bluuebunny/crossref_metadata_2025 huggingface dataset:
Lessons from Le Coteau landslide, Gatineau, Quebec
Authors: McRostie G. C. , St-Louis M. W.
Published: June 2008

A medium sized landslide occurred in 1971 in the suburban community of Gatineau, Quebec, near Hull and Ottawa. Five buildings containing 44 housing units were threatened by progressive advances of the slide. One partially completed building was destroyed by the slide. A municipal street was blocked by soil debris a few metres deep and more than 15 families were evacuated from their homes on an emergency basis.Over the succeeding three years, a sequence of events occurred. The municipal council revised the land zoning of the area. A technical study of the stability of the remaining hillside was carried out, and recommendations for slope flattening measures were made in detail. Lawsuits were filed by residents against the builder, the municipality, and insurance companies for both. The municipality refrained from initiating new remedial works promptly, owing to the legal responsibility this would have inferred. In the following springs of 1972–1974, the years after the first slides, further slides took place and all occupants of the threatened area were eventually evacuated.The builder went bankrupt, the loaning institution inherited the housing project, and the final outcome was abandonment of the project and demolition of the buildings, a costly experience for many of the people concerned.
Experimental evaluation of bearing capacity of footings subjected to inclined loads
Authors: Hanna A. M. , Meyerhof G. G.
Published: June 2008

The ultimate bearing capacity of footings subjected to axially inclined loads was investigated experimentally by conducting tests on model strip and circular footings on homogeneous sand and clay. The results were analyzed to determine the inclination factors, depth factors, and shape factors incorporated in the general bearing capacity equation for shallow foundations. These values are compared with the recommended values given in the Canadian Foundation Engineering Manual.
The mass strength of jointed residual soils
Authors: Koo Y. C.
Published: June 2008

Structural defects in the form of relict joints are frequently found in residual soils derived from the decomposition of igneous and metamorphic rocks. Previous studies indicate that the shear strength along relict joints is generally less than that of the intact material and therefore such joints form planes of weakness in the jointed soil. Slope designs in jointed soils, based on the strength of the intact material without considering the presence of adversely oriented relict joints, may be unsafe. The distribution of mass strength of jointed soils in the field is bimodal, with the intact strength as an upper limit and the joint strength as a lower limit; it varies with direction and with the geometry of the potential slip surface. In order to describe this behaviour, a probabilistic method to estimate the mass strength is presented and its practical application is illustrated by a case study.
Fifth Canadian Geotechnical Colloquium: Control of contaminant migration by the use of liners
Authors: Folkes David J.
Published: June 2008

Procedures satisfactory for the design of seepage control liners for hydraulic structures are not generally sufficient for the design of pollution control liners, where the primary intent is mitigation of contaminant migration effects on the environment. Contaminant migration rates and concentrations are controlled by seepage rate, dispersion and diffusion processes, and attenuation mechanisms such as filtration, precipitation, adsorption, and biodegradation. Both liner and subsoil (or bedrock) properties affect contaminant migration; thus, both should be considered as part of the overall liner system. Mechanisms for controlling migration are limited by the perceived extent of the liner system. Typical liner materials include compacted clays, admixes, polymeric membranes, spray-ons, and sealants. The field hydraulic properties, liner thickness, and liner–fluid compatibility should be considered in design
Coupled soil-atmosphere modelling for soil evaporation
Authors: Wilson G. Ward , Fredlund D.G. , Barbour S.L.
Published: June 2008

Traditional methods of evaluating evaporation provide an estimate of the maximum or potential rate of evaporation determined on the basis of climatic conditions. Methods such as these are appropriate for open water or fully saturated soil surfaces. Actual rates of evaporation from unsaturated soil surfaces are generally greatly reduced relative to the potential rate of evaporation. A theoretical model for predicting the rate of evaporation from soil surfaces is presented in this paper. The model is based on a system of equations for coupled heat and mass transfer in soil. Darcy's Law and Fick's Law are used to describe the flow of liquid water and water vapour, respectively. Heat flow is evaluated on the basis of conductive and latent heat fluxes. Dalton's Law is used to calculate the rate of soil evaporation to the atmosphere based on the suction at the soil surface. The soil–atmosphere model was used to predict soil evaporation rates, water-content profiles, and temperature profiles for a controlled column evaporation test over a 42 day period. The values computed by the soil–atmosphere model agreed well with the values measured for two columns of Beaver Creek sand in the evaporation test. Key words : modelling, evaporation, unsaturated, soil surfaces.
A new approach to the analysis of high-strain dynamic pile test data
Authors: Robert Yves
Published: June 2008

High-strain dynamic pile tests using the pile driving analyzer (PDA) and the Case method have been available in Canada for over 15 years. During that period of time, the hardware has evolved considerably but the way the data is interpreted has basically remained the same. The evaluation of the bearing capacity of the tested pile still uses the Case method, with the Case J factor being calculated either from the results of a static load test or, more often, from the results of one or more CAPWAP (Case pile wave analysis program) analyses. A computer program has been developed to estimate the bearing capacity of piles using the dynamic test results produced by the PDA. This program uses direct correlations between PDA data and CAPWAP results. It also includes an artificial intelligence module trained to predict CAPWAP pile capacity. It is not designed to replace the CAPWAP program, but rather to indicate when an additional CAPWAP analysis might be required. Key words : dynamic load test, computer program, artificial intelligence, CAPWAP, Case method.
Application of Terzaghi's consolidation theory to nearly saturated soils
Authors: Vaziri Hans H. , Christian Harold A.
Published: June 2008

Terzaghi's one-dimensional consolidation theory is modified to account for the compressibility of fluid and solid phases. The proposed modified equations can be used to analyze the consolidation response of unsaturated soils over the saturation range where the gases remain in an occluded form (generally within a range between 80 and 100aturation); however, such applications are subject to the same limitations and idealizations implicit in Terzaghi's classical consolidation theory. The purpose of this note, therefore, is to offer a simple solution and not to unravel the complexities involved in general analysis of flow and deformation response of unsaturated soils. The proposed approach involves defining the consolidation coefficient, and hence the time factor, in terms of an equivalent fluid compressibility. This equivalent fluid is assumed to represent the compressibility characteristics of all the compressible phases that constitute the soil skeleton. The proposed generalized form of Terzaghi's consolidation equations is shown to qualitatively capture the consolidation behaviour of unsaturated soils. To test the validity of the formulations presented, one-dimensional oedometer tests were performed on specimens of Lantz clay that had been prepared at different saturation levels; satisfactory agreement was achieved between the theoretical and measured data at two states of saturation. Key words : consolidation, theoretical solutions, oedometer test, compressible fluid, occluded gas.
Localized-orbital locator (LOL) profiles of chemical bonding
Authors: Jacobsen Heiko
Published: June 2008

We examine a recently introduced descriptor of chemical bonding, the localized-orbital locator (LOL), which is based on the kinetic-energy density (τ). Examples are presented for prototypical chemical bonds, such as single, double, and triple bonds, for bonding in transition metal complexes, for three-center two-electron bonds, as well as for hypervalent molecules. The topology of LOL is analyzed in terms of (3,–3) attractors (Γ). The influence of core electrons for chemical bonding is investigated, and a LOL-VSEPR (valence shell electron pair repulstion) relationship is established. Further, we compare LOL to the related electron localization function (ELF).Key words: chemical bonding, kinetic-energy density, localized-electron locator, VSEPR theory.
Asymmetric oxidation of 2-(arylsulfenyl)pyrroles
Authors: Thompson Alison , Garabatos-Perera Jose R , Gillis H Martin
Published: June 2008

The asymmetric oxidation of prochiral 2-(arylsulfenyl)pyrroles has been investigated. A marked electronic effect within the substrate significantly influenced the degree of enantioselectivity obtained, with very high enantio selectivity being obtained for 5-(nitrobenzensulfenyl)pyrrole-2-carboxaldehydes using Ti(i-PrO)4/(+)-(R,R)-DET/H2O/CHP. This result bodes well for optimizing the asymmetric oxidation of other diaryl sulfides, substrates that have previously given only low enantiomeric excesses.Key words: asymmetric oxidation, sulfide, sulfoxide, pyrrole.
QTAIM–DI–VISAB computational study on the Diels–Alder reaction of cyclopentadiene — On the nature of the so-called secondary orbital interactions
Authors: Werstiuk Nick Henry , Sokol Wojciech
Published: June 2008

We have undertaken a QTAIM–DI–VISAB computational study of the dimerization of cyclopentadiene (1), the archetypal example of a Diels–Alder reaction that has been studied experimentally and computationally. Secondary orbital interactions (SOIs) that have gained acceptance in the interpretation of stereoselectivities seen in many cycloaddition reactions have been used to account for the fact that the endo isomer was the kinetic product of the reaction. To this point, “classical” MO analyses along with a variety of arbitrarily assigned solid and dashed lines (solid lines and bold dashes for “primary” interactions and dashed and dotted lines to differentiate between different SOI schemes) have been used in an attempt to describe the bonding of the transition states. Yet, the existence of SOIs has been challenged. Our interest in applying QTAIM to fundamental chemical problems in physical organic chemistry, with the goal of refining our knowledge of the bonding in transition-states and ground-state molecules while obviating the need to use a variety of confusing arbitrarily assigned dashed and dotted lines, led us to a QTAIM–DI–VISAB computational study of the endo and exo dimerizations of 1 at the DFT B3PW91 and MPW1PW91 levels. We have characterized the bonding interactions between cyclopentadiene rings in the various transition states and show that “normal” bonds are present where SOIs have been considered to exist. There is no need to use different types of dashed and dotted lines. An analysis of the changes in atom energies revealed that the significant destabilization of the carbon atoms in achieving the TSs (potentially leading to a very high barrier) is ameliorated by a stabilization of the hydrogen atoms leading to the relatively low barrier for the D–A reaction.Key words: cyclopentadiene dimerization, bispericyclic transition states, DFT calculations, QTAIM–DI–VISAB analysis, bonding, atom energy analysis.
Time course of regression of the protection conferred by simulated high altitude to rat myocardium: correlation with mtNOS
Authors: La Padula Pablo , Bustamante Juanita , Czerniczyniec Analía , Costa Lidia E.
Published: June 2008

During acclimatization to sustained hypobaric hypoxia, retardation of age-associated decline in left ventricle mechanical activity and improved posthypoxic recovery were accompanied by upregulation of mitochondrial nitric oxide synthase (mtNOS). To evaluate the time course of regression of these effects on deacclimatization, rats exposed to 53.8 kPa in a hypopressure chamber for 5 mo were returned to 101.3 kPa, whereas controls remained at 101.3 kPa throughout the study. At three time points, contractile function in response to calcium and to hypoxia-reoxygenation (H/R) were determined in papillary muscle, and NOS activity and expression were determined in mitochondria isolated from left ventricle. Developed tension was, before H/R, 65, 58, and 40%, and, after H/R, 129, 107, and 71% higher than in controls at 0.4, 2, and 5 mo of normoxia, respectively. Maximal rates of contraction and relaxation followed a similar pattern. All three parameters showed a linear decline during deacclimatization, with mean half-time ( t1/2) of 5.9 mo for basal mechanical activity and 5.3 mo for posthypoxic recovery. Left ventricle mtNOS activity was 42, 27, and 20% higher than in controls at 0.4, 2, and 5 mo, respectively ( t1/2= 5.0 mo). The expression of mtNOS showed similar behavior. The correlation of mtNOS activity with muscle contractility sustained a biphasic modulation, suggesting an optimal mtNOS activity. This experimental model would provide the most persistent effect known at present on preservation of myocardial mechanical activity and improved tolerance to O2deprivation. Results support the putative role of mtNOS in the mechanism involved.
TATA Box-Binding Protein–Associated Factor 12 Is Important for RAS-Induced Transformation Properties of Colorectal Cancer Cells
Authors: Voulgari Angeliki , Voskou Stella , Tora Làszlò , Davidson Irwin , Sasazuki Takehiko , Shirasawa Senji , Pintzas Alexander
Published: June 2008

Activating mutations in the RAS proto-oncogene result in constant stimulation of its downstream pathways, further leading to tumorigenesis. Transcription factor IID (TFIID) can be regulated by cellular signals to specifically alter transcription of particular subsets of genes. To investigate potential links between the regulation of TFIID function and the RAS-induced carcinogenesis, we monitored the expression of the TATA box-binding protein and its associated factors (TAF) in human colon carcinoma cells. We primarily identified TAF12 levels as being up-regulated in cell lines bearing natural RAS mutations or stably overexpressing a mutated RAS isoform via a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase–dependent pathway. We further showed by electrophoretic mobility shift assays and chromatin immunoprecipitation that the ETS1 protein was interacting with an ETS-binding site on the TAF12 promoter and was regulating TAF12 expression. The binding was enhanced in extracts from oncogenic RAS-transformed cells, pointing to a role in the RAS-mediated regulation of TAF12 expression. Reduction of TAF12 levels by small interfering RNA treatment induced a destabilization of the TFIID complex, enhanced E-cadherin mRNA and protein levels, and reduced migration and adhesion properties of RAS-transformed cells with epithelial to mesenchymal transition. Overall, our study indicates the importance of TAF12 in the process of RAS-induced transformation properties of human colon cells and epithelial to mesenchymal transition, most notably those related to increased motility, by regulating specifically expression of genes such as E-cadherin. (Mol Cancer Res 2008;6(6):1071–83)
Targeting Nuclear Factor-κB Activation Pathway by Thymoquinone: Role in Suppression of Antiapoptotic Gene Products and Enhancement of Apoptosis
Authors: Sethi Gautam , Ahn Kwang Seok , Aggarwal Bharat B.
Published: June 2008

Thymoquinone (TQ), derived from the medicinal plant Nigella sativa, exhibits antiinflammatory and anticancer activities through mechanism(s) that is not fully understood. Because numerous effects modulated by TQ can be linked to interference with the nuclear factor-κB (NF-κB) signaling, we investigated in detail the effect of this quinone on NF-κB pathway. As examined by DNA binding, we found that TQ suppressed tumor necrosis factor–induced NF-κB activation in a dose- and time-dependent manner and inhibited NF-κB activation induced by various carcinogens and inflammatory stimuli. The suppression of NF-κB activation correlated with sequential inhibition of the activation of IκBα kinase, IκBα phosphorylation, IκBα degradation, p65 phosphorylation, p65 nuclear translocation, and the NF-κB–dependent reporter gene expression. TQ specifically suppressed the direct binding of nuclear p65 and recombinant p65 to the DNA, and this binding was reversed by DTT. However, TQ did not inhibit p65 binding to DNA when cells were transfected with the p65 plasmid containing cysteine residue 38 mutated to serine. TQ also down-regulated the expression of NF-κB–regulated antiapoptotic (IAP1, IAP2, XIAP Bcl-2, Bcl-xL, and survivin), proliferative (cyclin D1, cyclooxygenase-2, and c-Myc), and angiogenic (matrix metalloproteinase-9 and vascular endothelial growth factor) gene products. This led to potentiation of apoptosis induced by tumor necrosis factor and chemotherapeutic agents. Overall, our results indicate that the anticancer and antiinflammatory activities previously assigned to TQ may be mediated in part through the suppression of the NF-κB activation pathway, as shown here, and thus may have potential in treatment of myeloid leukemia and other cancers. (Mol Cancer Res 2008;6(6):1059–70)
The RNA Exosome Component hRrp6 Is a Target for 5-Fluorouracil in Human Cells
Authors: Kammler Susanne , Lykke-Andersen Søren , Jensen Torben Heick
Published: June 2008

The drug 5-fluorouracil (5-FU) is a widely used chemotherapeutic in the treatment of solid tumors. Recently, the essential 3′-5′ exonucleolytic multisubunit RNA exosome was implicated as a target for 5-FU in yeast. Here, we show that this is also the case in human cells. HeLa cells depleted of the inessential exosome component hRrp6, also called PM/Scl100, are significantly growth impaired relative to control cells after 5-FU administration. The selective stabilization of bona fide hRrp6 RNA substrates on 5-FU treatment suggests that this exosome component is specifically targeted. Consistently, levels of hRrp6 substrates are increased in two 5-FU–sensitive cell lines. Interestingly, whereas down-regulation of all tested core exosome components results in decreased hRrp6 levels, depletion of hRrp6 leaves levels of other exosome components unchanged. Taken together, our data position hRrp6 as a promising target for antiproliferative intervention. (Mol Cancer Res 2008;6(6):990–5)
Effects of Raf Kinase Inhibitor Protein Expression on Metastasis and Progression of Human Epithelial Ovarian Cancer
Authors: Li Hong Zhao , Wang Yue , Gao Yan , Shao Jie , Zhao Xiu Lan , Deng Wei Min , Liu Yi Xin , Yang Jie , Yao Zhi
Published: June 2008

Loss of function of metastasis suppressor genes is an important step in the progression to a malignant tumor type. Studies in cell culture and animal models have suggested a role of Raf kinase inhibitor protein (RKIP) in suppressing the metastatic spread of prostate cancer, breast cancer, and melanoma cells. However, the function of RKIP in ovarian cancer (OVCA) has not been reported. To explore the potential role of RKIP in epithelial OVCA metastasis, we detected the expression levels of RKIP protein in tissue samples from patients with epithelial OVCA. Consequently, the expression of RKIP is reduced in the poorly differentiated OVCA than in the well-differentiated and moderately differentiated OVCA. In addition, in vitro cell invasion assay indicated that the RKIP expression was inversely associated with the invasiveness of five OVCA cell lines. Consistent with this result, the cell proliferation, anchorage-independent growth, cell adhesion, and invasion were decreased in RKIP overexpressed cells but increased in RKIP down-regulated cells. Further investigation indicated that RKIP inhibited OVCA cell proliferation by altering cell cycle progression rather than promoting apoptosis. Furthermore, the overexpression of RKIP suppressed the ability of human OVCA cells to metastasize when the tumor cells were transplanted into nude mice. Our data show the effect of RKIP on the proliferation, migration, or adhesion of OVCA cells. These results indicate that RKIP is also a metastasis suppressor gene of human epithelial OVCA. (Mol Cancer Res 2008;6(6):917–28)
Risk Factors for Dysmenorrhea and Its Severity in Women with Ovarian Endometriomas
Authors: Liu Xishi , Yuan Lei , Wang Yuedong , Shen Fanghua , Guo Sun-Wei
Published: June 2008

Objective: To identify factors associated with the risk of developing dysmenorrhea or the severity of dysmenorrhea in women with surgically confirmed ovarian endometriomas. Study Design: 710 patients with surgically diagnosed ovarian endometriomas were interviewed and their charts read. Fourteen factors were considered. Among the 710 patients, 376 patients had major complaint of dysmenorrhea and were evaluated to identify factors associated with the severity of dysmenorrhea. Results: The logistic regression model identified younger age at surgery, previous medication use, presence of adhesion, and presence of adenomyosis as risk factors for dysmenorrhea. For the severity of dysmenorrhea, the presence of adenomyosis was consistently and robustly identified by several statistical models with rather different assumptions as the factor associated with severity. The rAFS stage was also associated with the severity, but the association may be explained by the presence of adenomyosis. Conclusion: The presence of adenomyosis has been consistently identified as a risk factor for both dysmenorrhea and its severity. Younger age at surgery, presence of adhesion, and previous use of endometriosis-related medication are additional risk factors for dysmenorrhea. For the severity of dysmenorrhea, there are other factors than the presence of adenomyosis that may influence the severity of dysmenorrhea.
Gestational Diabetes: Using a Portable Glucometer to Simplify the Approach to Screening
Authors: Agarwal Mukesh M. , Dhatt Gurdeep S. , Safraou Mohamed-Faouzi
Published: June 2008

Background: In populations at a high-risk for gestational diabetes (GDM), the recommendation of screening every pregnant woman with the oral glucose tolerance test (OGTT) is very demanding. Aim: To assess the usefulness of the portable, plasma optimized glucometer in simplifying the approach to screening of GDM. Methods: 1,662 pregnant women underwent the one-step 75 g OGTT for routine screening of GDM, as defined by the criteria of the American Diabetes Association. The glucometer was used to measure the initial fasting venous whole blood glucose (FBG) to assess its value as a screening test in predicting the need to proceed with the OGTT. Results: 186 (11.2%) women had GDM. The area under the receiver operating characteristic curve (AUC) of the FBG was 0.876 (95% CI 0.847–0.906). A FBG threshold (at an acceptable sensitivity of 85%) independently could ‘rule-out’ GDM in 1,138 (68.5%) women; i.e. over two-thirds of the women would not need to continue with the cumbersome OGTT. Conclusions: Using the glucometer to initially measure the venous FBG as a screen can help to significantly reduce the number of OGTTs needed for the diagnosis of GDM. This algorithm offers a simple, practical, cost-effective and patient-friendly approach for the screening of GDM.
Evaluation of Choline Acetyltransferase Gene Polymorphism (2384 G/A) in Alzheimer’s Disease and Mild Cognitive Impairment
Authors: Tang Muni , Rao Dongping , Ma Cui , Guo Yangbo , Han Haiying , Ling Kangguang , Ling Yuhua
Published: June 2008

Background/Aims: It has been hypothesized that choline acetyltransferase (ChAT) activity might be associated with cognitive impairment in Alzheimer’s disease (AD). A functional single nucleotide polymorphism (2384 G/A) of ChAT was proposed to be associated with AD risk and age of onset. The aim of this study was to evaluate this polymorphism in a cohort of Chinese AD patients and patients with mild cognitive impairment (MCI). Methods: We conducted a case-control study in 273 cases of sporadic AD, 97 MCI patients and 271 nondemented controls from the Chinese Han population. Results: In AD, ChAT 2384 A carriers had a significantly earlier age of onset and worse individual cognitive function in Fuld Object-Memory Evaluation; in MCI, the carriers of both 2384 A and ApoE Ε4 had a significantly earlier age of onset. Conclusion:ChAT 2384 A allele is a risk factor for AD and MCI.
Magnetic Resonance Spectroscopy Performance for Detection of Dementia, Alzheimer’s Disease and Mild Cognitive Impairment in a Community-Based Survey
Authors: García Santos J.M. , Gavrila D. , Antúnez C. , Tormo M.J. , Salmerón D. , Carles R. , Jiménez Veiga J. , Parrilla G. , Torres del Río S. , Fortuna L. , Navarro C.
Published: June 2008

Background/Aims: To evaluate 1H-labelled magnetic resonance spectroscopy (MRS) in patients with a low Mini Mental State Examination (MMSE) score identified during a dementia community-based survey. Methods: A population sample of 1,500 individuals (>64 years old) was randomly selected. Two hundred and fifteen individuals (MMSE ≤24) were sorted into clinical groups: dementia, Alzheimer’s disease, mild cognitive impairment (MCI), normal. Up to 56 of these individuals attended the MRS appointment. Two single-voxel sequences (TR 1,500, TE 35/144 ms) were carried out in the posterior cingulate gyrus of each individual, and the ratios N-acetylaspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myo-inositol (mI)/Cr, NAA/mI and NAA/Cho were compared statistically. The ability of MRS to distinguish clinical groups was assessed by receiver-operating characteristics analysis. Cognition effects on metabolite ratios were estimated, with gender and cognition as categorical variables and age as a continuous covariate. Results: NAA/Cr and NAA/Cho ratios were lower in dementia or Alzheimer’s disease than in MCI and normal groups. The NAA/Cr ratio at TE 35 ms performed best when distinguishing dementia or Alzheimer’s disease from non-demented subjects (cut-off point 1.40). MRS could not distinguish between MCI patients and normal subjects. Dementia was an independent predictor of metabolite values. Conclusion: In a population sample, conventional MRS still proved to be a useful tool for dementia discrimination, but it is potentially far less useful as a surrogate marker for MCI.
BCR-ABL in Chronic Myelogenous Leukemia – How Does It Work?
Authors: Goldman John M. , Melo Junia V.
Published: June 2008

The discovery of the BCR-ABL fusion gene on the Philadelphia (Ph) chromosome in 1985 was the start of a new era in understanding the molecular basis of hematologic malignancies. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the Bcr-Abl oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with chronic myelogenous leukemia (CML) in the chronic phase. However, we still do not know for sure whether the BCR-ABL fusion gene is really the initiating lesion for the chronic phase of CML and we have an incomplete understanding of the so-called genomic instability that underlies the production of the fusion gene and predisposes the Ph-positive clone to acquire further genetic events that lead to advanced-phase disease. Moreover, it is clear that though some of the mutant Ph-positive subclones that develop in patients taking tyrosine kinase inhibitors (TKIs) are the direct cause of the resistance observed, in other cases, its cause is unclear. It is likely that in the next few years we will see (1) improved methods for predicting responses to TKIs, (2) the use of TKIs in combination with other effective molecules such as farnesyl transferase inhibitors, and (3) a gradual reduction in the proportion of chronic-phase patients resistant to therapy.
JAK2 and MPL Mutations in Myeloproliferative Neoplasms
Authors: Koppikar Priya , Levine Ross L.
Published: June 2008

The Philadelphia chromosome-negative myeloproliferative disorders (MPDs) polycythemia vera (PV), essential thrombocytosis (ET) and primary myelofibrosis (PMF) are characterized by increased proliferation of terminally differentiated myeloid cells. Although these disorders were recognized as clonal hematopoietic stem cell disorders more than 3 decades ago, little was known about the genetic basis for these disorders until 2005 when a single recurrent mutation in the JAK2 tyrosine kinase (JAK2V617F) was identified in >90% of patients with PV and in a significant proportion of patients with ET and PMF. JAK2V617F is a constitutively active tyrosine kinase and has transforming properties in vitro and in vivo, providing validation JAK2V617F is a bona fide oncogene which contributes to MPD pathogenesis. Subsequent studies of JAK2V617F-negative MPDs have identified mutations in JAK2 exon 12 and MPL, and these mutations also result in constitutive activation of JAK2 signaling. In this review, we will discuss the genetics of PV, ET and PMF with regard to known somatic mutations, the role of these mutations in hematopoietic transformation and the therapeutic implications of these findings.
A Comparison of Abdominal Cavity Bacterial Contamination of Laparoscopy and Laparotomy for Colorectal Cancers
Authors: Saida Yoshihisa , Nagao Jiro , Nakamura Yasushi , Nakamura Yoichi , Enomoto Toshiyuki , Katagiri Miwa , Kusachi Shinya , Watanabe Manabu , Sumiyama Yoshinobu
Published: June 2008

Background/Aim: To compare intra-abdominal remnant bacterium between laparotomy and laparoscopic colorectal surgery. Methods: 72 patients with nonobstructive colorectal cancer were divided into two groups: laparotomy (47 cases) and laparoscopic surgery (25 cases). At the beginning of the operation just after the laparotomy incision was made or the trocars were inserted, 10 ml saline was irrigated into the Douglas pouch and collected through Nelaton’s catheter. Just before closing the wound, 10 ml saline was collected in the same way as the initial lavage in both groups. The collected saline as a specimen was determined to obtain the number of surviving bacterium. Results: No growth of bacteria was observed at the beginning of both operations. The remnant bacterial detection rates from the lavage fluid collected just before closing the wound were 23 of 47 cases (49%) in the laparotomy group and 7 of 25 cases (28%) in the laparoscopic surgery group; higher detection was observed in the laparotomy group. The mean bacteria cell counts after lavage were 4.6 × 106 CFU/ml of aerobic bacteria and 1.9 × 103 CFU/ml of anaerobic bacteria in the laparotomy group and 1.8 × 104 CFU/ml of aerobic bacteria and 1.6 × 102 CFU/ml in the laparoscopic surgery group: the laparotomy group demonstrated an apparently higher number of remnant bacterium. Conclusions: In colorectal resections, laparoscopic surgery demonstrated a lower incidence of intra-abdominal contamination than laparotomy.
Surgical Treatment of Gastric Gastrointestinal Stromal Tumors: Analysis of 92 Operated Patients
Authors: Lai I-Rue , Chen Chiung-Nien , Lin Ming-Tsan , Lee Po-Huang
Published: June 2008

Aim: To review and evaluate the clinicopathological factors predictive of recurrence after surgical resection for gastrointestinal stromal tumor (GIST) of the stomach. Methods: The clinicopathological records of 92 gastric GIST patients who were operated upon at a single institute from 1996 to 2005 were retrospectively reviewed and assessed for recurrence-free survival. Results: The patients included 43 men and 49 women. Their ages ranged from 25 to 91 years. The size of the tumors varied from 0.8 to 47.7 cm (median 5.8; 95% CI 6.4–9.2 cm). All but one operative margin were clear. The follow-up period ranged from 11 to 112 months (median 31, 95% CI 33.7–43.5 months). Fifteen patients (16%) developed disease recurrence, of which liver metastasis was the most common. Only 1 of the patients with tumors <4 cm developed recurrence. The 3-year recurrence-free survival rates for patients with tumors smaller or larger than 4 cm were 93 and 56.0%, respectively (p < 0.01). Multivariate analysis showed that the tumor size was the independent factor that was inversely associated with recurrence-free survival. Conclusion: The tumor size is an important prognostic factor for recurrence after surgery. Early excision is recommended for gastric GISTs even of small size.
Metastatic Tumor Doubling Time Is an Independent Predictor of Intrapulmonary Recurrence after Pulmonary Resection of Solitary Pulmonary Metastasis from Colorectal Cancer
Authors: Tomimaru Yoshito , Noura Shingo , Ohue Masayuki , Okami Jiro , Oda Kazuyuki , Higashiyama Masahiko , Yamada Terumasa , Miyashiro Isao , Ohigashi Hiroaki , Yano Masahiko , Kodama Ken , Ishikawa Osamu , Murata Kohei , Yokouchi Hideoki , Sasaki Yo , Kameyama Masao , Imaoka Shingi
Published: June 2008

Background: Several investigators have previously reported the prognostic factors affecting survival after a surgical resection of pulmonary metastasis from colorectal cancer (CRC). However, there have so far been no reports describing prognostic factors related to the tumor doubling time (TDT) of pulmonary metastasis. Methods: 65 patients with solitary pulmonary metastasis from CRC were retrospectively reviewed and the prognostic factors after pulmonary resection including TDT were analyzed. Results: The 5-year intrapulmonary recurrence-free survival rates after pulmonary resection was 59.9%. The TDT of pulmonary metastasis (<100 vs. 100 days or higher) was only a significant prognostic factor in intrapulmonary recurrence after the pulmonary resection (p = 0.0006). The 5-year overall survival rate after the pulmonary resection was 64.2%. Preoperative serum carcinoembryonic antigen (CEA) level (<5 vs. 5 ng/ml or higher) was the only significant prognostic factor in overall survival after the pulmonary resection (p = 0.0049). The overall survival of patients whose TDT was 100 days or higher tended to be better than that of patients whose TDT was <100 (p = 0.0631). Conclusions: The TDT of solitary pulmonary metastasis is a significant prognostic factor after surgery for solitary pulmonary metastasis from CRC.
Low Tissue Inhibitor of Metalloproteinases 3 and High Matrix Metalloproteinase 14 Levels Defines a Subpopulation of Highly Invasive Foam-Cell Macrophages
Authors: Johnson Jason L. , Sala-Newby Graciela B. , Ismail Yasmin , Aguilera Concepción M. , Newby Andrew C.
Published: June 2008

Objective—

An excess of metalloproteinases (MMPs) over tissue inhibitors of metalloproteinases (TIMPs) may favor atherosclerotic plaque rupture. We compared TIMP levels in nonfoamy and foam-cell macrophages (FCM) generated in vivo.

Methods and Results—

In vivo generated rabbit FCM exhibited 84% reduced TIMP-3 protein compared to nonfoamy macrophages, and immunocytochemistry revealed a TIMP-3 negative subset (28%). Strikingly, only TIMP-3 negative FCM invaded a synthetic basement membrane, and invasion was inhibited by exogenous TIMP-3. TIMP-3 negative FCM also had increased proliferation and apoptosis rates compared to TIMP-3 positive cells, which were retarded by exogenous TIMP-3; this also reduced gelatinolytic activity. TIMP-3 negative FCM were found at the base of advanced rabbit plaques and in the rupture-prone shoulders of human plaques. To explain the actions of low TIMP-3 we observed a 26-fold increase in MT1-MMP (MMP-14) protein in FCM. Adding an MT1-MMP neutralizing antibody reduced foam-cell invasion, apoptosis, and gelatinolytic activity. Furthermore, MT1-MMP overexpressing and TIMP-3 negative FCM were found at the same locations in atherosclerotic plaques.

Conclusions—

These results demonstrate that TIMP-3 is downregulated in a distinct subpopulation of FCM which have increased MMP-14. These cells are highly invasive and have increased proliferation and apoptosis, all properties expected to destabilise atherosclerotic plaques.
Neurotrophin p75 Receptor (p75
NTR
) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis
Authors: Caporali Andrea , Pani Elisabetta , Horrevoets Anton J.G. , Kraenkel Nicolle , Oikawa Atsuhiko , Sala-Newby Graciela B. , Meloni Marco , Cristofaro Brunella , Graiani Gallia , Leroyer Aurelie S. , Boulanger Chantal M. , Spinetti Gaia , Yoon Sung Ok , Madeddu Paolo , Emanueli Costanza
Published: June 2008

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75
NTR
), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced
p75

NTR

expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular
p75

NTR

gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact,
p75

NTR

depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of
ITGB1 [beta (1) integrin]
,
BIRC5 (survivin
),
PTTG
1 (
securin
) and
VEZF1
. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of
p75

NTR

. Collectively, our data newly demonstrate the antiangiogenic action of p75
NTR
and open new avenues for the therapeutic use of p75
NTR
inhibition to combat diabetes-induced microvascular liabilities.
Redox-Sensitive Signaling by Angiotensin II Involves Oxidative Inactivation and Blunted Phosphorylation of Protein Tyrosine Phosphatase SHP-2 in Vascular Smooth Muscle Cells From SHR
Authors: Tabet Fatiha , Schiffrin Ernesto L. , Callera Glaucia E. , He Ying , Yao Guoying , Östman Arne , Kappert Kai , Tonks Nicholas K. , Touyz Rhian M.
Published: June 2008

Angiotensin II (Ang II) signaling in vascular smooth muscle cells (VSMCs) involves reactive oxygen species (ROS) through unknown mechanisms. We propose that Ang II induces phosphorylation of growth signaling kinases by redox-sensitive regulation of protein tyrosine phosphatases (PTP) in VSMCs and that augmented Ang II signaling in spontaneously hypertensive rats (SHRs) involves oxidation/inactivation and blunted phosphorylation of the PTP, SHP-2. PTP oxidation was assessed by the in-gel PTP method. SHP-2 expression and activity were evaluated by immunoblotting and by a PTP activity assay, respectively. SHP-2 and Nox1 were downregulated by siRNA. Ang II induced oxidation of multiple PTPs, including SHP-2. Basal SHP-2 content was lower in SHRs versus WKY. Ang II increased SHP-2 phosphorylation and activity with blunted responses in SHRs. Ang II—induced SHP-2 effects were inhibited by valsartan (AT1R blocker), apocynin (NAD(P)H oxidase inhibitor), and Nox1 siRNA. Ang II stimulation increased activation of ERK1/2, p38MAPK, and AKT, with enhanced effects in SHR. SHP-2 knockdown resulted in increased AKT phosphorylation, without effect on ERK1/2 or p38MAPK. Nox1 downregulation attenuated Ang II–mediated AKT activation in SHRs. Hence, Ang II regulates PTP/SHP-2 in VSMCs through AT1R and Nox1-based NAD(P)H oxidase via two mechanisms, oxidation and phosphorylation. In SHR Ang II–stimulated PTP oxidation/inactivation is enhanced, basal SHP-2 expression is reduced, and Ang II–induced PTP/SHP-2 phosphorylation is blunted. These SHP-2 actions are associated with augmented AKT signaling. We identify a novel redox-sensitive SHP-2–dependent pathway for Ang II in VSMCs. SHP-2 dysregulation by increased Nox1-derived ROS in SHR is associated with altered Ang II–AKT signaling.
Role of Oxidant Stress on AT1 Receptor Expression in Neurons of Rabbits With Heart Failure and in Cultured Neurons
Authors: Liu Dongmei , Gao Lie , Roy Shyamal K. , Cornish Kurtis G. , Zucker Irving H.
Published: June 2008

We have previously reported that the expression of Angiotensin II (Ang II) type 1 receptors (AT1R) was increased in the rostral ventrolateral medulla (RVLM) of rabbits with chronic heart failure (CHF) and in the RVLM of normal rabbits infused with intracerebroventricular (ICV) Ang II. The present study investigated whether oxidant stress plays a role in Ang II–induced AT1R upregulation and its relationship to the transcription factor activator protein 1 (AP1) in CHF rabbits and in the CATHa neuronal cell line. In CATHa cells, Ang II significantly increased AT1R mRNA by 123±11%,
P
<0.01; c-Jun mRNA by 90±20%,
P
<0.01; c-fos mRNA by 148±49%,
P
<0.01; NADPH oxidase activity by 126±43%,
P
<0.01 versus untreated cells. Tempol and Apocynin reversed the increased expression of AT1R mRNA, c-Jun mRNA, c-fos mRNA, and superoxide production induced by Ang II. We also examined the effect of ICV Tempol on the RVLM of CHF rabbits. Compared to vehicle treated CHF rabbits, Tempol significantly decreased AT1R protein expression (1.6±0.29 versus 0.88±0.16,
P
<0.05), phosphorylated Jnk protein (0.4±0.05 versus 0.2±0.04,
P
<0.05), cytosolic phosphorylated c-Jun (0.56±0.1 versus 0.36±0.05,
P
<0.05), and nuclear phosphorylated c-Jun (0.67±0.1 versus 0.3±0.08,
P
<0.01). Tempol also significantly decreased the AP-1–DNA binding activity in the RVLM of CHF rabbits compared to the vehicle group (9.14×10
3
versus 41.95×10
3
gray level
P
<0.01). These data suggest that Ang II induces AT1R upregulation at the transcriptional level by induction of oxidant stress and activation of AP1 in both cultured neuronal cells and in intact brain of rabbits. Antioxidant agents may be beneficial in CHF and other states where brain Ang II is elevated by decreasing AT1R expression through the Jnk and AP1 pathway.
“Machinery Has Completely Taken Over”: The Diffusion of the Mechanical Cotton Picker, 1949–1964
Authors: Heinicke Craig , Grove Wayne A.
Published: June 2008

Hand picking of cotton in the United States virtually disappeared twenty years after the first mechanical harvester was marketed in 1949. Contrary to received accounts, southern social institutions did not impede the diffusion of the mechanical cotton picker from the West to the cotton belt in the South so much as environmental factors and educational attainment did. Rising cotton yields and exogenous technological change drove diffusion by reducing the costs of machine harvesting. Labor displacement resulting from the cotton picker occurred only in a concentrated burst after 1959.
A Maximum Entropy Model of Phonotactics and Phonotactic Learning
Authors: Hayes Bruce , Wilson Colin
Published: June 2008

The study of phonotactics is a central topic in phonology. We propose a theory of phonotactic grammars and a learning algorithm that constructs such grammars from positive evidence. Our grammars consist of constraints that are assigned numerical weights according to the principle of maximum entropy. The grammars assess possible words on the basis of the weighted sum of their constraint violations. The learning algorithm yields grammars that can capture both categorical and gradient phonotactic patterns. The algorithm is not provided with constraints in advance, but uses its own resources to form constraints and weight them. A baseline model, in which Universal Grammar is reduced to a feature set and an SPE-style constraint format, suffices to learn many phonotactic phenomena. In order for the model to learn nonlocal phenomena such as stress and vowel harmony, it must be augmented with autosegmental tiers and metrical grids. Our results thus offer novel, learning-theoretic support for such representations. We apply the model in a variety of learning simulations, showing that the learned grammars capture the distributional generalizations of these languages and accurately predict the findings of a phonotactic experiment.
Free Word Order, (Non)configurationality, and Phases
Authors: Kiss Katalin É.
Published: June 2008

The article argues that a particular implementation of phase theory makes it possible to account for seemingly contradictory facts of Hungarian that no other framework has been able to handle. Namely, (a) Hungarian word order is fixed preverbally and free postverbally. The fixed word order of a string is liberated when it is crossed by V-movement. (b) Grammatical phenomena sensitive to c-command provide evidence of both configurationality and nonconfigurationality. The proposal is based on the following assumptions: The derivation of the Hungarian sentence involves a lexical phase (PredP) and a functional phase (a TP or a FocP), both headed by the raised V. When the functional phase is constructed, the silent lower copies of the V and their projections are deleted, which results in the flattening of the phasal domain. Grammatical phenomena indicative of a hierarchical structure are interpreted on the hierarchical domain of the lexical phase, whereas those indicative of a flat structure are interpreted on the flattened domain of the functional phase. The sister constituents of the flattened domain of the functional phase can be linearized in a free order in PF.
On the Validation of the Simulation of Early Season Precipitation on the Island of Puerto Rico Using a Mesoscale Atmospheric Model
Authors: Comarazamy Daniel E. , González Jorge E.
Published: June 2008

The ability of a mesoscale atmospheric model to reproduce the spatial distribution of the precipitation of the Caribbean island of Puerto Rico during an early rainfall season month (April) is evaluated in this paper, taking the month of April 1998 as the primary test case, and analyzed in detail with subsequent simulations for April 1993. The monthly accumulated rainfall was simulated using the Regional Atmospheric Modeling System (RAMS), and the results were validated with precipitation data from 15 cooperative stations located throughout the island. The monthlong numerical simulation for April 1998 replicated the observed precipitation pattern, including the general spatial distribution, and daily and monthly totals, to varying degrees of accuracy. At specific locations, errors ranged from 2% in the rainy mountains to 82% in the San Juan metropolitan area, with a general tendency of the model to produce lower precipitation values throughout the simulation domain. An error analysis proved that the accuracy of the simulation is independent of elevation. The station data showed two dominant precipitation events during the month of April 1998: one on 2 April and the other on 16 April. The model was able to replicate the precipitation observed during the first precipitation event with less precision than for the second event. This might be attributed to the model’s inability to capture the large-scale forcing that produced the recorded amounts of rainfall observed during the second precipitation event. The results for total accumulated precipitation for April 1993 were very similar to the results for the April 1998 simulation, for both the spatial distribution and total values of rainfall.