothelial (soluble VCAM-1) activation. Baseline FMD was comparable in the two groups, both on day I (pre-treatment: aspirin = 3.1 ± 0.5%, nitroaspirin = 3.9 ± 0.7%, p=NS), and on day 28 (aspirin = 3.4 ± 0.7%, NCX 4016 = 3.2 ± 0.6%, p=NS). Maximal treadmill exercise induced an acute worsening of FMD in both groups at baseline (aspirin = –1.15%, nitroaspirin = –1.76%); after four weeks treatment, the impairment of FMD induced by exercise was still present in the aspirin-treated group (- 1.46%) while it was abolished in the NCX 4016-treated group (+ 0.79%, p= 0.038 vs. aspirin). Similarly, exercise induced an increase of plasma elastase and of sVCAM-l which were not affected by aspirin while they were suppressed by NCX 4016. Maximal treadmill exercise induces a systemic arterial endothelial dysfunction in patients with intermittent claudication. A nitric oxide-donating aspirin, but not aspirin, prevents effort-induced endothelial dysfunction.
Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation
Authors: Wrobleski Shirley , Longo Chris , Bedard Patricia , Kaila Neelu , Shaw George , Londy Frank , Rohrer Suzan , Fex Beverly , Zajkowski Paul , Meier Thomas , Hawley Angela , Farris Diana , Ballard Nicole , Henke Peter , Schaub Robert , Wakefield Thomas , Myers Daniel
Published: February 2007

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMVVH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p<0.01). LMVVH opening evident after balloon deflation slightly deteriorated overtime compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMVVH and control animals six hours post thrombus induction (p<0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.
Factor XIII Val34Leu variant protects against coronary artery disease
Authors: Bereczky Zsuzsanna , Katona Éva , Ádány Róza , Muszbek László , Vokó Zoltán
Published: February 2007

Several studies suggested that Val34Leu variant of factor XIII (FXIII) might have a protective effect against coronary artery disease (CAD), but studies not supporting these findings have also been published. The authors performed a meta-analysis of 16 studies on 5,346 cases and 7,053 controls that investigated the association between Val34Leu polymorphism and CAD defined as history of myocardial infarction or significant stenosis on a coronary artery assessed by coronary angiography. Because of the heterogeneity of the study-specific results, the pooled effect estimates were calculated by a random-effects empirical Bayes model. The combined odds ratios for CAD were 0.82 (95% confidence interval [95% Cl] 0.73, 0.94) for the heterozygotes of the FXIIIVal34Leu variant, 0.89 (95% CI 0.69, 1.13) for the homozygotes, and 0.81 (95% CI 0.70, 0.92) for the heterozygotes and homozygotes combined. The results were essentially the same when only myocardial infarction was considered as outcome. The beneficial effect of the polymorphism might be smaller than the effect estimates obtained in this metaanalysis, because the analysis raised the possibility of publication bias. Data published in the literature suggest that gene-gene and gene-environmental interactions might significantly influence the protective effect of FXIII-AVal34Leu polymorphism.
Clinical and Genetic Correlates of Aldosterone-to-Renin Ratio and Relations to Blood Pressure in a Community Sample
Authors: Newton-Cheh Christopher , Guo Chao-Yu , Gona Philimon , Larson Martin G. , Benjamin Emelia J. , Wang Thomas J. , Kathiresan Sekar , O’Donnell Christopher J. , Musone Stacy L. , Camargo Amy L. , Drake Jared A. , Levy Daniel , Hirschhorn Joel N. , Vasan Ramachandran S.
Published: February 2007

Aldosterone:renin ratio (ARR) is used to screen for hyperaldosteronism. Data regarding correlates of ambulatory ARR in the community and its relation to hypertension incidence are limited. We defined clinical correlates of ARR, determined its heritability, tested for association and linkage, and related ARR to blood pressure (BP) progression in nonhypertensive individuals among 3326 individuals from the Framingham Heart Study (53% women; mean age: 59 years). Ambulatory morning ARR (serum aldosterone and plasma renin concentrations) were related to clinical covariates, genetic variation across the
REN
locus, a 10-cM linkage map, and among nonhypertensive participants (n=1773) to progression of ≥1 Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure BP category (optimal: <120/80 mm Hg, normal: 120 to 129/80 to 84 mm Hg, high normal: 130 to 139/85 to 89 mm Hg, hypertension: ≥140/90 mm Hg), or incident hypertension (systolic BP: ≥140 mm Hg, diastolic BP: ≥90 mm Hg, or use of antihypertensive treatment). ARR was positively associated with age, female sex, untreated hypertension, total/high-density lipoprotein cholesterol ratio, hormone replacement therapy, and β-blocker use, but negatively associated with angiotensin-converting enzyme inhibitor and diuretic use. ARR was heritable (h
2
=0.40), had modest linkage to chromosome 11p (logarithm of the odds: 1.89), but was not associated with 17 common variants in
REN
(n=1729). On follow-up (mean: 3 years), 607 nonhypertensive individuals (34.2%) developed BP progression, and 283 (16.0%) developed hypertension. Higher baseline logARR was associated with increased risk of BP progression (odds ratio per SD increment: 1.23; 95% CI: 1.11 to 1.37) and hypertension incidence (odds ratio per SD increment: 1.16; 95% CI: 1.00 to 1.33). ARR is a heritable trait influenced by clinical and genetic factors. There is a continuous gradient of increasing risk of BP progression across ARR levels in nonhypertensive individuals.
Corin I555(P568) Allele Is Associated With Enhanced Cardiac Hypertrophic Response to Increased Systemic Afterload
Authors: Rame J. Eduardo , Drazner Mark H. , Post Wendy , Peshock Ronald , Lima Joao , Cooper Richard S. , Dries Daniel L.
Published: February 2007

Corin activates pro–A-type naturetic peptide and pro–B-type naturetic peptide into biologically active molecules. We recently identified a minor allele in the corin gene defined by 2 highly linked single nucleotide polymorphisms (T555I and Q568P), which was associated with hypertension in blacks. Because of the direct antihypertrophic effects of the natriuretic peptide system, we hypothesized that the minor corin I555(P568) allele would be associated with an enhanced hypertrophic response to pressure overload. The relationship between systolic blood pressure and indexed left ventricular mass, derived from cardiac MRI, was analyzed in the Dallas Heart Study as a function of corin allele status. The Multi-Ethnic Study of Atherosclerosis was used as a validation cohort. All of the analyses were limited to self-identified blacks without treatment for hypertension. In addition, we genotyped 2114 markers highly informative for African ancestry in the Dallas Heart Study and derived a covariate representing African ancestry for multivariate models. In adjusted analysis, the corin I555(P568) allele was an independent predictor of left-ventricular mass in subjects with elevated systolic blood pressure. Linear spline regression analysis confirmed a significant interaction (
P
=0.002) between the corin I555(P568) allele and systolic blood pressure as a predictor of left ventricular mass in subjects with systolic blood pressure >120 mm Hg, and this nonlinear interaction was replicated in the Multi-Ethnic Study of Atherosclerosis. In the Dallas Heart Study, the corin I555(P568) allele was also associated with an increased odds for prevalent left ventricular hypertrophy in the presence of untreated hypertension. These data suggest that the corin I555(P568) allele represents a cardiac hypertrophy-sensitizing genetic locus in systemic hypertension.
Polymorphism of
CYP11B2
Determines Salt Sensitivity in Japanese
Authors: Iwai Naoharu , Kajimoto Kazuaki , Tomoike Hitonobu , Takashima Naoyuki
Published: February 2007

Aldosterone plays essential roles in body fluid and electrolyte homeostasis and blood pressure. However, the association between polymorphisms in the
CYP11B2
gene and hypertension is controversial. We resequenced
CYP11B1
and
CYP11B2
and identified 35 polymorphisms in this region. We performed association studies between the plasma aldosterone concentration and 13 polymorphisms in this region in 1443 subjects. The subjects were all obtained from the Suita Cohort Study. Multiple regression analysis indicated that aldosterone levels were determined by renin activity, age, total cholesterol, and hematocrit. Residuals of the aldosterone levels after adjusting for these confounding factors were nominally associated with the T(−344)C (
P
=0.0026), C(595)T (
P
=0.0180), −(4837)C (
P
=0.0310), and G(4936)A (
P
=0.0498) polymorphisms. Only the T(−344)C polymorphism was significantly associated with the aldosterone level after a correction for multiple testing (Bonferroni). A significant interaction was observed between the T(−344)C polymorphism and renin activity in determining aldosterone levels. Moreover, a significant interaction was observed in 2063 subjects between urinary sodium excretion, which reflects sodium intake, and the T(−344)C polymorphism in determining systolic blood pressure. Only subjects with the TT genotype showed a positive correlation between urinary sodium excretion and systolic blood pressure. In vitro experiments confirmed the functional significance of this T(−344)C polymorphism in terms of angiotensin II reactivity. Thus, the T(−344)C polymorphism in
CYP11B2
appears to affect salt sensitivity in Japanese and to have clinical significance.
Diurnal, Seasonal, and Blood-Processing Patterns in Levels of Circulating Fibrinogen, Fibrin D-Dimer, C-Reactive Protein, Tissue Plasminogen Activator, and von Willebrand Factor in a 45-Year-Old Population
Authors: Rudnicka Alicja R. , Rumley Ann , Lowe Gordon D.O. , Strachan David P.
Published: February 2007

Background—

Circulating levels of fibrinogen, fibrin D-dimer, C-reactive protein (CRP), tissue plasminogen activator antigen (t-PA) and von Willebrand factor are associated with incident coronary heart disease. We describe cross-sectional diurnal, seasonal, and blood-processing patterns for these variables, and assess whether they represent important sources of variability that should be taken into account in epidemiological studies or for additional risk prediction in individuals.

Methods and Results—

A total of 9377 men and women aged 45 years were visited in their homes and blood-sampled for fibrinogen, D-dimer, CRP, t-PA, and von Willebrand factor. These variables were examined in relation to the time of blood sample collection, day of the year, and delay in processing. All variables exhibited statistically significant diurnal sinusoidality (
P
≤0.02). Our models predicted a peak rise for fibrinogen and von Willebrand factor at midday, with overall diurnal variations of 3% and 10%, respectively, after adjustment for standard cardiovascular risk factors. D-dimer exhibited a peak at 14:00 hours, CRP at 15:00 hours, and t-PA at 10:00 hours with diurnal variations of 10%, 34%, and 55%, respectively, after full adjustment. All variables except CRP showed seasonal heterogeneity. Greater delays in processing blood samples were associated with higher levels of t-PA in particular. The proportion of variation attributed to the diurnal, seasonal, and processing effects was 2% for fibrinogen and von Willebrand factor; 9% for D-dimer, 1% for CRP, and 16% for t-PA.

Conclusions—

Temporal variations are important sources of heterogeneity that may bias the analysis of epidemiological studies and coronary heart disease risk prediction in individuals. Sample-processing delay is particularly important for t-PA.
Remote Magnetic Navigation to Guide Endocardial and Epicardial Catheter Mapping of Scar-Related Ventricular Tachycardia
Authors: Aryana Arash , d’Avila Andre , Heist E. Kevin , Mela Theofanie , Singh Jagmeet P. , Ruskin Jeremy N. , Reddy Vivek Y.
Published: February 2007

Background—

The present study examines the safety and feasibility of using a remote magnetic navigation system to perform endocardial and epicardial substrate-based mapping and radiofrequency ablation in patients with scar-related ventricular tachycardia (VT).

Methods and Results—

Using the magnetic navigation system, we performed 27 procedures on 24 consecutive patients with a history of VT related to myocardial infarction, dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, hypertrophic cardiomyopathy, or sarcoidosis. Electroanatomic mapping of the left ventricular, right ventricular, and ventricular epicardial surfaces was constructed in 24, 10, and 12 patients, respectively. Complete-chamber VT activation maps were created in 4 patients. A total of 77 VTs were inducible, of which 21 were targeted during VT with the remotely navigated radiofrequency ablation catheter alone. With a combination of entrainment and activation mapping, 17 of 21 VTs (81%) were successfully terminated in a mean of 8.4±8.2 seconds; for the remainder, irrigated radiofrequency ablation was necessary. The mean fluoroscopy times for endocardial and epicardial mapping were 27±23 seconds (range, 0 to 105 seconds) and 18±18 seconds (range, 0 to 49 seconds), respectively. In concert with a manually navigated irrigated ablation catheter, 75 of 77 VTs (97%) were ultimately ablated. Four patients underwent a second procedure for recurrent VT, 3 with the magnetic navigation system. After 1.2 procedures per patient, VT did not recur during a mean follow-up of 7±3 months (range, 2 to 12 months).

Conclusions—

The present study demonstrates the safety and feasibility of remote catheter navigation to perform substrate mapping of scar-related VT in a wide range of disease states with a minimal amount of fluoroscopy exposure.
Malaya, 1948: Britain's Asian Cold War?
Authors: Deery Phillip
Published: February 2007

In 1948, at a time of severe economic austerity, the British Labour government committed itself to a costly and protracted campaign against a Communist foe in the Far East, despite not having any U.S. support for the endeavor. Clement Attlee's government in Britain argued that the Malayan Emergency (1948–1960) was necessary to counter Soviet attempts to use the local Communist party in support of Moscow's expansionist designs. Subsequently, many commentators and historians accepted this judgment, at least to some degree. In reality, the rebellion, far from being carefully coordinated or meticulously organized, was inadequately planned and poorly executed. The 1948 insurrection cannot be understood without recognizing the influence of indigenous pressures and internal developments, which were more crucial than the external Cold War dimension.
Transparency and Security Competition: Open Skies and America's Cold War Statecraft, 1948–1960
Authors: Marquardt James J.
Published: February 2007

In recent years, scholars have devoted considerable attention to the role of transparency in international relations. U.S. efforts during the early Cold War to press for greater openness as a way of reducing tensions with the Soviet Union are often cited by specialists on military transparency. Yet the ill-fated Open Skies proposal has not been thoroughly investigated. This article draws on primary documents from the Truman and Eisenhower administrations to show that proponents of transparency have generally drawn the wrong conclusions about Open Skies. The U.S. proposal for a system of aerial observation was part and parcel of a strategy to contain and ultimately defeat the Soviet Union. Consequently, Open Skies does not conform to the logic of transparency as a confidence-building measure; it instead affirms basic realist thinking about the competition for security between rivals. Future scholarship that appreciates how the quest for a more open world is affected by the competition for security would improve our understanding of the causes, consequences, and limitations of transparency.