bluuebunny/crossref_metadata_2025 huggingface dataset:
Field evaluation of methane migration predictions
Authors: McOmber Ronald M. , Moore Charles A. , Beatty Brian W.
Published: June 2008

Methane migration field data obtained at the Mississauga landfill in Mississauga, Ontario was used to verify computer model predictions. Because a migration control system had been in operation at the site for a year, the soil adjacent to the landfill was initially free of methane. Thus, it was possible to verify the models by first shutting down the control system. Then gas probes installed in the soils adjacent to the landfill were used to monitor the ensuing outward migration of methane. This paper compares the data obtained with computer model predictions for purely diffusional gas flow and for combined pressure–diffusional gas flow. In the region within 25 m of the landfill the computer predictions compared well with the observed field concentrations; however, beyond 25 m the observed gas concentrations exceeded predictions. The gas behavior at one probe in particular was not adequately predicted. The computer model was used to further investigate this anomoly.
Behaviour of cemented tailings sands
Authors: Mitchell R. J. , Wong B. C.
Published: June 2008

Bulk pours of cemented tailings sands are used as ground control backfill in underground mines. This paper presents laboratory test data relating design factors, such as cement content, pour pulp density, and curing humidity, to backfill strength. Unconfined strengths were found to increase with increased cement content, increased pulp density, decreased porosity, and decreased curing humidity. Numerical relations between these factors are presented. Test data showing the behaviour of cemented tailings under triaxial compression are also presented. These data indicate that there is a relation between the unconfined strength and the strength envelope defined by c, [Formula: see text] parameters and that either strength can be used in design providing the confining stresses do not approach those required to cause cement bond crushing. Some practical considerations with regard to backfilling with cemented tailings are discussed. Keywords: cemented sand, tailings, strength, curing effects, mine backfill.
Bearing capacity of foundations on a weak sand layer overlying a strong deposit
Authors: Hanna A. M.
Published: June 2008

The ultimate bearing capacity of footings resting on subsoils consisting of a weak sand layer overlying a strong deposit has been investigated. Based on model tests of strip and circular footings in a loose or compact sand layer overlying a dense sand deposit, the classical equation of bearing capacity of footings on homogeneous sand was extended to cover cases of these footings in layered sands where the upper layer is the weaker. The theory compared well with the available model test results. Design charts are presented.
Displacement-pile behaviour in a soft marine clay
Authors: Lehane B.M. , Jardine R.J.
Published: June 2008

The paper presents the results of field experiments performed using the Imperial College instrumented displacement pile in a soft, sensitive marine clay at Bothkennar, Scotland. These results are compared with data from similar programmes of experiments performed in other clay types with this pile so that some of the major factors controlling displacement-pile performance may be identified. Key words : displacement pile, instrumentation, sensitive clay, effective stress design.
A comparison of pressuremeter test results in sea ice
Authors: Steel A. , Clark J.I. , Morin P.
Published: June 2008

The results of short-term pressuremeter tests from three different sea ice environments are presented. These results are used to derive mechanical properties of the ice, to compare the ice types, and to evaluate the Texam pressuremeter as an instrument for the field assessment of ice sheets and ice packs. The results are also compared with those existing in the literature. It was found that the strength of the sea ice was affected most significantly by temperature, but also by salinity and to a lesser extent by confining pressure and ice structure. The Texam pressuremeter operated well in the given field environment and will prove to be a valuable piece of equipment for determining the characteristics of these important ice formations. Key words : pressuremeter, sea ice, short-term tests, strength, salinity, confining pressure, temperature.
2′F-Arabinonucleic acids (2′F-ANA) — History, properties, and new frontiers
Authors: Watts Jonathan K , Damha Masad J
Published: June 2008

The development of arabinonucleosides and oligoarabinonucleotides is described, focusing especially on 2′-deoxy-2′-fluoroarabinonucleosides (araF-N) and -oligonucleotides (2'F-ANA). In addition to their chemical and enzymatic synthesis, we discuss various properties of 2′F-ANA: hydrolytic stability (to nucleases, acids, and bases), binding affinity to complementary strands, structure and conformation, and optimization of RNase H activity. We also discuss the use of 2′F-ANA in gene-silencing approaches (antisense, siRNA), and in the stabilization of higher-order structures (such as triplexes and quadruplexes) including aptamers. Finally, we examine several other oligonucleotide derivatives based on 2′F-ANA and look ahead to the future of 2′-fluoroarabinonucleosides and -oligonucleotides.Key words: arabinonucleic acids, 2′F-ANA, antisense oligonucleotides, siRNA, modified oligonucleotides.
Vicarious nucleophilic amination of nitroquinolines with 4-amino-1,2,4-triazole
Authors: Szpakiewicz Barbara , Grzegożek Maria
Published: June 2008

3-, 5-, 6-, 7- and 8-Nitroquinolines react with 4-amino-1,2,4-triazole in basic medium (potassium tert-butoxide-dimethyl sulfoxide) giving amino products of the vicarious nucleophilic substitution (VNS) of hydrogen, predominantly at ortho position to the nitro group, except 8-nitroquinoline, which reacts at para position. Additionally, furazano[3,4-f]- and furazano[3,4-h]quinoline were obtained in the case of 5- and 8- nitroquinoline, respectively. 2-Nitroquinoline was aminated to 2-quinolino(1,2,4-triazol-4-yl)amine in these conditions.Key words: nitroquinolines, vicarious nucleophilic substitution (VNS), 4-amino-1,2,4-triazole.
Substituent effects, Arrhenius activation parameters, and rate constants for the photo–Claisen rearrangement of allyl aryl ethers
Authors: Gonzalez Carlos M , Pincock James A
Published: June 2008

The temperature-dependence of fluorescence quantum yields in both methanol and methylcyclohexane has been used to obtain the rate constants of reaction for the activated process that converts the singlet excited state S1 of a set of ring-substituted aryl allyl ethers to an intermediate radical pair in the photo–Claisen rearrangement. These rate constants are correlated with the O–H bond dissociation energy of the corresponding ring-substituted phenols; that is, electron-donating groups (CH3, OCH3) accelerate the reaction relative to electron-withdrawing groups (CF3, CN). The rate constants obtained span two orders of magnitude, from 5.4 × 107 s–1 for X = 3–CN to 800 × 107 s–1 for X = 4–OCH3, in methylcylcohexane. Moreover, the rate constants are similar in the two solvents, methanol and methcyclohexane, indicating that radical pairs, not ion pairs, are the reactive intermediates, as expected on the basis of previous mechanistic proposals for the photo–Claisen rearrangement. Finally, the rate constants obtained by this temperature-dependent method are in good agreement with those previously reported from a method using the corresponding unreactive anisoles as a model.Key words: allyl aryl ethers, photo–Claisen rearrangement, substituent effects, activation parameters.
An efficient procedure for the TEMPO-catalyzed oxidation of alcohols to aldehydes and ketones using ferric chloride hexahydrate as terminal oxidant
Authors: Kumar R Senthil , Karthikeyan K , Perumal Paramasivan T
Published: June 2008

A simple, efficient procedure for the oxidation of alcohols by catalytic 2,2,6,6-tetramethyl-piperidyl-1-oxy (TEMPO) was developed using FeCl3·6H2O as the terminal oxidant. The reaction gives high yield of the corresponding aldehydes and ketones with no over oxidation to the acid.Key words: oxidation, TEMPO, FeCl3·6H2O.
PMA/SiO2 – An efficient recyclable heterogeneous catalyst for the synthesis of homoallyl alcohols and amines under solvent-free conditions
Authors: Das Biswanath , Kumar Rathod Aravind , Thirupathi Ponnaboina , Suneel Kanaparthy , Sunitha Pothkan
Published: June 2008

Aldehydes and imines can efficiently undergo nucleophilic addition reaction with allyltributylstannane in the presence of phosphomolybdic acid supported on silica (PMA/SiO2) under solvent free-conditions to form the corresponding homoallyl alcohols and amines respectively at room temperature in excellent yields. The catalyst can be easily recovered and re-used.Key words: homoallyl alcohol, homoallyl amine, phosphomolybdic acid, heterogeneous catalyst, allyltributylstannane, solvent-free conditions.
The unambiguous assignment of NMR spectra of per-O-methylated 6-mono and 6,6-diamino-β-cyclodextrins
Authors: Díaz T. Eduardo , Jankowski Christopher K , Hocquelet Celine , del Rio P. Federico , Barrios Héctor
Published: June 2008

The step-by-step analysis of high-resolution proton and 13C NMR spectra of per-O-methylated-6-monoamino and 6,6-diamino-A,D-β-cyclodextrins is described. Selected 2-D experiments (COSY, NOESY, HSQC, DEPT, and HMBC) allowed us to challenge the current interpretation. The full assignment of the proton and carbon-13 NMR spectra of these two compounds was performed enabling us to complete the assignment of NMR spectra acquired at 500 and 800 MHz for these important synthetic intermediates.Key words: COSY, NOESY, HSQC, DEPT, HMBC, NMR, 6-amino-β-cyclodextrins, 6,6-diamino-β-cyclodextrins.
SOME NEW CLASS OF CHAPLYGIN WORMHOLES
Authors: RAHAMAN F. , KALAM M. , RAHMAN K. A.
Published: June 2008

Some new class of Chaplygin wormholes are investigated in the framework of a Chaplygin gas with the equation of state [Formula: see text]. Since empty spacetime (p = ρ = 0) does not follow Chaplygin gas, so the interior Chaplygin wormhole solutions will never be asymptotically flat. For this reason, we have to match our interior wormhole solution with an exterior vacuum solution, i.e. Schwarzschild solution at some junction interface, say r = a. We also discuss the total amount of matter characterized by Chaplygin gas that supplies fuel to construct a wormhole.
DO ACTIVE GALACTIC NUCLEI CONVERT DARK MATTER INTO VISIBLE PARTICLES?
Authors: GRIB A. A. , PAVLOV YU. V.
Published: June 2008

The hypothesis that dark matter consists of superheavy particles with the mass close to the Grand Unification scale is investigated. These particles were created from vacuum by the gravitation of the expanding Universe and their decay led to the observable baryon charge. Some part of these particles with the lifetime larger than the time of breaking of the Grand Unification symmetry became metastable and survived up to the modern time as dark matter. However, in active galactic nuclei due to large energies of dark matter particles swallowed by the black hole and the possibility of the Penrose process for rotating black hole the opposite process can occur. Dark matter particles become interacting. Their decay on visible particles at the Grand Unification energies leads to the flow of ultra high energy cosmic rays observed by the Auger group. Numerical estimates of the effect leading to the observable numbers are given.
Endogenous ghrelin and 5-HT regulate interdigestive gastrointestinal contractions in conscious rats
Authors: Taniguchi Hiroshi , Ariga Hajime , Zheng Jun , Ludwig Kirk , Mantyh Christopher , Pappas Theodore N. , Takahashi Toku
Published: June 2008

Endogenous ghrelin causes interdigestive contractions of the stomach in rats. In contrast, previous studies showed that 5-HT3 and 5-HT4 receptors were involved in regulating intestinal interdigestive contractions. We studied the possible role of endogenous ghrelin and 5-HT regulating interdigestive gastrointestinal (GI) contractions in rats. Four strain gauge transducers were implanted on the antrum, duodenum, and proximal and distal jejunum. After an overnight fast, GI contractions were recorded in freely moving conscious rats and ghrelin receptor antagonists [(d-lys3)GHRP6; 1 μmol/kg], 5-HT3 antagonists (Ondansetron; 0.5 mg/kg) and 5-HT4 antagonists (GR 125,487; 1 mg/kg) were administered (bolus iv). To evaluate the relationship between the luminal concentrations of 5-HT and phase III-like contractions of the duodenum, duodenal juice was collected via the intraduodenal catheter. 5-HT content of the duodenal juice was measured by HPLC. (d-lys3)GHRP6 significantly attenuated the occurrence and amplitude of phase III-like contractions of the antrum, but not the duodenum and jejunum. 5-HT4 antagonists significantly reduced spontaneous phase III-like contractions of the jejunum, without affecting those of the antrum and duodenum. In contrast, 5-HT3 antagonists did not affect phase III-like contractions in GI tract. Luminal concentration of 5-HT at the phase III-like contraction (36.0 ± 13.3 ng/ml, n = 9) was significantly higher than that at the phase I-like contractions of the duodenum (4.9 ± 1.6 ng/ml, n = 9, P < 0.05). It is suggested that released ghrelin from the gastric mucosa mediates gastric phase III-like contractions, whereas 5-HT released from enterochromaffin cells of the duodenal mucosa mediates intestinal phase III-like contractions via 5-HT4 receptors.
High intraluminal pressure via H2O2 upregulates arteriolar constrictions to angiotensin II by increasing the functional availability of AT1 receptors
Authors: Bagi Zsolt , Erdei Nora , Koller Akos
Published: June 2008

Previously, we found that high intraluminal pressure leads to production of reactive oxygen species (ROS) and also upregulates several components of the renin-angiotensin system in the wall of small arteries. We hypothesized that acute exposure of arterioles to high intraluminal pressure in vitro via increasing ROS production enhances the functional availability of type 1 angiotensin II (Ang II) receptors (AT1 receptors), resulting in sustained constrictions. In arterioles (∼180 μm) isolated from rat skeletal muscle, Ang II elicited dose-dependent constrictions, which decreased significantly by the second application [maximum (max.): from 59% ± 4% to 26% ± 5% at 10−8 M; P < 0.05] in the presence of 80 mmHg of intraluminal pressure. In contrast, if the arterioles were exposed to high intraluminal pressure (160 mmHg for 30 min), Ang II-induced constrictions remained substantial on the second application (max.: 51% ± 3% at 10−8 M). In the presence of Tiron and polyethylene glycol (PEG)-catalase, known to reduce the level of superoxide anion and hydrogen peroxide (H2O2), second applications of Ang II evoked similarly reduced constrictions, even after high-pressure exposure (29% ± 4% at 10−8 M). Furthermore, when arterioles were exposed to H2O2 (for 30 min, 10−7 M, at normal 80 mmHg pressure), Ang II-induced constrictions remained substantial on second applications (59% ± 5% at 10−8 M). These findings suggest that high pressure, likely via inducing H2O2 production, increases the functional availability of AT1 receptors and thus enhances Ang II-induced arteriolar constrictions. We propose that in hypertension–regardless of etiology–high intraluminal pressure, via oxidative stress, enhances the functional availability of AT1 receptors augmenting Ang II-induced constrictions.
Plasticity of pre- and postsynaptic GABAB receptor function in the paraventricular nucleus in spontaneously hypertensive rats
Authors: Li De-Pei , Yang Qing , Pan Hao-Min , Pan Hui-Lin
Published: June 2008

GABAB receptor function is upregulated in the paraventricular nucleus (PVN) of the hypothalamus in spontaneously hypertensive rats (SHR), but it is unclear whether this upregulation occurs pre- or postsynaptically. We therefore determined pre- and postsynaptic GABAB receptor function in retrogradely labeled spinally projecting PVN neurons using whole cell patch-clamp recording in brain slices in SHR and Wistar-Kyoto (WKY) rats. Bath application of the GABAB receptor agonist baclofen significantly decreased the spontaneous firing activity of labeled PVN neurons in both SHR and WKY rats. However, the magnitude of reduction in the firing rate was significantly greater in SHR than in WKY rats. Furthermore, baclofen produced larger membrane hyperpolarization and outward currents in labeled PVN neurons in SHR than in WKY rats. The baclofen-induced current was abolished by either including G protein inhibitor GDPβS in the pipette solution or bath application of the GABAB receptor antagonist in both SHR and WKY rats. Blocking N-methyl-d-aspartic acid receptors had no significant effect on baclofen-elicited outward currents in SHR. In addition, baclofen caused significantly greater inhibition of glutamatergic excitatory postsynaptic currents (EPSCs) in labeled PVN neurons in brain slices from SHR than WKY rats. By contrast, baclofen produced significantly less inhibition of GABAergic inhibitory postsynaptic currents (IPSCs) in labeled PVN neurons in SHR than in WKY rats. Although microinjection of the GABAB antagonist into the PVN increases sympathetic vasomotor tone in SHR, the GABAB antagonist did not affect EPSCs and IPSCs of the PVN neurons in vitro. These findings suggest that postsynaptic GABAB receptor function is upregulated in PVN presympathetic neurons in SHR. Whereas presynaptic GABAB receptor control of glutamatergic synaptic inputs is enhanced, presynaptic GABAB receptor control of GABAergic inputs in the PVN is attenuated in SHR. Changes in both pre- and postsynaptic GABAB receptors in the PVN may contribute to the control of sympathetic outflow in hypertension.
Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: role of antioxidant and antiapoptotic signaling
Authors: Jha Saurabh , Calvert John W. , Duranski Mark R. , Ramachandran Arun , Lefer David J.
Published: June 2008

Hydrogen sulfide (H2S) is an endogenously produced gaseous signaling molecule with diverse physiological activity. The potential protective effects of H2S have not been evaluated in the liver. The purpose of the current study was to investigate if H2S could afford hepatoprotection in a murine model of hepatic ischemia-reperfusion (I/R) injury. Hepatic injury was achieved by subjecting mice to 60 min of ischemia followed by 5 h of reperfusion. H2S donor (IK1001) or vehicle were administered 5 min before reperfusion. H2S attenuated the elevation in serum alanine aminotransferase (ALT) by 68.6% and aspartate aminotransferase (AST) by 70.8% compared with vehicle group. H2S-mediated cytoprotection was associated with an improved balance between reduced glutathione (GSH) vs. oxidized glutathione (GSSG), an attenuated formation of lipid hydroperoxides, and an increased expression of thioredoxin-1 (Trx-1). Furthermore, H2S inhibited the progression of apoptosis after I/R injury by increasing the protein expression of heat shock protein (HSP-90) and Bcl-2. These results indicate that H2S protects the murine liver against I/R injury through an upregulation of intracellular antioxidant and antiapoptotic signaling pathways.
Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts
Authors: O'Brien J. Darcy , Howlett Susan E.
Published: June 2008

The impact of ischemic preconditioning (IPC) on contraction, Ca2+ homeostasis, and cell survival was compared in isolated ventricular myocytes from young adult (∼3 mo) and aged (∼24 mo) male Fischer-344 rats. Myocytes were field stimulated at 4 Hz (37°C). Contraction (edge detector) and intracellular Ca2+ (fura-2) were measured simultaneously. Viability was assessed with trypan blue. All cells were exposed to 30 min of simulated ischemia followed by reperfusion. Some cells were preconditioned by exposure to 5 min of simulated ischemia before prolonged ischemia. Pretreatment with IPC abolished postischemic contractile depression, inhibited diastolic contracture, and increased Ca2+ transient amplitudes in reperfusion in young adult and aged cells. IPC did not affect the modest rise in diastolic Ca2+ in ischemia in young adult myocytes. However, IPC abolished the marked rise in diastolic Ca2+ observed in ischemia and early reperfusion in aged myocytes. IPC also suppressed mechanical alternans in ischemia in aged cells, but younger myocytes showed little evidence of mechanical alternans whether or not cells were preconditioned. IPC markedly improved cell viability in reperfusion in young adult but not aged cells. These results suggest that IPC augments the recovery of contractile function in reperfusion by increasing Ca2+ transient amplitudes in ventricular myocytes from young adult and aged rats. IPC reduced diastolic Ca2+ accumulation in ischemia in aged myocytes, which may diminish the severity of mechanical alternans in aged cells. Nonetheless, the efficacy of IPC is compromised in aging, as IPC did not improve survival of aged myocytes exposed to ischemia and reperfusion.
Systems-Level Analysis of ErbB4 Signaling in Breast Cancer: A Laboratory to Clinical Perspective
Authors: Chuu Chih-Pin , Chen Rou-Yu , Barkinge John L. , Ciaccio Mark F. , Jones Richard B.
Published: June 2008

Although expression of the ErbB4 receptor tyrosine kinase in breast cancer is generally regarded as a marker for favorable patient prognosis, controversial exceptions have been reported. Alternative splicing of ErbB4 pre-mRNAs results in the expression of distinct receptor isoforms with differential susceptibility to enzymatic cleavage and different downstream signaling protein recruitment potential that could affect tumor progression in different ways. ErbB4 protein expression from nontransfected cells is generally low compared with ErbB1 in most cell lines, and much of our knowledge of the role of ErbB4 in breast cancer is derived from the ectopic overexpression of the receptor in non–breast-derived cell lines. One of the primary functions of ErbB4 in vivo is in the maturation of mammary glands during pregnancy and lactation induction. Pregnancy and extended lactation durations have been correlated with reduced risk of breast cancer, and the role of ErbB4 in tumor suppression may therefore be linked with its role in lactation. Most reports are consistent with a role for ErbB4 in reversing growth stimuli triggered by other ErbB family members during puberty. In this report, we provide a systems-level examination of several reports highlighting the seemingly opposing roles of ErbB4 in breast cancer and potential explanations for the discrepancies and draw the conclusion that future studies examining the function of ErbB4 in breast cancer should also take into account the pregnancy history, lactation status, and hormone supplementation or ablation history of the patient from whom the tumor or tumor cells are derived. (Mol Cancer Res 2008;6(6):885–91)
Active Ras Triggers Death in Glioblastoma Cells through Hyperstimulation of Macropinocytosis
Authors: Overmeyer Jean H. , Kaul Aparna , Johnson Erin E. , Maltese William A.
Published: June 2008

Expression of activated Ras in glioblastoma cells induces accumulation of large phase-lucent cytoplasmic vacuoles, followed by cell death. This was previously described as autophagic cell death. However, unlike autophagosomes, the Ras-induced vacuoles are not bounded by a double membrane and do not sequester organelles or cytoplasm. Moreover, they are not acidic and do not contain the autophagosomal membrane protein LC3-II. Here we show that the vacuoles are enlarged macropinosomes. They rapidly incorporate extracellular fluid-phase tracers but do not sequester transferrin or the endosomal protein EEA1. Ultimately, the cells expressing activated Ras detach from the substratum and rupture, coincident with the displacement of cytoplasm with huge macropinosome-derived vacuoles. These changes are accompanied by caspase activation, but the broad-spectrum caspase inhibitor carbobenzoxy-Val-Ala-Asp-fluoromethylketone does not prevent cell death. Moreover, the majority of degenerating cells do not exhibit chromatin condensation typical of apoptosis. These observations provide evidence for a necrosis-like form of cell death initiated by dysregulation of macropinocytosis, which we have dubbed “methuosis.” An activated form of the Rac1 GTPase induces a similar form of cell death, suggesting that Ras acts through Rac-dependent signaling pathways to hyperstimulate macropinocytosis in glioblastoma. Further study of these signaling pathways may lead to the identification of other chemical and physiologic triggers for this unusual form of cell death. (Mol Cancer Res 2008;6(6):965–77)
The Effect of Transforming Growth Factor β on Human Neuroendocrine Tumor BON Cell Proliferation and Differentiation Is Mediated through Somatostatin Signaling
Authors: Leu Frank P. , Nandi Minesh , Niu Congrong
Published: June 2008

The dual effect of the ubiquitous inflammatory cytokine transforming growth factor β1 (TGFβ) on cellular proliferation and tumor metastasis is intriguing but complex. In epithelial cell– and neural cell–derived tumors, TGFβ serves as a growth inhibitor at the beginning of tumor development but later becomes a growth accelerator for transformed tumors. The somatostatin (SST) signaling pathway is a well-established antiproliferation signal, and in this report, we explore the interplay between the SST and TGFβ signaling pathways in the human neuroendocrine tumor cell line BON. We defined the SST signaling pathway as a determinant for neuroendocrine tumor BON cells in responding to TGFβ as a growth inhibitor. We also determined that TGFβ induces the production of SST and potentially activates the negative growth autocrine loop of SST, which leads to the downstream induction of multiple growth inhibitory effectors: protein tyrosine phosphatases (i.e., SHPTP1 and SHPTP2), p21Waf1/Cip1, and p27Kip1. Concurrently, TGFβ down-regulates the growth accelerator c-Myc protein and, collectively, they establish a firm antiproliferation effect on BON cells. Additionally, any disruption in the activation of either the TGFβ or SST signaling pathway in BON leads to “reversible” neuroendocrine-mesenchymal transition, which is characterized by the loss of neuroendocrine markers (i.e., chromogranin A and PGP 9.5), as well as the altered expression of mesenchymal proteins (i.e., elevated vimentin and Twist and decreased E-cadherin), which has previously been associated with elevated metastatic potential. In summary, TGFβ-dependent growth inhibition and differentiation is mediated by the SST signaling pathway. Therefore, any disruption of this TGFβ-SST connection allows BON cells to respond to TGFβ as a growth accelerator instead of a growth suppressor. This model can potentially apply to other cell types that exhibit a similar interaction of these pathways. (Mol Cancer Res 2008;6(6):1029–42)
Cell Cycle Regulator GeneCDC5L, a Potential Target for 6p12-p21 Amplicon in Osteosarcoma
Authors: Lu Xin-Yan , Lu Yaojuan , Zhao Yi-Jue , Jaeweon Kim , Kang Jason , Xiao-Nan Li , Ge Gouqing , Meyer Rene , Perlaky Laszlo , Hicks John , Chintagumpala Murali , Cai Wei-Wen , Ladanyi Marc , Gorlick Richard , Lau Ching C. , Pati Debananda , Sheldon Michael , Rao Pulivarthi H.
Published: June 2008

Osteosarcoma is a primary malignant tumor of bone arising from primitive bone-forming mesenchymal cells and accounts for ∼60% of malignant bone tumors. Our comparative genomic hybridization (CGH) studies have identified frequent amplification at 6p12-p21, 12q13-q15, and 17p11.2 in osteosarcoma. Of these amplified regions, 6p12-p21 is particularly interesting because of its association with progression and poor prognosis in patients with osteosarcoma. In an attempt to identify aberrantly expressed gene(s) mapping to the 6p12-p21 amplicon, a region-specific array was generated using 108 overlapping BAC and P1 clones covering a 28.8-Mb region at 0.26-Mb intervals. Based on array CGH analysis, the 6p amplicon was refined to 7.9 Mb between the clones RP11-91E11 and RP1-244F2 and 10 amplified clones, with possible target genes, were identified. To study the expression pattern of the target genes from the hotspot amplicon and known candidate genes from 6p12-21, we did quantitative reverse transcription-PCR analysis of MAPK14, MAPK13, CDKN1A, PIM1, MDGA1, BTB9, DNAH8, CCND3, PTK7, CDC5L, and RUNX2 on osteosarcoma patient samples and seven cell lines. The combined array CGH and quantitative reverse transcription-PCR analysis identified amplification and overexpression of CDC5L, CCND3, and RUNX2. We screened these three genes for protein expression by Western blotting and immunohistochemistry and detected overexpression of CDC5L. Furthermore, we used an in vivo assay to show that CDC5L possesses potential oncogenic activity. These results indicate that CDC5L, a cell cycle regulator important for the G2-M transition, is the most likely candidate oncogene for the 6p12-p21 amplicon found in osteosarcoma. (Mol Cancer Res 2008;6(6):937–46)
Secreted Frizzled-Related Protein 4 Regulates Two Wnt7a Signaling Pathways and Inhibits Proliferation in Endometrial Cancer Cells
Authors: Carmon Kendra S. , Loose David S.
Published: June 2008

In the endometrium, hormonal effects on epithelial cells are often elicited through stromal hormone receptors via unknown paracrine mechanisms. Several lines of evidence support the hypothesis that Wnts participate in stromal-epithelial cell communication. Wnt7a is expressed in the luminal epithelium, whereas the extracellular modulator of Wnt signaling, secreted frizzled-related protein 4 (SFRP4), is localized to the stroma. Studies have reported that SFRP4 expression is significantly decreased in endometrial carcinoma and that both SFRP4 and Wnt7a genes are differentially regulated in response to estrogenic stimuli. Aberrant Wnt7a signaling irrevocably causes organ defects and infertility and contributes to the onset of disease. However, specific frizzled receptors (Fzd) that bind Wnt7a and the particular signal transduction pathway each Wnt7a-Fzd pair activates have not been identified. Additionally, the function of SFRP4 in the endometrium has not been addressed. We show here that Wnt7a coimmunoprecipitates with Fzd5, Fzd10, and SFRP4 in Ishikawa cells. Wnt7a binding to Fzd5 was shown to activate β-catenin/canonical Wnt signaling and increase cellular proliferation. Conversely, Wnt7a signaling mediated by Fzd10 induced a noncanonical c-Jun NH2-terminal kinase–responsive pathway. SFRP4 suppresses activation of Wnt7a signaling in both an autocrine and paracrine manner. Stable overexpression of SFRP4 and treatment with recombinant SFRP4 protein inhibited endometrial cancer cell growth in vitro. These findings support a mechanism by which the nature of the Wnt7a signal in the endometrium is dependent on the Fzd repertoire of the cell and can be regulated by SFRP4. (Mol Cancer Res 2008;6(6):1017–28)
Prostate-Specific Kallikreins-2 and -4 Enhance the Proliferation of DU-145 Prostate Cancer Cells through Protease-Activated Receptors-1 and -2
Authors: Mize Gregory J. , Wang Wenbin , Takayama Thomas K.
Published: June 2008

A major characteristic of prostate cancer is the elevation of serum levels of prostate-specific antigen (hK3) and hK2, which are tumor markers that correlate with advancing stages of disease. Including hK4, these three kallikrein serine proteases are almost exclusively produced by the prostate. Prostate cancer cells have been recently shown to overexpress protease-activated receptors (PAR), which can be potentially activated by kallikreins and can regulate tumor growth. Here, we show that recombinant hK2 and hK4 activate ERK1/2 signaling of DU-145, PC-3, and LNCaP prostate cancer cells, which express both PAR1 and PAR2. These kallikreins also stimulate the proliferation of DU-145 cells. Pretreatment of hK2 and hK4 with the serine protease inhibitor, aprotinin, blocks the responses in DU-145 cells, and small interfering RNA against PAR1 and PAR2 also inhibits ERK1/2 signaling. To determine which PAR is activated by hK2 and hK4, a cell line that expresses a single PAR, a PAR1 knockout mouse lung fibroblast cell line transfected with PAR1 (KOLF-PAR1) or PAR2 (KOLF-PAR2) was used. hK4 activates both PAR1 and PAR2, whereas hK2 activates PAR2. hK4 generates more phosphorylated ERK1/2 than hK2. These data indicate that prostatic kallikreins (hK2 and hK4) directly stimulate prostate cancer cell proliferation through PAR1 and/or PAR2 and may be potentially important targets for future drug therapy for prostate cancer. (Mol Cancer Res 2008;6(6):1043–51)
Common Predictors of Excessive Adiposity in Children from a Region with High Prevalence of Overweight
Authors: Basaldúa Nancy , Chiquete Erwin
Published: June 2008

Aim: To identify risk factors other than energy intake or expenditure that can predict adiposity and overweight in children from a region with high prevalence of obesity. Methods: We studied 551 children aged 6–12 years (50.5% girls) from a city in the North of Mexico. Tetrapolar bioimpedance was used to assess body fat content. Overweight was estimated by analysis of age- and gender-standardized body mass index (BMI) relative to reference data of the International Obesity Task Force (BMIs that predict obesity in adulthood). Multivariate analyses were modeled to find independent predictors of adiposity. Results: The frequency of overweight/obesity was 37.6%. There were no differences between genders with respect to weight, height and BMI; however, age-standardized percentage of body fat and a sedentary lifestyle were higher in girls than in boys (p < 0.001). Independent predictors of overweight/obesity were having first-degree relatives with obesity [adjusted odds ratio (OR) 2.26, 95% confidence interval (CI) 1.40–3.64], sedentary lifestyle (OR 1.58, 95% CI 1.05–2.37) and being the third child or younger in offspring (OR 1.59, 95% CI 1.02–2.47). Predictors of body fat in the highest quartile of the sample were having first-degree relatives with obesity (OR 2.59, 95% CI 1.41–4.74), female gender (OR 5.60, 95% CI 3.22–9.77) and being the third child or younger in offspring (OR 2.07, 95% CI 1.22–3.51). These effects could not be explained by social class, ethnicity, maternal age and duration of breastfeeding. Conclusions: Risk factors easily identified by history-taking can predict childhood adiposity and the high risk of obesity in adulthood. Having a first-degree relative with obesity underscores the impact of genes and the family lifestyle on excessive adiposity. Being the third child or younger may denote different nurture practices in offspring; however, this factor deserves more exploration.
Effects of Simultaneous Intakes of Fish Oil and Green Tea Extracts on Plasma, Glucose, Insulin, C-Peptide, and Adiponectin and on Liver Lipid Concentrations in Mice Fed Low- and High-Fat Diets
Authors: Shirai Nobuya , Suzuki Hiramitsu
Published: June 2008

Aims: The purpose of this study was to clarify the effects of a simultaneous intake of fish oil and green tea extracts (GTE) on plasma lipids, glucose (Glu), insulin, C-peptide, and adiponectin concentrations and on liver lipids in mice fed low- and high-fat diets. Methods: Male mice (5 months old) were fed low-fat (5%) or high-fat (20%) diets containing 0% (5 or 20% lard), 1% (4 or 19% lard) or 5% (0 or 15% lard) fish oil with or without 1% GTE for 3 months. Results: Single or combined intakes of fish oil and GTE intakes significantly lowered plasma and liver total cholesterol (T-chol) and triacylglycerol (TG) concentrations in mice on high-fat diets. However, a positive effect of GTE alone was not observed in the plasma T-chol and TG concentrations of mice on low-fat diets. Plasma Glu concentrations were significantly lowered by dietary fish oil in mice on the low- and high-fat diets. A tendency of GTE intake to decrease plasma Glu in mice on both the low- and high-fat diets was not significant. An intake of GTE only minimally influenced plasma insulin, C-peptide, and adiponectin concentrations, but fish oil supplementation increased the adiponectin concentration in mice on the low- and high-fat diets. GTE addition to the diets had no adverse effects on reductions by fish oil. Conclusion: These results suggest that a simultaneous intake of fish oil and GTE can improve plasma and liver lipid and plasma Glu profiles in mice fed a high-fat diet without any negative interactions of fish oil and GTE.
KIT and Mastocytosis
Authors: Lim Ken-Hong , Pardanani Animesh , Tefferi Ayalew
Published: June 2008

KIT is a receptor tyrosine kinase that is functionally relevant for hematopoiesis, mast cell development and function, gametogenesis and melanogenesis. Normal KIT signaling requires binding to stem cell factor, and PI3K-Akt is one of the putative effector pathways. In humans, germline loss-of-function KIT mutations have been associated with piebaldism – an autosomal dominant condition characterized by depigmented patches of skin and hair. Gain-of-function KIT mutations are usually acquired and have been associated with myeloid malignancies including core binding factor acute myeloid leukemia and systemic mastocytosis (SM), germ cell tumors, gastrointestinal stromal tumors and sinonasal T cell lymphomas. KITD816V is the most prevalent KIT mutation in mast cell disease and occurs in more than 90% of the cases that fulfill the World Health Organization diagnostic criteria for SM. However, its precise pathogenetic contribution is not well understood. In clinical practice, SM is considered either indolent or aggressive depending on the respective absence or presence of symptomatic target organ dysfunction aside from skin disease. In general, conventional therapy for SM is suboptimal, and efforts are under way to develop and employ small molecule drugs that target mutant KIT.
A New Technique for Intraoperative Continuous Biliary Drainage during Pancreatoduodenectomy
Authors: Doi Ryuichiro , Kami Kazuhiro , Kida Atsushi , Nagai Kazuyuki , Ogawa Kohei , Kawaguchi Yoshiya , Egawa Hiroto , Uemoto Shinji
Published: June 2008

Background: The common hepatic duct is divided during the early stage of pancreatoduodenectomy. Complete and prolonged closure of the proximal common duct stump can cause liver damage in the course of this long operation, resulting in associated complications. Methods: We performed intraoperative continuous external bile drainage by a new method using a novel drainage clamp in 47 consecutive patients (drainage clamp group) and compared postoperative liver enzyme levels, inflammation markers, morbidity, and outcomes with those of a conventional clamp group (n = 40). Results: The drainage clamp group had significantly lower transaminase levels within the first 14 postoperative days than the conventional clamp group. The number of patients with elevated transaminase was significantly less in drainage clamp group than conventional clamp group (p < 0.001). There were no significant differences between these two groups in terms of mortality rates and postoperative morbidity. Conclusion: Intraoperative complete closure of the common hepatic duct contributed to postoperative elevated transaminase levels, and the continuous decompression of the hepatic duct during pancreatoduodenectomy is beneficial to patients by avoiding liver dysfunction. The novel drainage clamp is a safe and useful tool for pancreatoduodenectomy and other operative procedure where extrahepatic bile duct is dissected.
Outcomes of Sphincter-Saving Operation for Rectal Cancer without Protective Stoma and Pelvic Drain, and Risk Factors for Anastomotic Leakage
Authors: Lohsiriwat Varut , Lohsiriwat Darin , Boonnuch Wiroon , Chinswangwatanakul Vitoon , Akaraviputh Thawatchai , Riansuwan Woramin , Lert-akyamanee Narong
Published: June 2008

Background/Aims: To evaluate the outcomes of sphincter-saving operation for rectal cancer without protective stoma and pelvic drain and to determine factors influencing anastomotic leakage. Methods: We investigated 170 patients undergoing elective sphincter-saving operation without protective stoma and pelvic drain during 2003–2006 in a single institution. Early postoperative outcomes were evaluated. 17 independent patient-, tumor-, and treatment-related variables were analyzed by a multivariate model to determine their association with anastomotic leakage. Results: The patients’ median age was 64 years. Median tumor height was 8 cm (range 3–15) from the anal verge. Overall 30-day mortality rate was 1.2%. Postoperative complications were diagnosed in 38 patients (22%) including 14 cases of anastomotic leakage (8.2%), of which 10 cases (71%) required surgical intervention. Tumor height within 5 cm from the anal verge was the only independent factor for leakage (OR 4.04; 95% CI 1.25–13.08). Conclusion: A sphincter-saving operation without a protective stoma and pelvic drain can be performed safely in the vast majority of rectal cancer patients. Tumor height within 5 cm from the anal verge is an independent risk factor for anastomotic leakage. Thus, the routine use of a protective stoma and pelvic drainage might be unnecessary.
Sphingomyelin Synthase 2 Deficiency Attenuates NFκB Activation
Authors: Hailemariam Tiruneh K. , Huan Chongmin , Liu Jing , Li Zhiqiang , Roman Christopher , Kalbfeisch Michael , Bui Hai H. , Peake David A. , Kuo Ming-Shang , Cao Guoqing , Wadgaonkar Raj , Jiang Xian-Cheng
Published: June 2008

Background—

NFκB has long been regarded as a proatherogenic factor, mainly because of its regulation of many of the proinflammatory genes linked to atherosclerosis. Metabolism of sphingomyelin (SM) has been suggested to affect NFκB activation, but the mechanism is largely unknown. SMS2 regulates SM levels in cell plasma membrane and lipid rafts and has a potential to regulate NFκB activation.

Methods and Results—

To investigate the role of SMS2 in NFκB activation we used macrophages from SMS2 knockout (KO) mice and SMS2 siRNA-treated HEK 293 cells. We found that NFκB activation and its target gene expression are attenuated in macrophages from SMS2 KO mice in response to lipopolysaccharide (LPS) stimulation and in SMS2 siRNA- treated HEK 293 cells after tumor necrosis factor (TNF)–α simulation. In line with attenuated NFκB activation, we found that SMS2 deficiency substantially diminished the abundance of toll like receptor 4 (TLR4)-MD2 complex levels on the surface of macrophages after LPS stimulation, and SMS2 siRNA treatment reduced TNF-α-stimulated lipid raft recruitment of TNF receptor-1 (TNFR1) in HEK293 cells. SMS2 deficiency decreased the relative amounts of SM and diacylglycerol (DAG) and increased ceramide, suggesting multiple mechanisms for the decrease in NFκB activation.

Conclusions—

SMS2 is a modulator of NFκB activation, and thus it could play an important role in NFκB-mediated proatherogenic process.
Variables Associated With 7-Day, 30-Day, and 1-Year Fatality After Ischemic Stroke
Authors: Saposnik Gustavo , Hill Michael D. , O'Donnell Martin , Fang Jiming , Hachinski Vladimir , Kapral Moira K.
Published: June 2008

Background and Purpose—

Seven-day, 30-day, and 1-year case-fatality indicators have been used to compare stroke care among hospitals, provinces, and countries and to implement quality improvement strategies. However, limited information is available concerning variables associated with stroke case fatality at these different points in time. We sought to identify and compare variables associated with 7-day, 30-day, and 1-year stroke fatality.

Methods—

This was a cohort study of consecutive patients with acute ischemic stroke admitted to 11 stroke centers in Ontario, Canada, between July 2003 and March 2005 and captured in the Registry of the Canadian Stroke Network (RCSN). The RCSN database was linked to administrative databases to capture all deaths occurring within 7, 30, and 365 days of hospital admission for ischemic stroke. Logistic regression was used to determine variables associated with stroke fatality at each time point. Outcome measures were all-location mortality within 7 days, 30 days, and 1 year of hospital admission.

Results—

Our cohort included 3631 patients admitted with ischemic stroke. Seven-day case fatality was 6.9% (249/3631), 30-day case fatality was 12.6% (457/3631), and 1-year case fatality was 23.6% (856/3631). In the multivariable analyses, stroke severity, neurologic deterioration during hospitalization, nonuse of antithrombotics during hospital admission, and lack of assessment by a stroke team were the most consistent predictors of case fatality at 7 days, 30 days, and 1 year after stroke. Physician experience in stroke management was inversely associated with 7-day and 30-day mortality, whereas age, comorbid illness, and pneumonia during hospital admission were associated with 30-day and 1-year mortality.

Conclusions—

Stroke severity and certain processes of care were associated with case fatality at 7days, 30 days, and 1 year after stroke. This information may be useful for comparing risk-adjusted case-fatality rates among hospitals and for implementing strategies to improve the processes and quality of care in the acute phase of stroke.
National Security and U.S. Immigration Policy, 1776–1790
Authors: Totten Robbie
Published: June 2008

An examination of U.S. immigration policy during the early Republic from a security perspective—a common analytical focus within the field of international relations—reveals the inadequacy of traditional economic and ideological interpretations. Security concerns, based on actual threats from Great Britain and Spain, permeated the arguments both for and against immigration. Those in favor of immigration hoped to strengthen the nation, primarily by providing soldiers and money for the military; those opposed to immigration feared that it would compromise national security by causing domestic unrest and exposing the new nation to espionage and terrorism. These issues are not unlike those that beset contemporary policymakers.
Assimilation of GRACE Terrestrial Water Storage Data into a Land Surface Model: Results for the Mississippi River Basin
Authors: Zaitchik Benjamin F. , Rodell Matthew , Reichle Rolf H.
Published: June 2008

Assimilation of data from the Gravity Recovery and Climate Experiment (GRACE) system of satellites yielded improved simulation of water storage and fluxes in the Mississippi River basin, as evaluated against independent measurements. The authors assimilated GRACE-derived monthly terrestrial water storage (TWS) anomalies for each of the four major subbasins of the Mississippi into the Catchment Land Surface Model (CLSM) using an ensemble Kalman smoother from January 2003 to May 2006. Compared with the open-loop CLSM simulation, assimilation estimates of groundwater variability exhibited enhanced skill with respect to measured groundwater in all four subbasins. Assimilation also significantly increased the correlation between simulated TWS and gauged river flow for all four subbasins and for the Mississippi River itself. In addition, model performance was evaluated for eight smaller watersheds within the Mississippi basin, all of which are smaller than the scale of GRACE observations. In seven of eight cases, GRACE assimilation led to increased correlation between TWS estimates and gauged river flow, indicating that data assimilation has considerable potential to downscale GRACE data for hydrological applications.