bluuebunny/crossref_metadata_2025 huggingface dataset:
Postnatal maturation modulates relationships among cytosolic Ca2+, myosin light chain phosphorylation, and contractile tone in ovine cerebral arteries
Authors: Sandoval Renan J. , Injeti Elisha R. , Gerthoffer William T. , Pearce William J.
Published: July 2007

The present study tests the hypothesis that age-related changes in patterns of agonist-induced myofilament Ca2+sensitization involve corresponding differences in the relative contributions of thick- and thin-filament regulation to overall myofilament Ca2+sensitivity. Posterior communicating cerebral arteries from term fetal and nonpregnant adult sheep were used in measurements of cytosolic Ca2+, myosin light chain (MLC) phosphorylation, and contractile tensions induced by varying concentrations of K+or serotonin [5-hydroxytryptamine (5-HT)]. The results were used to assess the relative contributions of the relationships between cytosolic Ca2+and MLC phosphorylation (thick-filament reactivity), along with the relationships between MLC phosphorylation and contractile tension (thin-filament reactivity), to overall myofilament Ca2+sensitivity. For K+-induced contractions, both fetal and adult arteries exhibited similar basal myofilament Ca2+sensitivity. Despite this similarity, thick-filament reactivity was greater in fetal arteries, whereas thin-filament reactivity was greater in adult arteries. In contrast, 5-HT-induced contractions exhibited increased myofilament Ca2+sensitivity compared with K+-induced contractions for both fetal and adult cerebral arteries, and the magnitude of this effect was greater in fetal compared with adult arteries. When interpreted together with our previous studies of 5-HT-induced myofilament Ca2+sensitization, we attributed the present effects to agonist enhancement of thick-filament reactivity in fetal arteries mediated by G protein receptor activation of a PKC-independent but RhoA-dependent pathway. In adult arteries, agonist stimulation enhanced thin-filament reactivity was also probably mediated through G protein-coupled activation of RhoA-dependent and PKC-independent mechanisms. Overall, the present data demonstrate that agonist-enhanced myofilament Ca2+sensitivity can be partitioned into separate thick- and thin-filament effects, the magnitudes of which are different between fetal and adult cerebral arteries.
Systemic nitric oxide synthase inhibition improves coronary flow reserve to adenosine in patients with significant stenoses
Authors: Kaufmann Philipp A. , Rimoldi Ornella E. , Gnecchi-Ruscone Tomaso , Luscher Thomas F. , Camici Paolo G.
Published: July 2007

We studied the impact of systemic infusion of the nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (l-NMMA) on coronary flow reserve (CFR) in patients with coronary artery disease (CAD). We have previously demonstrated that CFR to adenosine was significantly increased after systemic infusion of l-NMMA in normal volunteers but not in recently transplanted denervated hearts. At baseline, myocardial blood flow (MBF; ml·min−1·g−1) was measured at rest and during intravenous administration of adenosine (140 μg·kg−1·min−1) in 10 controls (47 ± 5 yr) and 10 CAD patients (58 ± 8 yr; P < 0.01 vs. controls) using positron emission tomography and 15O-labeled water. Both MBF measurements were repeated during intravenous infusion of 10 mg/kg l-NMMA. CFR was calculated as the ratio of MBF during adenosine to MBF at rest. CFR was significantly higher in healthy volunteers than in CAD patients and increased significantly after l-NMMA in controls (4.00 ± 1.10 to 6.15 ± 1.35; P < 0.0001) and in patients, both in territories subtended by stenotic coronary arteries (>70% luminal diameter; 2.06 ± 1.13 to 3.21 ± 1.07; P < 0.01) and in remote segments (3.20 ± 1.23 to 3.92 ± 1.62; P < 0.05). In conclusion, CFR can be significantly increased in CAD by a systemic infusion of l-NMMA. Similarly to our previous findings in normal volunteers, this suggests that adenosine-induced hyperemia in CAD patients is constrained by a mechanism that can be relieved by systemic NOS inhibition with l-NMMA.
Protein kinase C-ε coimmunoprecipitates with cytochrome oxidase subunit IV and is associated with improved cytochrome-coxidase activity and cardioprotection
Authors: Guo Dehuang , Nguyen Tiffany , Ogbi Mourad , Tawfik Huda , Ma Guochun , Yu Qilin , Caldwell Robert W. , Johnson John A.
Published: July 2007

We have utilized an in situ rat coronary ligation model to establish a PKC-ε cytochrome oxidase subunit IV (COIV) coimmunoprecipitation in myocardium exposed to ischemic preconditioning (PC). Ischemia-reperfusion (I/R) damage and PC protection were confirmed using tetrazolium-based staining methods and serum levels of cardiac troponin I. Homogenates prepared from the regions at risk (RAR) and not at risk (RNAR) for I/R injury were fractionated into cell-soluble (S), 600 g low-speed centrifugation (L), Percoll/Optiprep density gradient-purified mitochondrial (M), and 100,000 g particulate (P) fractions. COIV immunoreactivity and cytochrome- c oxidase activity measurements estimated the percentages of cellular mitochondria in S, L, M, and P fractions to be 0, 55, 29, and 16%, respectively. We observed 18, 3, and 3% of PKC-δ, -ε, and -ζ isozymes in the M fraction under basal conditions. Following PC, we observed a 61% increase in PKC-ε levels in the RAR M fraction compared with the RNAR M fraction. In RAR mitochondria, we also observed a 2.8-fold increase in PKC-ε serine 729 phosphoimmunoreactivity (autophosphorylation), indicating the presence of activated PKC-ε in mitochondria following PC. PC administered before prolonged I/R induced a 1.9-fold increase in the coimmunoprecipitation of COIV, with anti-PKC-ε antisera and a twofold enhancement of cytochrome- c oxidase activity. Our results suggest that PKC-ε may interact with COIV as a component of the cardioprotection in PC. Induction of this interaction may provide a novel therapeutic target for protecting the heart from I/R damage.
Basolateral chloride current in human airway epithelia
Authors: Itani Omar A. , Lamb Fred S. , Melvin James E. , Welsh Michael J.
Published: July 2007

Electrolyte transport by airway epithelia regulates the quantity and composition of liquid covering the airways. Previous data indicate that airway epithelia can absorb NaCl. At the apical membrane, cystic fibrosis transmembrane conductance regulator (CFTR) provides a pathway for Cl− absorption. However, the pathways for basolateral Cl− exit are not well understood. Earlier studies, predominantly in cell lines, have reported that the basolateral membrane contains a Cl− conductance. However, the properties have varied substantially in different epithelia. To better understand the basolateral Cl− conductance in airway epithelia, we studied primary cultures of well-differentiated human airway epithelia. The basolateral membrane contained a Cl− current that was inhibited by 4,4′-diisothiocyanostilbene-2,2′-disulfonic acid (DIDS). The current-voltage relationship was nearly linear, and the halide selectivity was Cl− > Br− >> I−. Several signaling pathways increased the current, including elevation of cellular levels of cAMP, activation of protein kinase C (PKC), and reduction of pH. In contrast, increasing cell Ca2+ and inducing cell swelling had no effect. The basolateral Cl− current was present in both cystic fibrosis (CF) and non-CF airway epithelia. Likewise, airway epithelia from wild-type mice and mice with disrupted genes for ClC-2 or ClC-3 all showed similar Cl− currents. These data suggest that the basolateral membrane of airway epithelia possesses a Cl− conductance that is not due to CFTR, ClC-2, or ClC-3. Its regulation by cAMP and PKC signaling pathways suggests that coordinated regulation of Cl− conductance in both apical and basolateral membranes may be important in controlling transepithelial Cl− movement.
Disruption of NO-cGMP signaling by neonatal hyperoxia impairs relaxation of lung parenchyma
Authors: Sopi Ramadan B. , Haxhiu Musa A. , Martin Richard J. , Dreshaj Ismail A. , Kamath Suneel , Zaidi Syed I. A.
Published: July 2007

Exposure of immature lungs to hyperoxia for prolonged periods contributes to neonatal lung injury and airway hyperreactivity. We studied the role of disrupted nitric oxide-guanosine 3′,5′-cyclic monophosphate (NO-cGMP) signaling in impairing the relaxant responses of lung tissue from hyperoxia-exposed rat pups. Pups were exposed to ≥95% O2 or room air for 7 days starting from days 1, 5, or 14. The animals were killed, lungs were removed, and 1-mm-thick lung parenchymal strips were prepared. Lung parenchymal strips of room air or hyperoxic pups were preconstricted using bethanechol and then graded electrical field stimulation (EFS) was applied to induce relaxation. EFS-induced relaxation of lung parenchymal strips was greater at 7 and 12 days than at 21 days in room air-exposed rat pups. Hyperoxic exposure significantly reduced relaxation at 7 and 12 days but not 21 days compared with room air exposure. NO synthase blockade with Nω-nitro-l-arginine methyl ester diminished relaxant responses in room air but not in hyperoxic pups at 12 days. After incubation with supplemental l-arginine, the relaxation response of hyperoxic strips was restored. cGMP, a key mediator of the NO signaling pathway, also decreased in strips from hyperoxic vs. room air pups and cGMP levels were restored after incubation with supplemental l-arginine. In addition, arginase activity was significantly increased in hyperoxic lung parenchymal strips compared with room air lung parenchymal strips. These data demonstrate disruption of NO-cGMP signaling in neonatal rat pups exposed to hyperoxia and show that bioavailability of the substrate l-arginine is implicated in the predisposition of this model to airway hyperreactivity.
TRPV4 initiates the acute calcium-dependent permeability increase during ventilator-induced lung injury in isolated mouse lungs
Authors: Hamanaka Kazutoshi , Jian Ming-Yuan , Weber David S. , Alvarez Diego F. , Townsley Mary I. , Al-Mehdi Abu B. , King Judy A. , Liedtke Wolfgang , Parker James C.
Published: July 2007

We have previously implicated calcium entry through stretch-activated cation channels in initiating the acute pulmonary vascular permeability increase in response to high peak inflation pressure (PIP) ventilation. However, the molecular identity of the channel is not known. We hypothesized that the transient receptor potential vanilloid-4 (TRPV4) channel may initiate this acute permeability increase because endothelial calcium entry through TRPV4 channels occurs in response to hypotonic mechanical stress, heat, and P-450 epoxygenase metabolites of arachidonic acid. Therefore, permeability was assessed by measuring the filtration coefficient (Kf) in isolated perfused lungs of C57BL/6 mice after 30-min ventilation periods of 9, 25, and 35 cmH2O PIP at both 35°C and 40°C. Ventilation with 35 cmH2O PIP increased Kf by 2.2-fold at 35°C and 3.3-fold at 40°C compared with baseline, but Kf increased significantly with time at 40°C with 9 cmH2O PIP. Pretreatment with inhibitors of TRPV4 (ruthenium red), arachidonic acid production (methanandamide), or P-450 epoxygenases (miconazole) prevented the increases in Kf. In TRPV4−/− knockout mice, the high PIP ventilation protocol did not increase Kf at either temperature. We have also found that lung distention caused Ca2+ entry in isolated mouse lungs, as measured by ratiometric fluorescence microscopy, which was absent in TRPV4−/− and ruthenium red-treated lungs. Alveolar and perivascular edema was significantly reduced in TRPV4−/− lungs. We conclude that rapid calcium entry through TRPV4 channels is a major determinant of the acute vascular permeability increase in lungs following high PIP ventilation.
Exposure of differentiated airway smooth muscle cells to serum stimulates both induction of hypoxia-inducible factor-1α and airway responsiveness to ACh
Authors: Chachami Georgia , Hatziefthimiou Apostolia , Liakos Panagiotis , Ioannou Maria G. , Koukoulis Georgios K. , Bonanou Sofia , Molyvdas Paschalis-Adam , Simos George , Paraskeva Efrosyni
Published: July 2007

Airway smooth muscle (ASM) cells are characterized by phenotypic plasticity and can switch between differentiated and proliferative phenotypes. In rabbit tracheal ASM cells that had been differentiated in vitro by serum starvation, readdition of FBS caused initiation of proliferation and induction of nuclear and transcriptionally active hypoxia-inducible factor (HIF)-1α. In addition, FBS stimulated the induction of HIF-1α by the hypoxia mimetic cobalt. Treatment with actinomycin D, cycloheximide, the phosphatidylinositol 3-kinase inhibitors LY-294002 and wortmannin or the reactive oxygen species scavenger diphenyleneiodonium inhibited the FBS-dependent induction of HIF-1α. These data indicate that, in differentiated ASM cells, FBS upregulates HIF-1α by a transcription-, translation-, phosphatidylinositol 3-kinase-, and reactive oxygen species-dependent mechanism. Interestingly, addition of FBS and cobalt also induced HIF-1α in organ cultures of rabbit trachea strips and synergistically increased their contractile response to ACh, suggesting that HIF-1α might be implicated in airway hypercontractility.
LGL1, a novel branching morphogen in developing kidney, is induced by retinoic acid
Authors: Quinlan Jacklyn , Kaplan Feige , Sweezey Neil , Goodyer Paul
Published: August 2007

Late-gestation lung protein 1 (LGL1) is a glycoprotein secreted by fetal lung mesenchyme that stimulates branching morphogenesis of the developing lung bud. We show that Lgl1 mRNA and protein are also expressed in mesenchymally derived lineages of fetal kidney. Although Lgl1 expression is stimulated by glucocorticoids in kidney cells, cortisol (10−7M) actually suppresses ureteric bud branching of fetal kidneys from HoxB7/GFP mice in explant culture. However, early branching morphogenesis in the lung and kidney is stimulated by retinoic acid, and we identified putative retinoic acid response elements in the Lgl1 promoter. All- trans-retinoic acid (10−6M) stimulated Lgl1 promoter activity and endogenous Lgl1 mRNA expression in vitro. Branching of cultured fetal kidney explants was increased in the presence of all- trans retinoic acid (10−6M). Heterozygous Lgl1 knockout mice were crossed to HoxB7/GFP mice to visualize the extent of ureteric bud branching at fetal stages. At embryonic (E) days E12.5–E13.0, mutant Lgl1+/−embryos showed a 20% reduction in ureteric bud branching compared with wild-type littermates. We propose a model in which retinoic acid stimulates branching morphogenesis by activating Lgl1 early in development. The prominent effects of glucocorticoids on Lgl1 expression in late lung development suggest a second role for LGL1 in alveolar maturation.
Activation and involvement of p53 in cisplatin-induced nephrotoxicity
Authors: Wei Qingqing , Dong Guie , Yang Tianxin , Megyesi Judit , Price Peter M. , Dong Zheng
Published: August 2007

Cisplatin, a widely used chemotherapy drug, induces acute kidney injury, which limits its use and efficacy in cancer treatment. However, the molecular mechanism of cisplatin-induced nephrotoxicity is currently unclear. Using pharmacological and gene knockout models, we now demonstrate a pathological role for p53 in cisplatin nephrotoxicity. In C57BL/6 mice, cisplatin treatment induced p53 phosphorylation and protein accumulation, which was accompanied by the development of acute kidney injury. p53 was induced in both proximal and distal tubular cells and partially colocalized with apoptosis. Pifithrin-α, a pharmacological inhibitor of p53, suppressed p53 activation and ameliorated kidney injury during cisplatin treatment. Moreover, cisplatin-induced nephrotoxicity was abrogated in p53-deficient mice. Compared with wild-type animals, p53-deficient mice showed a better renal function, less tissue damage, and fewer apoptotic cells. In addition, cisplatin induced less apoptosis in proximal tubular cells isolated from p53-deficient mice than the cells from wild-type animals. Together these results suggest the involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity.
Ouabain modulation of cellular calcium stores and signaling
Authors: Edwards Aurélie , Pallone Thomas L.
Published: August 2007

Ouabain-like factors modulate intracellular Ca2+ concentrations and Ca2+ stores. Recently, a role for Na+-K+-ATPase Na+ transport inhibition as a pivotal event in ouabain signaling was questioned (Kaunitz JD. Am J Physiol Renal Physiol 290: F995–F996, 2006). In the present study, we used a mathematical model of Ca2+ trafficking in cytoplasm and subplasmalemmal microdomains to simulate the pathways through which ouabain can affect Ca2+ signaling: inhibition of active transport by Na+-K+-ATPase α1- and α2-isoforms, activation of inositol trisphosphate (IP3) production, and increased IP3 receptor (IP3R) conductance. A fundamental prediction is that Na+-K+-ATPase inhibition favors sarcoplasmic reticulum Ca2+ store loading, whereas Src-mediated increases in IP3 production and IP3R sensitization favor store depletion. The model predicts that α2-isoform inhibition generates a peak-and-plateau pattern of cytosolic Ca2+ concentration ([Ca2+]cyt) elevation, whereas α1-isoform inhibition yields a monophasic rise. The effects of ouabain-mediated increases in IP3 production or IP3R conductance on [Ca2+]cyt depend on their relative distributions between cellular microdomains and the bulk cytoplasm. Simulations suggest that the intracellular localization of IP3 production is a pivotal determinant of the changes in compartmental Ca2+ concentrations that can be induced by ouabain. As a consequence of sequestration of the ouabain-sensitive α2-isoform into microdomains, inhibition of the α2-isoform in rodents is not predicted to significantly affect cytosolic Na+ concentration. Model simulations support the hypothesis that ouabain can enhance agonist-evoked [Ca2+]cyt transients when its predominant effect is to inhibit α2-isoform Na+ transport and, thereby, increase Ca2+ loading into sarcoplasmic reticulum stores.
The role of ICAM-1 in endotoxin-induced acute renal failure
Authors: Wu Xiaoyan , Guo Rongqing , Wang Ying , Cunningham Patrick N.
Published: August 2007

The pathogenesis of acute renal failure (ARF) occurring during the course of sepsis is incompletely understood. Intercellular adhesion molecule-1 (ICAM-1) is a key cell adhesion molecule upregulated by LPS, which binds to the integrins CD11a/CD18 and CD11b/CD18 present on the surface of leukocytes. We hypothesized that ICAM-1 facilitates renal injury in LPS-induced ARF. To test this, three groups of mice ( n = 8 per group) were injected intraperitoneally with 6 mg/kg LPS: 1) normal C57BL/6 mice, 2) mice with a targeted deficiency of ICAM-1 (ICAM-1−/−), and 3) mice expressing very low levels of CD18 (CD18-def). ICAM-1−/−mice were significantly resistant to LPS-mediated ARF, as opposed to CD18-def mice, which developed severe ARF, as did wild-type controls (48 h blood urea nitrogen 143 ± 31.5, 70.8 ± 24.4, and 185 ± 16.6 mg/dl in wild-type, ICAM-1−/−, and CD18-def mice, respectively, P < 0.05). At death, ICAM-1−/−mice had significantly less renal neutrophil infiltration than the other two groups, as well as less histological tubular injury. Depletion of neutrophils with mAb Gr-1 led to a profound exaggeration of tumor necrosis factor (TNF) release and high mortality, but neutrophil-depleted mice receiving 10-fold less LPS were protected against ARF despite TNF release similar to what is normally associated with LPS-induced ARF. LPS caused a significant increase in renal expression of chemokines; however, this increase was significantly exaggerated in CD18-def mice, which may account for their lack of protection. In conclusion, these data show that ICAM-1 plays a key role in LPS-induced ARF.
Sensitivity of breast cancer cells to erlotinib depends on cyclin-dependent kinase 2 activity
Authors: Yamasaki Fumiyuki , Zhang Dongwei , Bartholomeusz Chandra , Sudo Tamotsu , Hortobagyi Gabriel N. , Kurisu Kaoru , Ueno Naoto T.
Published: August 2007

Inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinases, such as erlotinib and gefitinib, have not been very effective in the treatment of breast cancer although many breast cancer cells express EGFR. To address this apparent paradox, we examined possible predictors of the sensitivity of 10 breast cancer cell lines to erlotinib in light of cyclin-dependent kinase 2 (CDK2), considered the farthest downstream kinase that controls cell cycling in the EGFR signaling pathway. Expression of EGFR and HER2 were not associated with sensitivity to erlotinib. Expression of phosphorylated (p-)tyrosine, p-Akt, phosphorylated extracellular signal-regulated kinase (p-ERK) 1/ERK2 (p42/p44), and p27 after treatment of erlotinib was not associated with erlotinib sensitivity. However, suppression of CDK2 activity after erlotinib treatment correlated with erlotinib sensitivity (P < 0.0001). Restoration of CDK2 activity partially restored proliferation and induced erlotinib resistance in erlotinib-sensitive cell lines, indicating that sensitivity to erlotinib in these breast cancer cells depends, at least in part, on CDK2 activity. p27, an inhibitor of CDK2, was not translocated into the nucleus in erlotinib-resistant cell lines. Knocking down p27 protein partially blocked erlotinib-induced cell death and cell cycle arrest. These findings indicate that the ability of erlotinib to suppress CDK2 activity is critical for cellular sensitivity to erlotinib, regardless of EGFR expression level, and that the presence of p27 in the cytoplasm also participates in erlotinib resistance. [Mol Cancer Ther 2007;6(8):2168–77]
Differentially expressed genes in radioresistant nasopharyngeal cancer cells: gp96 and GDF15
Authors: Chang Joseph Tung-Chieh , Chan Shih-Hsuan , Lin Chien-Yu , Lin Ting-Yang , Wang Hung-Ming , Liao Chun-Ta , Wang Tzu-Hao , Lee Li-Yu , Cheng Ann-Joy
Published: August 2007

Radiotherapy is the major treatment modality for nasopharyngeal cancer (NPC), but in some cases, the disease is radioresistant. We designed this study to identify genes that may be involved in this resistance. We first established two radioresistant subclone cell lines derived from NPC parental cell lines (NPC-076 and NPC-BM1) by treating the cells with four rounds of sublethal ionizing radiation. cDNA microarray analysis was then done, comparing the two resistant cell lines with their corresponding parental cell lines. Seven genes were found to be up-regulated in radioresistant subclones, including gp96 and GDF15, which had shown highest overexpressions. We constructed small interfering RNA plasmids (gp96si and GDF15si) and transfected them into NPC cells to knock down these genes and examine whether this changed their response to radiation. Both gp96si and GDF15si transfectants had radiation-induced growth delay and reduction in colonogenic survival compared with control cells. Knockdown of either gp96 or GDF15 increased the proportion of the cells in G2-M phase, the most radiosensitive phase of the cell cycle. We have therefore identified at least two genes, gp96 and GDF15, involved in radioresistance of NPC cell lines and showed that knockdown of the genes enhances radiosensitivity. [Mol Cancer Ther 2007;6(8):2271–9]
A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor–dependent tumor growth in vivo
Authors: Ji Qun-sheng , Mulvihill Mark J. , Rosenfeld-Franklin Maryland , Cooke Andrew , Feng Lixin , Mak Gilda , O'Connor Matthew , Yao Yan , Pirritt Caroline , Buck Elizabeth , Eyzaguirre Alexandra , Arnold Lee D. , Gibson Neil W. , Pachter Jonathan A.
Published: August 2007

Insulin-like growth factor-I receptor (IGF-IR) and its ligands, IGF-I and IGF-II, are up-regulated in a variety of human cancers. In tumors, such as colorectal, non–small cell lung, ovarian, and pediatric cancers, which may drive their own growth and survival through autocrine IGF-II expression, the role of IGF-IR is especially critical. Here, we present a novel small-molecule IGF-IR kinase inhibitor, cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo[1,5-a]pyrazin-8-ylamine (PQIP), which displayed a cellular IC50 of 19 nmol/L for inhibition of ligand-dependent autophosphorylation of human IGF-IR with 14-fold cellular selectivity relative to the human insulin receptor. PQIP showed minimal activity against a panel of 32 other protein kinases. It also abolished the ligand-induced activation of downstream phosphorylated AKT and phosphorylated extracellular signal-regulated kinase 1/2 in both IGF-IR transfectant cells and a GEO human colorectal cancer cell line. Analysis of GEO cells revealed a significant level of both phosphorylated IGF-IR and IGF-II expression. Furthermore, inactivation of IGF-II in conditioned GEO culture medium by a neutralizing antibody diminished IGF-IR activation, indicating the presence of a functional IGF-II/IGF-IR autocrine loop in GEO cells. Once daily oral dosing of PQIP induced robust antitumor efficacy in GEO xenografts. The antitumor efficacy correlated with the degree and duration of inhibition of tumor IGF-IR phosphorylation in vivo by this compound. Moreover, when mice were treated for 3 days with a dose of PQIP that maximally inhibited tumor growth, only minor changes in blood glucose were observed. Thus, PQIP represents a potent and selective IGF-IR kinase inhibitor that is especially efficacious in an IGF-II–driven human tumor model. [Mol Cancer Ther 2007;6(8):2158–67]
The PPAR-Gamma Activator Rosiglitazone Fails to Lower Plasma Growth Hormone and Insulin-Like Growth Factor-1 Levels in Patients with Acromegaly
Authors: Bastemir Mehmet , Akin Fulya , Yaylali Guzin Fidan
Published: August 2007

Background/Aim: Despite combined therapy consisting of surgery, external X-ray, and medical therapy, a significant number of acromegaly patients continue to have uncontrolled growth hormone (GH) secretion and active disease. These patients, particularly those with large or invasive tumors, require additional therapy to decrease their GH levels. Our aim was to investigate whether patients with documented GH-secreting pituitary adenomas leading to acromegaly would respond with attenuation of GH and insulin-like growth factor-1 (IGF-1) levels after treatment with a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist. Methods: We conducted prospective analyses in the Endocrinology Clinic of the Pamukkale University. Acromegaly patients who had active disease participated in two admissions: before and after 6 weeks of daily treatment with 8 mg of oral rosiglitazone. Four male and 3 female patients have completed the study. Basal and nadir GH levels during an oral glucose tolerance test were determined, and the IGF-1 and IGF-binding protein-3 levels were also measured both before and 6 weeks after the rosiglitazone treatment. Results: Treatment with rosigitazone did not reduce basal and nadir GH levels during the oral glucose tolerance test and the IGF-1 levels in the patient population as a whole (p > 0.05). Conclusions: The PPAR-γ activator rosiglitazone, used at maximum approved dosage, did not reduce plasma GH and IGF-1 levels in patients with acromegaly. Further studies with higher doses and longer duration of PPAR-γ agonist administration would be required to determine its usefulness in the treatment in this group of patients.
Secretion of Apolipoprotein E From Macrophages Occurs via a Protein Kinase A– and Calcium-Dependent Pathway Along the Microtubule Network
Authors: Kockx Maaike , Guo Dongni Lily , Huby Thierry , Lesnik Philippe , Kay Jason , Sabaretnam Tharani , Jary Eve , Hill Michael , Gaus Katharina , Chapman John , Stow Jennifer L. , Jessup Wendy , Kritharides Leonard
Published: July 2007

Macrophage-specific expression of apolipoprotein (apo)E protects against atherosclerosis; however, the signaling and trafficking pathways regulating secretion of apoE are unknown. We investigated the roles of the actin skeleton, microtubules, protein kinase A (PKA) and calcium (Ca
2+
) in regulating apoE secretion from macrophages. Disrupting microtubules with vinblastine or colchicine inhibited basal secretion of apoE substantially, whereas disruption of the actin skeleton had no effect. Structurally distinct inhibitors of PKA (H89, KT5720, inhibitory peptide PKI
14–22
) all decreased basal secretion of apoE by between 50% to 80% (
P
<0.01). Pulse-chase experiments demonstrated that inhibition of PKA reduced the rate of apoE secretion without affecting its degradation. Confocal microscopy and live cell imaging of apoE–green fluorescent protein–transfected RAW macrophages identified apoE–green fluorescent protein in vesicles colocalized with the microtubular network, and inhibition of PKA markedly inhibited vesicular movement. Chelation of intracellular calcium ([Ca
2+
]
i
) with 1,2-bis(2-aminophenoxy)ethane-
N
,
N
,
N
′,
N
′-tetraacetate-acetoxymethyl ester (BAPTA-AM) inhibited apoE secretion by 77.2% (
P
<0.01). Injection of c57Bl6 apoE
+/+
bone marrow–derived macrophages into the peritoneum of apoE
−/−
C57Bl6 mice resulted in time-dependent secretion of apoE into plasma, which was significantly inhibited by transient exposure of macrophages to BAPTA-AM and colchicine and less effectively inhibited by H89. We conclude that macrophage secretion of apoE occurs via a PKA- and calcium-dependent pathway along the microtubule network.
Voting and Liberty
Authors: Palonen Kari
Published: August 2007

In this paper, the author takes up the opposition between liberty and dependence proposed by Quentin Skinner and applies it to the analysis of the debates involving voting rights and regulations. The goal here is to examine the rhetoric supporting different positions in favor and against the extension of suffrage, the exclusion of certain groups, etc. The author points out that dependence can be detected even in democratic societies that lack traditional hierarchies. A similar effort is made to think how commitment, deliberation, and contestation can take place in the context of today's representative democracy in ways that enhance freedom instead of endangering it.
Global Patterns of Low-Mode Internal-Wave Propagation. Part I: Energy and Energy Flux
Authors: Alford Matthew H. , Zhao Zhongxiang
Published: August 2007

Extending an earlier attempt to understand long-range propagation of the global internal-wave field, the energy E and horizontal energy flux F are computed for the two gravest baroclinic modes at 80 historical moorings around the globe. With bandpass filtering, the calculation is performed for the semidiurnal band (emphasizing M2 internal tides, generated by flow over sloping topography) and for the near-inertial band (emphasizing wind-generated waves near the Coriolis frequency). The time dependence of semidiurnal E and F is first examined at six locations north of the Hawaiian Ridge; E and F typically rise and fall together and can vary by over an order of magnitude at each site. This variability typically has a strong spring–neap component, in addition to longer time scales. The observed spring tides at sites northwest of the Hawaiian Ridge are coherent with barotropic forcing at the ridge, but lagged by times consistent with travel at the theoretical mode-1 group speed from the ridge. Phase computed from 14-day windows varies by approximately ±45° on monthly time scales, implying refraction by mesoscale currents and stratification. This refraction also causes the bulk of internal-tide energy flux to be undetectable by altimetry and other long-term harmonic-analysis techniques. As found previously, the mean flux in both frequency bands is O(1 kW m−1), sufficient to radiate a substantial fraction of energy far from each source. Tidal flux is generally away from regions of strong topography. Near-inertial flux is overwhelmingly equatorward, as required for waves generated at the inertial frequency on a β plane, and is winter-enhanced, consistent with storm generation. In a companion paper, the group velocity, ĉg ≡ FE−1, is examined for both frequency bands.
The Effect of a New Drag-Law Parameterization on Ice Shelf Water Plume Dynamics
Authors: Wilchinsky Alexander V. , Feltham Daniel L. , Holland Paul R.
Published: August 2007

A drag law accounting for Ekman rotation adjacent to a flat, horizontal boundary is proposed for use in a plume model that is written in terms of the depth-mean velocity. The drag law contains a variable turning angle between the mean velocity and the drag imposed by the turbulent boundary layer. The effect of the variable turning angle in the drag law is studied for a plume of ice shelf water (ISW) ascending and turning beneath an Antarctic ice shelf with draft decreasing away from the grounding line. As the ISW plume ascends the sloping ice shelf–ocean boundary, it can melt the ice shelf, which alters the buoyancy forcing driving the plume motion. Under these conditions, the typical turning angle is of order −10° over most of the plume area for a range of drag coefficients (the minus sign arises for the Southern Hemisphere). The rotation of the drag with respect to the mean velocity is found to be significant if the drag coefficient exceeds 0.003; in this case the plume body propagates farther along and across the base of the ice shelf than a plume with the standard quadratic drag law with no turning angle.
The effect of background music and background noise on the task performance of introverts and extraverts
Authors: Cassidy Gianna , MacDonald Raymond A.R.
Published: August 2007

The study investigated the effects of music with high arousal potential and negative affect (HA), music with low arousal potential and positive affect (LA), and everyday noise, on the cognitive task performance of introverts and extraverts. Forty participants completed five cognitive tasks: immediate recall, free recall, numerical and delayed recall, and Stroop. Ten participants completed each of these tasks in one of four sound conditions: HA, LA, everyday noise and silence. Participants were also assessed for levels of introversion/ extroversion, and reported their music/noise and study preferences. Performance was lessened across all cognitive tasks in the presence of background sound (music or noise) compared to silence. HA and LA music produced differential distraction effects, with performance of all tasks being poorer in the presence of HA compared to LA and silence, in the presence of noise than silence across all tasks, and in the presence of noise than LA in three of the four tasks. Performance was moderated by internal arousal, with introverts performing better overall on each task except the Stroop, and appearing to be more detrimentally affected by the presence of HA music and noise.
Beyond Discontinuity: Expansive Organizational Learning Remembered
Authors: Engeström Yrjö , Kerosuo Hannele , Kajamaa Anu
Published: August 2007

We analyze traces of past organizational change projects in order to uncover dynamics of continuity and discontinuity of organizational learning in two Finnish primary health care organizations. The method of the study is `archaeological ethnography', which integrates narrative analysis of participants' accounts of past change efforts with analysis of documents and material traces of change. The study shows that similarly motivated expansive learning efforts initiated 15 years ago have been discontinuous in both organizations, punctuated by breaks between projects. But in one case, this discontinuity involved a radical shift in the direction of change efforts, while in the other case the discontinuous projects proceeded in basically the same direction. Mundane discontinuity needs to be distinguished from directional discontinuity. The former may be mended by actions of bridging, while the latter would require joint historical analysis, modeling and argumentation. Directionality emerges as a decisive element of organizational learning.
Simultaneity of Learning Orientations in a Marketing Agency
Authors: Swart Juani , Kinnie Nicholas
Published: August 2007

The dynamic internal and external environments faced by many professional service firms mean that the simultaneous exploiting of existing knowledge assets as well as exploring new knowledge capabilities become critical. These two modes of learning (March, 1991) can take place in two distinct time frames: the planned, longer-term and the accelerated, shorter-term. The ability to switch between these is critical to organizational success. This article draws on a case study of a marketing agency to illustrate how exploratory and exploitive learning takes place in both time frames. It demonstrates how the most important interactions between knowledge assets in each of these learning orientations create valuable outputs for clients.
Bilateral Arm Training With Rhythmic Auditory Cueing in Chronic Stroke: Not Always Efficacious
Authors: Richards Lorie G. , Senesac Claudia R. , Davis Sandra B. , Woodbury Michelle L. , Nadeau Stephen E.
Published: July 2007

Objective. Bilateral arm training with rhythmic auditory cueing (BATRAC) has been reported to be efficacious in promoting upper-extremity (UE) recovery in chronic stroke. We tested a modified form of BATRAC (modBATRAC) in a new group of participants with a condensed treatment regime to determine whether we could replicate these reported results. Methods. Fourteen subjects with chronic stroke completed 2 weeks of 2.25 hours per session, 4 sessions per week of modBATRAC. Results. No significant changes were observed in UE Fugl-Meyer or Wolf Motor Function Test scores. Subjects did report increased paretic UE use on the Motor Activity Log (mean change, 0.50; SD = 0.70). Conclusions. The results of this study offer only partial support for the efficacy of modBATRAC. As in previous trials, modBATRAC facilitated increased use of the paretic arm, but unlike previous trials, it did not increase motor performance. These differences may reflect a more temporally condensed training schedule and less impaired patients.
Joining of MoSi2 to 316L stainless steel using spark plasma sintering technique
Authors: Xu J. F. , Zhang X. B. , Fei Y. J. , Wu H. F. , Ye Y. F. , Li W.
Published: August 2007

The feasibility of joining MoSi2 to 316L stainless steel was investigated using the spark plasma sintering technique with nine graded materials. It was demonstrated that dense uniformed joints can be achieved with such graded interlayers because the coefficient of thermal expansion of each interlayer closely matched over a wide temperature range. Furthermore, such a compatibility between the graded interlayers prevented MoSi2 with low toughness from the occurrence of microcracks resulted from the residual stresses formed during cooling of the joint. In addition, it was found that the nine layer joint with a thickness of 1·0 mm for each layer exhibited the minimum residual stress when the compositional exponent is 0·8.
δ TRIP steel
Authors: Chatterjee S. , Murugananth M. , Bhadeshia H. K. D. H.
Published: August 2007

A combination of neural networks and genetic algorithms has been used to design a TRIP assisted steel in which the silicon concentration is kept low. In this context, the steel has a novel microstructure consisting of δ ferrite dendrites and a residual phase which at high temperatures is austenite. This austenite can, with appropriate heat treatment, evolve into a mixture of bainitic ferrite and carbon enriched retained austenite. The steel has been manufactured and tested to reveal a tensile strength of ∼ 1 GPa and a uniform elongation of 23%.
Effect of microstructural variables on tensile behaviour of A356 cast aluminium alloy
Authors: Hong S. J. , Kim S. S. , Lee J. H. , Kwon Y.-N. , Lee Y. S. , Lee J. H.
Published: August 2007

The effects of microstructural variables, including secondary dendrite arm spacing (SDAS), the size of primary α phase, the aspect ratio of eutectic Si particle and the thickness of eutectic wall structure, on tensile behaviour of A356 cast aluminium alloy, were quantitatively identified using linear regression analysis method. For systematic microstructural control of A356 specimen, directional solidification method was used with different solidification rates of 5, 25, 50 and 100 μm s−1 respectively. The linear regression analysis suggests that each microstructural variable affects tensile strength and tensile elongation of A356 cast aluminium alloy in a similar fashion. The change in tensile behaviour with varying microstructural variables in A356 cast aluminium alloy is discussed based on fractographic and micrographic observations.
Polymer derived nitride matrix composites reinforced by 2·5-dimensional silica fibre
Authors: Jiang Y. G. , Zhang C. R. , Cao F. , Wang S. Q. , Qi G. J. , Cao Y. B.
Published: August 2007

Polyborosilazane, a low viscosity preceramic polymer with good infiltration efficiency and high char yield, was used to prepare amorphous composites with polymer derived nitride matrix reinforced by 2·5-dimentional silica fibre, and the mechanical properties and microstructures were investigated. The composites without fibre coating showed typical brittle fracture behaviour with a smooth fracture surface and a longitude flexural strength of just 46·3 MPa whereas the composites with fibre coating exhibited non-brittle fracture behaviour with distinct fibre pull-out on the fracture surface and a high longitude flexural strength of 129·5 MPa. It was the controlled fibre/matrix interface by precoating treatment that contributed to the high mechanical property of the composites.
Distinct gene expression profiles of acute myeloid/T-lymphoid leukemia with silenced CEBPA and mutations in NOTCH1
Authors: Wouters Bas J. , Jordà Meritxell Alberich , Keeshan Karen , Louwers Irene , Erpelinck-Verschueren Claudia A. J. , Tielemans Dennis , Langerak Anton W. , He Yiping , Yashiro-Ohtani Yumi , Zhang Pu , Hetherington Christopher J. , Verhaak Roel G. W. , Valk Peter J. M. , Löwenberg Bob , Tenen Daniel G. , Pear Warren S. , Delwel Ruud
Published: August 2007

Gene expression profiling of acute myeloid leukemia (AML) allows the discovery of previously unrecognized molecular entities. Here, we identified a specific subgroup of AML, defined by an expression profile resembling that of AMLs with mutations in the myeloid transcription factor CCAAT/enhancer-binding protein alpha (C/EBPα), while lacking such mutations. We found that in these leukemias, the CEBPA gene was silenced, which was associated with frequent promoter hypermethylation. The leukemias phenotypically showed aberrant expression of T-cell genes, of which CD7 was most consistent. We identified 2 mechanisms that may contribute to this phenotype. First, absence of Cebpa led to up-regulation of specific T-cell transcripts (ie, Cd7 and Lck) in hematopoietic stem cells isolated from conditional Cebpa knockout mice. Second, the enhanced expression of TRIB2, which we identify here as a direct target of the T-cell commitment factor NOTCH1, suggested aberrantly activated Notch signaling. Putatively activating NOTCH1 mutations were found in several specimens of the newly identified subgroup, while a large set of control AMLs was mutation negative. A gene expression prediction signature allowed the detection of similar cases of leukemia in independent series of AML.
Late mortality after allogeneic hematopoietic cell transplantation and functional status of long-term survivors: report from the Bone Marrow Transplant Survivor Study
Authors: Bhatia Smita , Francisco Liton , Carter Andrea , Sun Can-Lan , Baker K. Scott , Gurney James G. , McGlave Philip B. , Nademanee Auayporn , O'Donnell Margaret , Ramsay Norma K. C. , Robison Leslie L. , Snyder David , Stein Anthony , Forman Stephen J. , Weisdorf Daniel J.
Published: August 2007

We assessed late mortality in 1479 individuals who had survived 2 or more years after allogeneic hematopoietic cell transplantation (HCT). Median age at HCT was 25.9 years and median length of follow-up was 9.5 years. The conditional survival probability at 15 years from HCT was 80.2% (SE = 1.9%) for those who were disease-free at entry into the cohort, and the relative mortality was 9.9 (95% confidence interval, 8.7-11.2). Relative mortality decreased with time from HCT, but remained significantly elevated at 15 years after HCT (standardized mortality ratio = 2.2). Relapse of primary disease (29%) and chronic graft-versus-host disease (cGVHD: 22%) were the leading causes of premature death. Nonrelapse-related mortality was increased among patients older than 18 years at HCT (18-45 years: relative risk [RR] = 1.7; 46+ years: RR = 3.7) and among those with cGVHD (RR = 2.7), and was lower among patients who received methotrexate for GVHD prophylaxis (RR = 0.5). HCT survivors were more likely to report difficulty in holding jobs (odds ratio [OR] = 13.9), and in obtaining health (OR = 7.1) or life (OR = 9.9) insurance compared with siblings. This study demonstrates that mortality rates remain twice as high as that of the general population among 15-year survivors of HCT, and that the survivors face challenges affecting their health and well-being.
Microbiologically documented infections and infection-related mortality in children with acute myeloid leukemia
Authors: Sung Lillian , Lange Beverly J. , Gerbing Robert B. , Alonzo Todd A. , Feusner James
Published: July 2007

The primary objective was to describe the prevalence and characteristics of microbiologically defined infections and infection-related mortality (IRM) in 492 children with acute myeloid leukemia enrolled on CCG 2961. Secondary objectives were to determine the relationship between demographic, disease-related, and therapeutic variables, and infections and IRM. Institutions documented infections prospectively. Age, ethnicity, body mass index, leukemia karyotype, treatment, and institutional size were examined for association with infection outcomes. More than 60% of children experienced such infections in each of 3 phases of chemotherapy. There were 58 infectious deaths; cumulative incidence of IRM was 11% plus or minus 2%. Thirty-one percent of infectious deaths were associated with Aspergillus, 25.9% with Candida, and 15.5% with alpha hemolytic streptococci. Age older than 16 years (hazard ratio [HR], 3.32; 95% confidence interval [CI], 1.87-5.89; P < .001), nonwhite ethnicity (HR, 1.85; 95% CI, 1.10-3.09; P = .02), and underweight status (HR, 3.06; 95% CI, 1.51-6.22; P = .002) were associated with IRM, while size of the treating institution was not. Thus, age, ethnicity, and BMI were important contributors to IRM. Fungi and Gram-positive cocci were the most common organisms associated with IRM and, in particular, Aspergillus species was the largest contributor to infectious deaths.