bluuebunny/crossref_metadata_2025 huggingface dataset:
Contrôle du roc de fondation de pieux forés à haute capacité
Authors: Tavenas F.
Published: July 2008

During the construction of an important foundation with high-capacity bored piles anchored in a shale of variable quality, a technique new to Canada has been used to control the quality of the rock and to determine the necessary depth of embedment of the piles. This technique consists of carrying out in situ shearing tests in boreholes below the presumed base of the piles with mean of a "Ménard pressuremeter". These tests allow a direct measurement of an elastic modulus and of a particular shearing resistance of the rock, as well as a semiempirical estimate of the point bearing capacity of the piles. A description of the project, the geological features of the site, and the testing technique is given in this paper, along with the results obtained in a number of typical borings. These results, as well as the validity of the technique, are confirmed by the results of a loading test on a small-diameter pile anchored in the rock.
Swelling Clay in Two Slope Failures at Toronto, Canada
Authors: Quigley R. M. , Matich M. A. J. , Horvath R. G. , Hawson H. H.
Published: July 2008

Swelling clay minerals present in stiff to hard glacio-lacustrine soils along part of the Don Valley Parkway, Toronto, are believed to have accelerated soil softening and subsequent failure of several slopes only 4 to 8 years after construction. Fairly low residual friction angles of 16° give some indication of the presence of these swelling minerals, whereas low activity values of 0.4 to 0.5 give no indication of their presence.Mineralogic analyses show the soils to consist of abundant illite, chlorite, and carbonate, and moderate amounts of quartz, feldspar, and swelling clay. The swelling clays (10–15% of soils) are an unusual pseudo-montmorillonite formed from soil-vermiculite by adsorption of complex aluminum and iron hydroxide cations in an ancient, acid, weathering environment. Since the clay beds studied have not themselves been weathered, then they must be erosion products from earlier geologic formations in the Toronto area which have not yet been identified.
Effective Stress Theory of Shrinkage Phenomena
Authors: Sridharan A. , Rao G. Venkatappa
Published: July 2008

Shrinkage is one of the important soil phenomena in which an engineer is interested. The various factors affecting shrinkage phenomena are discussed. The investigation deals with theoretical and experimental studies of the physical mechanism involved in the process of shrinkage of a clay soil. A modified effective stress concept has been made use of for a satisfactory explanation of the phenomena. The relative importance of dielectric constant (in effecting the electrical attractive and repulsive forces) and the surface tension on the shrinkage of a clay has been brought out, using various organic solvents as pore fluids. Kaolinite has been used in the experimental investigation which includes conventional shrinkage limit tests, tests on samples consolidated to 1 ton/ft2 (1.093 kg/cm2) with different fabric as well as the same initial fabric, tests on samples consolidated to different pressures, and finally tests on samples with constant external applied pressure. The experimental results reveal that the modified effective stress concept proposed governs the shrinkage phenomena. Though surface tension is believed to be the cause of shrinkage, it has been shown that the void ratio at the shrinkage limit is governed by the contact stress at particle contact and (or) between particles, as defined by the modified effective stress concept. The role of fabric and externally applied load on shrinkage is discussed.
Calculation of Passive Pressure in Sand
Authors: Graham James
Published: July 2008

Experimental investigations of passive earth pressures in sand show that current theoretical solutions overestimate failure loads and give incorrect stress distributions. Plasticity analysis has been used to examine the effects of changes in boundary friction and rotation preceding failure. Solutions have been developed to determine the magnitude of the scale effect due to the angle of shearing resistance of the sand varying with stress level in the failure zone. By assuming that the lower 30% of the wall does not reach plastic failure stresses, an assumption suggested by a recent experimental investigation, values of passive pressure coefficient Kp have been calculated, which agree well with experimental values over a wide range of sand densities.
Salvage of Heavy Construction Equipment by a Floating Ice Bridge
Authors: Kivisild H. R. , Rose G. D. , Masterson D. M.
Published: July 2008

During the summer of 1972, a barge load of heavy construction equipment under tow to the James Bay Project on the eastern shore of James Bay became grounded on a shoal at the mouth of the Fort George River, only a few miles from its intended destination. Federal Commerce and Navigation Limited retained Foundation of Canada Engineering Corporation Limited (FENCO) to study the feasibility of removing the heavy equipment from the barge by an overice crossing. FENCO personnel visited the site in November and December, 1972, compiled the necessary environmental data and designed a crossing consisting of ice built up by flooding. Following the completion of the 100 ft wide (30.48 m) and 74 in. thick (1.88 m) bridge by Sainte-Marie Construction, the ice bridge was instrumented and tested prior to and during the unloading process. Parameters measured were thickness, width, temperature, ice soundness, and deflections. Tide readings were also taken.Loads of 70 t and heavy trucks were removed with no problem. Deflections were very small and cracking was confined to the tidal zone.
Failure along Planes of Weakness
Authors: Lajtai E. Z.
Published: July 2008

The importance of the micro stress field in the failure of discontinuous rocks is emphasized. The factors controlling failure are identified as, the micro stress set up at the ends and at irregularities of joint segments, the macro stress which controls the growth of the microfracture to macroscopic dimensions, and the external constraint which may arrest the propagating failure surface. By causing microfracture, the micro stress is largely responsible for the destruction of the rock bridges and the asperities occurring along the plane of weakness. In the initial stages of failure, the various types of tensile and shear microfractures form a zig-zag pattern which on continued deformation becomes incorporated in a wide shear zone running along the original plane of weakness.
The Influence Surface Method for Floating Ice Plates
Authors: Palmer W. T.
Published: July 2008

In order to simplify the calculations of bending moments in floating ice plates subjected to slowly moving loads or static loads of short duration, influence functions for infinite plates floating on a liquid are derived and then presented graphically in the form of influence charts. The presented charts and analyses are based on the elastic theory of plates. It is shown how to use the charts in practice. Two numerical examples are presented.
The Role of Convective Heat Transport in the Thawing of Frozen Soils
Authors: Nixon John F.
Published: July 2008

One-dimensional solutions for the rate of thaw in frozen soils often neglect the effects of convective heat transfer in the thawing soil. To the present time, it has been difficult to assess the importance of such effects for thawing soils due to the complexities in obtaining solutions to the mathematical problem. This note describes a solution for a one-dimensional thawing problem of considerable practical interest, which accounts for convective heat transfer caused by the migration of melt water to the soil surface. The solution applies for a wide range of conditions likely to be experienced in the field, and demonstrates the very minor role played by convective heat transfer in determining the rate of thaw. It is encouraging to observe that for most one-dimensional thaw calculations, the effects of convective heat transfer may be neglected without significant loss in accuracy.
Use of centrifugal model testing to assess slope stability
Authors: Schofield A. N.
Published: July 2008

Centrifugal model tests increase total stress levels in small models made of natural or reconstituted soil, and allow direct observation of repeated failures. A novel use of a basket centrifuge is described in which slopes can be tested without end effects. When a series of models at various overconsolidation ratios was tested to failure the error in the safety factor predicted by a total stress analysis increased with the overconsolidation ratio. Other centrifuges are discussed and the advantage of large machines with balanced arms and swinging carriages are explained. Soil material behaviour discussed includes heat transfer and leaching. The paper concludes with a review of the present availability of and prospects for centrifugal model tests.
The determination of true orientations of fractures in rock cores
Authors: Lau J. S. O.
Published: July 2008

Determination of the true orientations of fractures in diamond drill cores obtained from deep boreholes in plutonic bodies is an essential requirement of the geoscience component of the Canadian Nuclear Fuel Waste Management Program. A reference line can be painted on the entire length of the rock core, indicating the orientation of the core, and the apparent orientation of the fracture can be measured from this reference line. This paper describes three methods that have been developed to convert the apparent orientation to true orientation, namely, stereographic projection, spherical trigonometry, and analytical geometry. The results obtained from these techniques were compared to assess their relative accuracy. Whereas the graphical method is more readily adaptable for use in the field, the mathematical methods can be computer-programmed and the programs GEOCORE and ORIENTC are available from the Geological Survey of Canada to facilitate the calculation of large volumes of data. Keywords: true orientation, fracture, rock core, stereographic projection, spherical trigonometry, analytical geometry.
Surface displacements in relation to shallow surface fractures and deep faulting
Authors: Zhong-Qi Wang , Hong-Qi Fang , Shu-Dong Zhao
Published: July 2008

This article describes different forms of surface displacement observed in association with faulting in the earthquake zones of Tangshan (Hebei Province of north China) and the southern part of Liao Ning Province. Shallow surface fractures appear to have only a limited effect on nearby surface and subsurface structures, but fractures that overlie deep faulting cause breakage of most surface structures. Shallow surface fractures tend to parallel the alignment of main shock and aftershock epicentres but may be displaced by some considerable distance from the alignment of such movements. The mechanisms linking seismic shock and displacements by shallow surface fractures require further investigation. Keywords: faulting, surface displacements, China.
Leda clay from deep boreholes at Hawkesbury, Ontario. Part I: Geology and geotechnique
Authors: Quigley Robert M. , Gwyn Q. H. J. , White Owen L. , Rowe R. Kerry , Haynes Janet E. , Bohdanowicz Anne
Published: July 2008

The geologic and geotechnical characteristics of thick soft Champlain Sea clay deposits at Hawkesbury, Ontario are presented in this paper. A second paper will deal with the mineralogy and geochemistry of the same deposits.A westerly clay plain at ~50 m and an easterly plain at ~75 m elevation occur in the area. Preconsolidation pressure versus depth curves obtained for clays from both deposits show marked preconsolidation near the top and bottom drainage boundaries and nearly normally consolidated conditions at the centre. This suggests that both sites were loaded by sandy fluvial (deltaic) sediments that were eroded ~70 years after deposition, an ancestral meander of the Ottawa River being responsible for the erosion on the lower clay plain. Two stratigraphic schemes compatible with the σP′ versus depth profiles are presented. For the lower elevation clay plain these schemes suggest erosion of 21 m of deltaic sands, a value generally confirmed by field studies of deltaic sand terraces to the west.The sensitivity of the lower level clays decreases from ~25 at surface to ~5 at depth. The upper level clays are very different, having a maximum sensitivity of ~20 at mid-depth and decreasing towards the top and bottom. These trends reflect differences in the liquidity index for both clays and in salinity for the lower level clays. The low values of sensitivity relate to the relatively high clay mineral content of 51% and salt content of 1–20 g/L measured on these partially "leached" clays. Keywords: Champlain clays, preconsolidation, diffusion, erosion, vane strength, salinity.
Nonlinear stress analysis of muskeg via finite element
Authors: Yong R. N. , Mohamed A. M. O. , Tali R. G.
Published: July 2008

The purpose of this paper is to provide a rational analytical means for predicting the performance of a muskeg deposit under loading. The analytical model employs the finite-element technique, which is extended to take into consideration the unusual constitutive behavior of the fibrous organic materials as well as the tension cut developing in these materials. The solution obtained using this model provides detailed stress and deformation fields within the loaded muskeg deposit. The applicability of the proposed analytical model is verified by conducting an appropriate experimental program. The results obtained from the model are found to be in good agreement with the experimental data. Key words: muskeg, loading, modelling, anisotropic, finite element, tension, compression.
Full-scale field studies of the dynamic response of piles embedded in partially frozen soils
Authors: Vaziri Hans , Han Yingcai
Published: July 2008

The influence of a frozen soil layer on the dynamic response of full-scale concrete piles subjected to strong horizontal excitation was studied. The study undertaken compares the field observations against the theoretical predictions and provides an insight into the role of the yielded zone (boundary zone) in theoretically matching the field observations. The field measurements are used to postulate empirical relationships that can be used under practical conditions to estimate the magnitude of soil separation around piles embedded in cohesive soils as a function of the maximum vibration amplitude. The tests performed indicate that the presence of a frozen soil layer, even at a modest thickness of less than 0.5 m, can significantly influence the dynamic response of piles; the horizontal stiffness of the pile was increased by one order of magnitude, and its resonant frequency was increased by a factor of four compared to the situation with no frozen soil layer. The qualitative and quantitative findings from this study are considered to have practical applications in the design of piles under similar conditions as well as in providing a field validation of the theoretical solutions that have been developed for analyzing the dynamic response of piles. Key words: dynamics, vibration, piles, full-scale tests, frozen soil, modelling, resonance, soil separation, soil yielding.
Electromagnetic mapping of saline contamination at an active brine pit
Authors: Ferguson I J , Taylor W J , Schmigel K
Published: July 2008

Frequency-domain and time-domain electromagnetic methods were used to investigate groundwater contamination at an active brine pit in southwestern Manitoba, Canada. The objectives of the survey were to delineate contamination suspected to be occuring at the site and to compare frequency-domain electromagnetic (FDEM) and time-domain electromagnetic (TDEM) measurements in a survey area containing pipelines, fences, and power lines. The survey successfully delineated a region of high conductivity around brine pit, confirming that leakage is occurring from the pit. Modelling of the FDEM results suggests the contamination is spreading within a series of shallow sand units. Comparison of FDEM and TDEM survey results indicate that small-separation FDEM systems are much more useful for mapping in a developed area containing sources of cultural noise. The FDEM systems permit rapid mapping of spatial variations in conductivity, are affected to only a limited degree by cultural features, and provide some resolution of the depth variation of conductivity at shallow depth. It was not possible to obtain useful TDEM measurements anywhere near the active brine pit because of the signal distortion in the late-time response.

Key words: geophysics, electromagnetic, brine pit, saline contamination.
Field estimation of waterice phase composition of permafrost samples using a calorimetric method
Authors: Fortier Richard , Allard Michel , Sheriff Fernando
Published: July 2008

Waterice phase composition of undisturbed frozen ground samples obtained with a U.S. Army Cold Regions Research and Engineering Laboratory (CRREL) core barrel at different depths in permafrost mounds at Kangiqsualujjuaq and Umiujaq in northern Quebec was measured in the field using an adiabatic calorimetric method. Although the theoretical basis of adiabatic calorimetry is not fully established and the required correction factors are not available, the phase composition curves of the Kangiqsualujjuaq silty clay and Umiujaq fine sand are close to the ones determined by nuclear magnetic resonance and isothermal calorimetry for two soils with similar grain size distributions (Suffield silty clay and Manchester fine sand). A better understanding of thermal and physicomechanical aspects of frozen ground could be gained from the stratigraphic profile of waterice phase composition in permafrost mounds measured with the adiabatic calorimetric method.

Key words: adiabatic calorimetry, unfrozen water content, permafrost, field tests.
Emplacement of the Etive Dyke Swarm, Scotland: implications of dyke morphology and AMS data
Authors: Morris George A. , Kamada Masumi , Martinez Victor
Published: July 2008

The Etive Dyke Swarm is the largest Caledonian dyke swarm in Britain and Ireland. Field and petrophysical (AMS–anisotropy of magnetic susceptibility) data are presented that indicate the dykes resulted from passive upwelling of magmas into fractures created by regional tectonic stresses. During the period of dyke intrusion (around 415 Ma) periodic episodes of sinistral transpression affected the region and were probably associated with sinistral movement on the Great Glen and other regional faults that lie subparallel (approximately 5° clockwise) from the long axis of the swarm. AMS data show that magma upwelled subvertically across the swarm and suggests that the dykes fed a volcanic field much larger than the now preserved Glencoe Volcano complex.
On the long-distance transport of Ferrar magmas
Authors: Leat Philip T.
Published: July 2008

The distribution and geochemical relationships of the Early Jurassic Ferrar large igneous province (LIP) are examined and it is concluded that they support the lateral flow model for the emplacement of the province, with a source along the strongly magmatic Early Jurassic Antarctica–Africa rifted margin. Published data and new analyses from the Pensacola Range are used to show that the dominant magma type in the Ferrar, the Mount Fazio chemical type (MFCT), occurs in the Theron Mountains, Shackleton Range, Whichaway Nunataks, Pensacola Mountains (all Antarctica) and South Africa, as well as well-known outcrops in Victoria Land, Antarctica, SE Australia and New Zealand. Chemical compositions are shown to be somewhat varied, but similar enough for them to be considered as representing closely related magmas. Examination of geochemical trends with distance from the interpreted magma source indicates that Mg# and MgO abundances decline with distance travelled, and it is argued that this is consistent with the lateral flow model. The Scarab Peak chemical type (SPCT), which occurs as sills in the Theron Mountains and Whichaway Nunataks, and as lavas in Victoria Land, is geochemically very homogeneous. Despite this, Mg#, MgO, Ti/Y and Ti/Zr all fall with distance from the interpreted source, consistent with fractional crystallization occurring during the lateral flow of the magmas. Flow took place in dykes or (more likely) sills. No feeder dyke swarm has been identified. The distances flowed, at least 4100 km for MFCT and 3700 km for SPCT, are the longest interpreted lateral magma flows on Earth.
Hyaloclastites, peperites and soft-sediment deformation textures of a shallow subaqueous Miocene rhyolitic dome-cryptodome complex, Pálháza, Hungary
Authors: Németh Károly , Pécskay Zoltán , Martin Ulrike , Gméling Katalin , Molnár Ferenc , Cronin Shane J.
Published: July 2008

The NE Tokaj Mountains at Pálháza in NE Hungary are made up of a complex association of Miocene rhyolitic shallow intrusions, cryptodomes and endogenous lava domes emplaced into and onto soft, wet pelitic sediment in a shallow submarine environment. The intrusive–extrusive complex shows a range of interaction textures with the host muddy sediment, ranging from blocky peperites, formed on a 0.1 m-scale, through to irregular contacts closely resembling globular mega-peperites, on a >10 m-scale. The over 200 m-thick igneous succession is interpreted to result from the pulsatory growth of shallow cryptodomes through muddy saturated host sediment. The intrusions eventually breached the sedimentary cover to build up thick
in situ
hyaloclastite piles in the shallow subaqueous environment. The coherent rhyolitic cryptodome facies is surrounded by intrusive hyaloclastite in the contact zone to the pelitic host sediment. In the upper level of the complex, rhyolitic dome rock is capped and surrounded by hyaloclastite formed due to quench fragmentation upon contact of the lava surface with sea water.
Introducing function extraction into software testing
Authors: Pleszkoch Mark G. , Linger Richard C. , Hevner Alan R.
Published: July 2008

Software testing can benefit from technologies that enable evolution toward increased engineering discipline. In current practice, software developers lack practical means to determine the full functional behavior of programs under development, and even the most thorough testing can provide only partial knowledge of behaviors. Thus, effective scientific principles and engineering technology for revealing software behavior should have a positive impact on software testing. This paper describes the emerging technology of function extraction (FX) for computing the behavior of programs to the maximum extent possible with mathematical precision. We explore how the use of FX technologies can transform methods for functional verification of software. An example illustrates the value of full behavior knowledge for complete and confident assessment of software function and fitness for use. We conclude by describing a transition strategy for introducing FX technology into the development and operation of software systems.
A New FRET‐Based Sensitive DNA Sensor for Medical Diagnostics using PNA Probe and Water‐Soluble Blue Light Emitting Polymer
Authors: Mathur Nidhi , Aneja Anamika , Bhatnagar P. K. , Mathur P. C.
Published: July 2008

A reliable, fast, and low‐cost biosensor for medical diagnostics using
DNA sequence detection has been developed and tested for the detection
of the bacterium “Bacillus anthracis.” In this sensor, Poly [9,9‐di (6,6′‐ N, N′ trimethylammonium) hexylfluorenyl‐2, 7‐diyl)‐alt‐co‐ (1,4‐phenylene)]
dibromide salt (PFP) has been taken as cationic conjugated polymer (CCP) and PNA
attached with fluorescein dye (PNAC∗) as a probe. The basic principle of this sensor is that when a PNAC∗ probe is hybridized with a single strand DNA (ssDNA) having
complementary sequence, Forster resonance energy transfer (FRET) may take place from PFP to the PNAC∗/DNA complex. If the FRET is efficient, the photoluminescence from the PFP will be highly quenched and that from PNAC∗ will be enhanced. On the other hand, if the DNA sequence is noncomplementary to PNA, FRET will not occur.
Toxoplasma Rhoptries: Unique Secretory Organelles and Source of Promising Vaccine Proteins for Immunoprevention of Toxoplasmosis
Authors: Dlugonska Henryka
Published: July 2008

Toxoplasma gondii is an obligate intracellular protozoan parasite classified in the phylum Apicomplexa, which includes numerous notable human and animal pathogens (Plasmodium species,
Cryptosporidium species, Neospora caninum, etc.). The invasive stages of apicomplexans are characterized by the presence of an apical complex composed of specialized cytoskeletal and secretory organelles, including rhoptries. Rhoptries, unique apical secretory organelles shared exclusively by all apicomplexan parasites, are known to be involved in an active parasite′s penetration into the host cell associated with the biogenesis of specific intracellular compartment, parasitophorous vacuole in which the parasite multiplies intensively, avoiding intracellular killing. Due to the key biological role of rhoptries, rhoptry proteins have recently become vaccine candidates for the prevention of several parasitoses, toxoplasmosis among them. The article presents current data on T. gondii rhoptries biology and new approaches to the development of effective vaccines against toxoplasmosis using rhoptry antigens.
Mesoscale Compositionally Modulated Nanocrystalline Ni‐Fe Electrodeposits for Nanopatterning Applications
Authors: Egberts P. , Hibbard G. D.
Published: July 2008

A considerable range of surface nanostructures can be fabricated by the selective dissolution of elements or phases from metallic alloys. Selectively etched electrodeposited multilayers may find useful application in optoelectronic and MEMS devices. One issue with electrodeposited multilayers is that the fine‐scale multilayer structure can often exhibit significant waviness if the band layer spacing is on the same order of magnitude as the grain size. In the present study, the mean grain size was reduced to below 10 nm in a compositionally modulated Ni‐Fe alloy. Preferential etching on the electroform cross‐section resulted in highly uniform and directional surface channels. The evolution of this nanopatterned surface morphology was characterized by atomic force microscopy and directional roughness parameters were obtained.
Differential bortezomib sensitivity in head and neck cancer lines corresponds to proteasome, nuclear factor-κB and activator protein-1 related mechanisms
Authors: Chen Zhong , Ricker Justin L. , Malhotra Pramit S. , Nottingham Liesl , Bagain Lorena , Lee Tin Lap , Yeh Ning T. , Van Waes Carter
Published: July 2008

Head and neck squamous cell carcinomas (HNSCC) exhibit constitutive activation of transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), which are modulated by the proteasome and promote resistance to cell death. HNSCC show variable sensitivity to the proteasome inhibitor bortezomib in vitro as well as in murine xenografts and patient tumors in vivo, and the mechanisms are not well understood. To address this question, the sensitivities of nine HNSCC cell lines to bortezomib were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and the potential relationship between the sensitivity and bortezomib effects on biological processes was examined in HNSCC lines of differential bortezomib sensitivity. The most sensitive cell line (UM-SCC-11B) underwent cell death at 10−9 mol/L in vitro and tumor regression at a maximally tolerated dose of bortezomib in a murine xenograft model. The differential sensitivity between UM-SCC-11A and UM-SCC-11B cells corresponded to differences in the extent of suppression of proteasome activity, ubiquitinated protein degradation, and NF-κB and AP-1 activation. Lower concentrations of bortezomib transiently increased NF-κB and sustained AP-1 activation in UM-SCC-11A cells. AP-1 reporter activity and cell density of UM-SCC-11A were suppressed when bortezomib was combined with c-Jun NH2-terminal kinase and p38 kinase pathways inhibitors. Thus, the differential sensitivities to bortezomib corresponded to dissimilar effects on the proteasome, NF-κB and AP-1 activities. Inhibition of c-Jun NH2-terminal kinase and p38 pathways blocked AP-1 activity and enhanced the antitumor effects. These findings revealed molecular mechanisms of bortezomib sensitivity and resistance, which are under development as biomarkers for clinical trials in patients with HNSCC. [Mol Cancer Ther 2008;7(7):1949–60]
Chemosensitizing effects of sphingosine kinase-1 inhibition in prostate cancer cell and animal models
Authors: Pchejetski Dimitri , Doumerc Nicolas , Golzio Muriel , Naymark Maria , Teissié Justin , Kohama Takafumi , Waxman Jonathan , Malavaud Bernard , Cuvillier Olivier
Published: July 2008

We have previously reported that, in prostate cancer, inhibition of the oncogenic sphingosine kinase-1/sphingosine 1-phosphate (SphK1/S1P) pathway is a key element in chemotherapy-induced apoptosis. Here, we show that selective pharmacologic inhibition of SphK1 triggers apoptosis in LNCaP and PC-3 prostate cancer cells, an effect that is reversed by SphK1 enforced expression. More importantly, we show for the first time that the up-regulation of the SphK1/S1P pathway plays a crucial role in the resistance of prostate cancer cells to chemotherapy. Importantly, pharmacologic SphK1 inhibition with the B-5354c compound sensitizes LNCaP and PC-3 cells to docetaxel and camptothecin, respectively. In vivo, camptothecin and B-5354c alone display a limited effect on tumor growth in PC-3 cells, whereas in combination there is a synergy of effect on tumor size with a significant increase in the ceramide to S1P sphingolipid ratio. To conclude, our study highlights the notion that drugs specifically designed to inhibit SphK1 could provide a means of enhancing the effects of conventional treatment through the prosurvival antiapoptotic SphK1/S1P pathway. [Mol Cancer Ther 2008;7(7):1836–45]
eIF4E knockdown decreases breast cancer cell growth without activating Akt signaling
Authors: Soni Alpana , Akcakanat Argun , Singh Gopal , Luyimbazi David , Zheng Yuhuan , Kim Doyil , Gonzalez-Angulo Ana , Meric-Bernstam Funda
Published: July 2008

Activation of translation initiation is essential for the malignant phenotype and is emerging as a potential therapeutic target. Translation is regulated by the expression of translation initiation factor 4E (eIF4E) as well as the interaction of eIF4E with eIF4E-binding proteins (e.g., 4E-BP1). Rapamycin inhibits translation initiation by decreasing the phosphorylation of 4E-BP1, increasing eIF4E/4E-BP1 interaction. However, rapamycin also inhibits S6K phosphorylation, leading to feedback loop activation of Akt. We hypothesized that targeting eIF4E directly would inhibit breast cancer cell growth without activating Akt. We showed that eIF4E is ubiquitously expressed in breast cancer cell lines. eIF4E knockdown by small interfering RNA inhibited growth in different breast cancer cell subtypes including triple-negative (estrogen receptor/progesterone receptor/HER-2–negative) cancer cells. eIF4E knockdown inhibited the growth of cells with varying total and phosphorylated 4E-BP1 levels and inhibited rapamycin-insensitive as well as rapamycin-sensitive cell lines. eIF4E knockdown led to a decrease in expression of cyclin D1, Bcl-2, and Bcl-xL. eIF4E knockdown did not lead to Akt phosphorylation but did decrease 4E-BP1 expression. We conclude that eIF4E is a promising target for breast cancer therapy. eIF4E-targeted therapy may be efficacious in a variety of breast cancer subtypes including triple-negative tumors for which currently there are no targeted therapies. Unlike rapamycin and its analogues, eIF4E knockdown is not associated with Akt activation. [Mol Cancer Ther 2008;7(7):1782–8]
Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids
Authors: Ackerman Margaret E. , Pawlowski David , Wittrup K. Dane
Published: July 2008

Poor tissue penetration is a significant obstacle to the development of successful antibody drugs for immunotherapy of solid tumors, and diverse alterations to the properties of antibody drugs have been made to improve penetration and homogeneity of exposure. However, in addition to properties of the antibody drug, mathematical models of antibody transport predict that the antigen expression level and turnover rate significantly influence penetration. As intrinsic antigen properties are likely to be difficult to modify, they may set inherent limits to penetration. Accordingly, in this study, we assess their contribution by evaluating the distance to which antibodies penetrate spheroids when these antigen properties are systematically varied. Additionally, the penetration profiles of antibodies against carcinoembryonic antigen and A33, two targets of clinical interest, are compared. The results agree well with the quantitative predictions of the model and show that localizing antibody to distal regions of tumors is best achieved by selecting slowly internalized targets that are not expressed above the level necessary for recruiting a toxic dose of therapeutic. Each antibody-bound antigen molecule that is turned over or present in excess incurs a real cost in terms of penetration depth—a limiting factor in the development of effective therapies for treating solid tumors. [Mol Cancer Ther 2008;7(7):2233–40]
Andrographolide sensitizes cancer cells to TRAIL-induced apoptosis via p53-mediated death receptor 4 up-regulation
Authors: Zhou Jing , Lu Guo-Dong , Ong Chye-Sun , Ong Choon-Nam , Shen Han-Ming
Published: July 2008

Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is an important member of the tumor necrosis factor subfamily with great potential in cancer therapy. Andrographolide (Andro), a diterpenoid lactone isolated from a traditional herbal medicine Andrographis paniculata, is known to possess potent anti-inflammatory and anticancer activities. Here, we showed that pretreatment with Andro significantly enhances TRAIL-induced apoptosis in various human cancer cell lines, including those TRAIL-resistant cells. Such sensitization is achieved through transcriptional up-regulation of death receptor 4 (DR4), a death receptor of TRAIL. In search of the molecular mechanisms responsible for DR4 up-regulation, we found that the tumor suppressor p53 plays an essential role in DR4 transcriptional activation. Andro is capable of activating p53 via increased p53 phosphorylation and protein stabilization, a process mediated by enhanced reactive oxygen species production and subsequent c-Jun NH2-terminal kinase activation. Pretreatment with an antioxidant (N-acetylcysteine) or a c-Jun NH2-terminal kinase inhibitor (SP600125) effectively prevented Andro-induced p53 activation and DR4 up-regulation and eventually blocked the Andro-induced sensitization on TRAIL-induced apoptosis. Taken together, these results present a novel anticancer effect of Andro and support its potential application in cancer therapy to overcome TRAIL resistance. [Mol Cancer Ther 2008;7(7):2170–80]
c-Jun knockdown sensitizes osteosarcoma to doxorubicin
Authors: Dass Crispin R. , Khachigian Levon M. , Choong Peter F.M.
Published: July 2008

The oncogene c-Jun has been found to be up-regulated in a variety of cancers, including osteosarcoma. Doxorubicin is a frontline chemotherapeutic against osteosarcoma, but is limited by toxicity. DNAzymes are oligonucleotides capable of specific catalysis of target mRNA. A biocompatible c-Jun DNAzyme nanoparticle formulated from chitosan regressed the growth and metastasis of pre-established tumors, especially in combination with doxorubicin. In vitro data confirmed that c-Jun knockdown chemosensitized these cells to doxorubicin treatment. c-Jun down-regulation–mediated tumor inhibition also led to concomitant decreased osteolysis. Clinically, knockdown of c-Jun with chitosan nanobiotechnology may proffer an improved treatment outcome for osteosarcoma. [Mol Cancer Ther 2008;7(7):1909–12]
Anti-ganglioside antibody-induced tumor cell death by loss of membrane integrity
Authors: Roque-Navarro Lourdes , Chakrabandhu Krittalak , de León Joel , Rodríguez Sandra , Toledo Carlos , Carr Adriana , de Acosta Cristina Mateo , Hueber Anne-Odile , Pérez Rolando
Published: July 2008

Gangliosides have been involved in multiple cellular processes such as growth, differentiation and adhesion, and more recently as regulators of cell death signaling pathways. Some of these molecules can be considered as tumor-associated antigens, in particular, N-glycolyl sialic acid–containing gangliosides, which are promising candidates for cancer-targeted therapy because of their low expression in normal human tissues. In this study, we provided the molecular and cellular characterization of a novel cell death mechanism induced by the anti-NGcGM3 14F7 monoclonal antibody (mAb) in L1210 murine tumor cell line but not in mouse normal cells (B and CD4+ T lymphocytes) that expressed the antigen. Impairment of ganglioside synthesis in tumor cells abrogated the 14F7 mAb cytotoxic effect; however, exogenous reincorporation of the ganglioside did not restore tumor cell sensitivity to 14F7 mAb-induced cytotoxicity. 14F7 F(ab′)2 but not Fab fragments retained the cytotoxic capacity of the whole mAb. By contrary, other mAb, which recognizes N-glycolylated gangliosides, did not show any cytotoxic effect. These mAbs showed quite different capacities to bind NGcGM3-positive cell lines measured by binding inhibition experiments. Interestingly, this complement-independent cell death mechanism did not resemble apoptosis, because no DNA fragmentation, caspase activation, or Fas mediation were observed. However, NGcGM3 ganglioside-mediated 14F7 mAb-induced cell death was accompanied by cellular swelling, membrane lesion formation, and cytoskeleton activation, suggesting an oncosis-like phenomenon. This novel mechanism of cell death lets us to support further therapeutic approaches using NGcGM3 as a molecular target for antibody-based cancer immunotherapy. [Mol Cancer Ther 2008;7(7):2033–41]
Chemoprevention by perillyl alcohol coupled with viral gene therapy reduces pancreatic cancer pathogenesis
Authors: Lebedeva Irina V. , Su Zhao-zhong , Vozhilla Nichollaq , Chatman Lejuan , Sarkar Devanand , Dent Paul , Athar Mohammad , Fisher Paul B.
Published: July 2008

Pancreatic cancer is one of the deadliest of cancers. Even with aggressive therapy, the 5-year survival rate is <5%, mandating development of more effective treatments. Melanoma differentiation–associated gene-7/interleukin-24 (mda-7/IL-24) shows potent antitumor activity against most cancers displaying safety with significant clinical efficacy. However, pancreatic cancer cells display inherent resistance to mda-7/IL-24 that is the result of a “protein translational block” of mda-7/IL-24 mRNA in these tumor cells. We now show that a dietary supplement perillyl alcohol (POH) has significant chemopreventive effects for pancreatic cancer and, when coupled with adenovirus-mediated mda-7/IL-24 gene therapy (Ad.mda-7), effectively eliminates s.c. and i.p. xenografts of human pancreatic cancer cells in nude mice, promoting enhanced survival. The combination of POH and Ad.mda-7 efficiently abrogates the mda-7/IL-24 protein translational block, resulting in MDA-7/IL-24 protein production and growth suppression. Of direct translational relevance, clinically achievable concentrations of POH with Ad.mda-7, both of which have been found safe and without toxic effects in human trials, were used. This novel and innovative approach combining a dietary agent and a virally delivered therapeutic cytokine provides a means of both preventing and treating human pancreatic cancer with significant clinical translational potential. [Mol Cancer Ther 2008;7(7):2042–50]
Genes Involved in Differentiation, Stem Cell Renewal, and Tumorigenesis Are Modulated in Telomerase-Immortalized Human Urothelial Cells
Authors: Chapman Emma J. , Kelly Gavin , Knowles Margaret A.
Published: July 2008

The expression of hTERT, the catalytic subunit of telomerase, immortalizes normal human urothelial cells (NHUC). Expression of a modified hTERT, without the ability to act in telomere maintenance, did not immortalize NHUC, confirming that effects at telomeres are required for urothelial immortalization. Previous studies indicate that inhibition of telomerase has an immediate effect on urothelial carcinoma (UC) cell line viability, before sufficient divisions to account for telomere attrition, implicating non–telomere effects of telomerase in UC. We analyzed the effects of telomerase on gene expression in isogenic mortal and hTERT-transduced NHUC. hTERT expression led to consistent alterations in the expression of genes predicted to be of phenotypic significance in tumorigenesis. A subset of expression changes were detected soon after transduction with hTERT and persisted with continued culture. These genes (NME5, PSCA, TSPYL5, LY75, IGFBP2, IGF2, CEACAM6, XG, NOX5, KAL1, and HPGD) include eight previously identified as polycomb group targets. TERT-NHUC showed overexpression of the polycomb repressor complex (PRC1 and PRC4) components, BMI1 and SIRT1, and down-regulation of multiple PRC targets and genes associated with differentiation. TERT-NHUC at 100 population doublings, but not soon after transduction, showed increased saturation density and an attenuated differentiation response, indicating that these are not acute effects of telomerase expression. Some of the changes in gene expression identified may contribute to tumorigenesis. Expression of NME5 and NDN was down-regulated in UC cell lines and tumors. Our data supports the concept of both telomere-based and non–telomere effects of telomerase and provides further rationale for the use of telomerase inhibitors in UC. (Mol Cancer Res 2008;6(7):1154–68)
Frequency and Timing of Loss of Imprinting at 11p13 and 11p15 in Wilms' Tumor Development
Authors: Brown Keith W. , Power Frances , Moore Beth , Charles Adrian K. , Malik Karim T.A.
Published: July 2008

Epigenetic changes occur frequently in Wilms' tumor (WT), especially loss of imprinting (LOI) of IGF2/H19 at 11p15. Our previous results have identified imprinted transcripts (WT1-AS and AWT1) from the WT1 locus at 11p13 and showed LOI of these in some WTs. In this article, we set out to test the relationship between LOI at 11p13 and 11p15 and their timing in WT progression relative to other genetic changes. We found a higher level (83%) of 11p13 LOI in WT than of 11p15 LOI (71%). There was no correlation between methylation levels at the 11p13 and 11p15 differentially methylated regions or between allelic expression of WT1-AS/AWT1 and IGF2. Interestingly, retention of normal imprinting at 11p13 was associated with a small group of relatively late-onset, high-stage WTs. An examination of genetic and epigenetic alterations in nephrogenic rests, which are premalignant WT precursors, showed that LOI at both 11p13 and 11p15 occurred before either 16q loss of heterozygosity (LOH) or 7p LOH. This suggests that these LOH events are very unlikely to be a cause of LOI but that LOH may act by potentiating the effects of overexpression of IGF2 and/or WT1-AS/AWT1 that result from LOI. (Mol Cancer Res 2008;6(7):1114–23)
Increased Rac1b Expression Sustains Colorectal Tumor Cell Survival
Authors: Matos Paulo , Jordan Peter
Published: July 2008

The small GTPase Rac1 can stimulate various signaling pathways that contribute to cell transformation. In particular, the activation of the NFκB transcription factor initiates an antiapoptotic response and promotes cell cycle progression through increased cyclin D1 expression. As a potential oncogenic mechanism to up-regulate this pathway, the overexpression of the Rac1b splicing variant was reported in some colorectal tumors. Rac1b exists predominantly in the active GTP-bound state and selectively promotes the pathway leading to NFκB activation. Here, we studied the role of endogenous Rac1b in colorectal cancer cells. We found that depletion of Rac1b by small interfering RNAs inhibited endogenous NFκB activation and reduced cell viability to 50% within 48 hours. This reduction was due to increased apoptosis, although a reduced G1-S progression rate was also observed. These data show, for the first time, that colorectal cells expressing alternative spliced Rac1b also depend on Rac1b signaling to sustain their survival. (Mol Cancer Res 2008;6(7):1178–84)
A Role for Fibroblasts in Mediating the Effects of Tobacco-Induced Epithelial Cell Growth and Invasion
Authors: Coppe Jean-Philippe , Boysen Megan , Sun Chung Ho , Wong Brian J.F. , Kang Mo K. , Park No-Hee , Desprez Pierre-Yves , Campisi Judith , Krtolica Ana
Published: July 2008

Cigarette smoke and smokeless tobacco extracts contain multiple carcinogenic compounds, but little is known about the mechanisms by which tumors develop and progress upon chronic exposure to carcinogens such as those present in tobacco products. Here, we examine the effects of smokeless tobacco extracts on human oral fibroblasts. We show that smokeless tobacco extracts elevated the levels of intracellular reactive oxygen, oxidative DNA damage, and DNA double-strand breaks in a dose-dependent manner. Extended exposure to extracts induced fibroblasts to undergo a senescence-like growth arrest, with striking accompanying changes in the secretory phenotype. Using cocultures of smokeless tobacco extracts–exposed fibroblasts and immortalized but nontumorigenic keratinocytes, we further show that factors secreted by extracts-modified fibroblasts increase the proliferation and invasiveness of partially transformed epithelial cells, but not their normal counterparts. In addition, smokeless tobacco extracts–exposed fibroblasts caused partially transformed keratinocytes to lose the expression of E-cadherin and ZO-1, as well as involucrin, changes that are indicative of compromised epithelial function and commonly associated with malignant progression. Together, our results suggest that fibroblasts may contribute to tumorigenesis indirectly by increasing epithelial cell aggressiveness. Thus, tobacco may not only initiate mutagenic changes in epithelial cells but also promote the growth and invasion of mutant cells by creating a procarcinogenic stromal environment. (Mol Cancer Res 2008;6(7):1085–98)
WT1 Induction of Mitogen-Activated Protein Kinase Phosphatase 3 Represents a Novel Mechanism of Growth Suppression
Authors: Morrison Debra J. , Kim Marianne K.H. , Berkofsky-Fessler Windy , Licht Jonathan D.
Published: July 2008

In its role as a tumor suppressor, WT1 transactivates several genes that are regulators of cell growth and differentiation pathways. For instance, WT1 induces the expression of the cell cycle regulator p21, the growth-regulating glycoprotein amphiregulin, the proapoptotic gene Bak, and the Ras/mitogen-activated protein kinase (MAPK) inhibitor Sprouty1. Here, we show that WT1 transactivates another important negative regulator of the Ras/MAPK pathway, MAPK phosphatase 3 (MKP3). In a WT1-inducible cell line that exhibits decreased cell growth and increased apoptosis on expression of WT1, microarray analysis showed that MKP3 is the most highly induced gene. This was confirmed by real-time PCR where MKP3 and other members of the fibroblast growth factor 8 syn expression group, which includes Sprouty 1 and the Ets family of transcription factors, were induced rapidly following WT1 expression. WT1 induction was associated with a block in the phosphorylation of extracellular signal-regulated kinase in response to epidermal growth factor stimulation, an effect mediated by MKP3. In the presence of a dominant-negative MKP3, WT1 could no longer block phosphorylation of extracellular signal-regulated kinase. Lastly, when MKP3 expression is down-regulated by short hairpin RNA, WT1 is less able to block Ras-mediated transformation of 3T3 cells. (Mol Cancer Res 2008;6(7):1225–31)