bluuebunny/crossref_metadata_2025 huggingface dataset:
Deposition of Tungsten Carbide Thin Films by Simultaneous RF Sputtering
Authors: Suda Yoshiyuki , Yukimura Ken , Nakamura Keiji , Takaki Koichi , Sakai Yosuke
Published: October 2006

Tungsten carbide (WC1-x
) thin films were deposited by simultaneous sputtering. Tungsten and carbon solid materials were simultaneously sputtered by argon ion bombardment and deposited on substrates. Argon plasma was triggered using an RF (13.56 MHz) power source. The aim of this study is to apply this sputtering technique in a plasma-based ion implantation and deposition (PBII&D) system for the surface modification of three-dimensional workpieces. The films' surfaces in both the presence and absence of tungsten were very smooth, and only a few metal droplets were seen. An in-depth X-ray photoelectron spectroscopy profile revealed the following: (1) the films deposited contain approximately 30% tungsten in the most-to-least film; (2) carbon atoms bonded to tungsten (C–W) as well as those bonded to carbon (C–C) are detected in the C 1s spectra; (3) the stoichiometry of the film for an argon ion sputter time between ∼400 and ∼1600 s is deduced as WC0.73±0.10. The Raman spectra and Tauc plot from the optical transparency showed that the films contain approximately 10% sp3 with a band gap of 1.1 eV.
Effect of Indium-Oxide Deposited Using an Oxygen Ion-Beam-Assisted-Deposition to Top-Emitting Organic Light-Emitting Diodes
Authors: Jeong Chang Hyun , Lim Jong Tae , Lee June Hee , Kim Mi Suk , Bae Jeong Woon , Yeom Geun Young
Published: October 2006

Indium oxide thin films have potential applications as cathodes in top-emitting organic light-emitting diodes (TEOLEDs). This study examined the characteristics of transparent conducting indium oxide (IO) films deposited by an oxygen ion-beam-assisted-deposition (IBAD) as a function of the applied oxygen ion energy (V
a). When TEOLED devices consisting of glass/Ag (100 nm)/ITO (125 nm)/2-TNATA (30 nm)/NPB (15 nm)/Alq3 (55 nm)/LiF (1 nm)/Al (2 nm)/Au (20 nm)/IO (100 nm) were fabricated at a lower V
a, a lower turn-on voltage was observed even though the maximum luminance (32,000 cd/m2) was similar one another. A V
a of approximately +50 V produced an IO film with a resistivity of 8.5×10-4 Ω·cm and a transmittance of 85%. The definition (I–V) characteristics of TEOLED devices with a cathode layer of Al (2 nm)/Au (20 nm)/IO (100 nm) were similar to the device fabricated with Al (2 nm)/Au (20 nm) only.
Dependences of Giant Magnetoresistance in Co/Cu Multilayers on Sputtering Conditions
Authors: Chen Changchuan , Suzuki Yusuke , Kato Takeshi , Iwata Satoshi , Tsunashima Shigeru , Toyoda Hirotaka , Sugai Hideo
Published: October 2006

The dependences of magnetoresistance properties in Co/Cu multilayers on sputtering conditions were investigated by measuring the energy distributions of Ar+ ions and metal atoms. It was found that the incident Ar+ ion energy to the substrate increased with decreasing distance D between the target and the substrate. When D was changed from 5 to 11 cm, the interface roughness estimated from low-angle X-ray diffraction was improved and the magnetoresistance ratio at the first peak was increased from 31 to 42% at room temperature. These results suggest that the incident Ar+ energy affects the magnetoresistance through the modification of interface roughness.
Rapid Recrystallization of Amorphous Silicon Utilizing Very-High-Frequency Microplasma Jet at Atmospheric Pressure
Authors: Ryo Mina , Sakurai Yusuke , Kobayashi Tomohiro , Shirai Hajime
Published: October 2006

The rapid recrystallization of amorphous silicon (a-Si) utilizing a very-high-frequency (VHF) plasma jet of argon (Ar) at atmospheric pressure is investigated. A highly crystallized polycrystalline Si film is synthesized by optimizing the translating velocity of the substrate stage and the flow rate of argon. The temperature of the plasma exposure area reaches 1350±300 °C and the recrystallization of a-Si proceeded with time constants of 30–50 ms. The effects of the translating velocity of the substrate stage and the flow rate of argon on the rapid recrystallization of a-Si are demonstrated along with its mechanism.
Surface Amination of Biopolymer Using Surface-Wave Excited Ammonia Plasma
Authors: Ogino Akihisa , Kral Martin , Narushima Kazuo , Yamashita Mitsuji , Nagatsu Masaaki
Published: October 2006

Surface-wave plasma has been used to modify polymer surfaces. The density and selectivity of the functionalizations are very important for biomaterial applications. Low-temperature plasma treatment has been successfully applied to many types of polymers to generate functional surfaces. In this study, we focus on the surface modification of amino groups on chitosan surfaces by ammonia plasma treatment. Chitosan is a nontoxic, biocompatible and biodegradable polymer, which promotes the scarless healing of skin through embolization. The experimental results of X-ray photoelectron spectroscopy measurements showed that the ammonia plasma exposure to the chitosan surface increased the nitrogen incorporation on the surface from 4.67 to 9.92%. The selectivity of amino group functionalizations (–NH2/N) increased from 53.7 to 78.4% after the plasma irradiation.
Modification of Glassy Carbon Surfaces by Atmospheric Pressure Cold Plasma Torch
Authors: Mortensen Henrik , Kusano Yukihiro , Leipold Frank , Rozlosnik Noemi , Kingshott Peter , Goutianos Stergios , Sørensen Bent F. , Stenum Bjarne , Bindslev Henrik
Published: October 2006

The effect of plasma treatment on glassy carbon (GC) surfaces was studied with adhesion improvement in mind. A newly constructed remote plasma source was used to treat GC plates. Pure He and a dilute NH3/He mixture were used as feed gases. Optical emission spectroscopy was performed for plasma torch diagnostics. The treatment resulted in surface etching, substantially enhanced by NH3, as well as a roughening of the surface as measured by atomic force microscopy. Furthermore, the treated area showed an increased wettability indicating the addition of polar functional groups to the surface. X-ray photoelectron spectroscopy confirmed the introduction of several oxygen and nitrogen containing surface functional groups. The adhesion to epoxy was dramatically improved after exposure to either plasma, the effect being largest when NH3 was present in the feed gas.
Mature landfill waste geochemical characteristics and implications for long-term secondary substance release
Authors: Fannin C. A. , Roberts R. D.
Published: October 2006

The traditional view that landfill waste is a long-term pollutant problem has been investigated as part of an evaluation of the properties of mature municipal solid waste (MSW) (>30 years old). This evaluation has shown that following the active biological period, the nature of the landfill waste mass has evolved from a pollutant source into a pollutant sink. The distribution coefficients (Log
R
d
) between the solution and the solid for Cd and Zn are in the order of Log 2.4 and maximum values of up to Log
R
d
3.3 are reported here. This demonstrates strong net partitioning to the solid phase from the aqueous phase, over and above that retained as part of the primary landfill source material. The sorption characteristics appear to be due to an almost unique formation of a soil-like substance with significant calcium carbonate and stable organic matter content, interspaced with non-degradable material. Although sulphide minerals were not identified directly from the waste samples characterized, their presence is suspected from the methanogenic conditions the waste was subjected to during the biologically active lifetime of the site. The resultant sorption capacity appears to be related to the residual biological mineral formation that provides both pH buffering and available adsorption surfaces. This pH buffering capacity also appears to compensate for any secondary release of metals from sulphide oxidation under aerobic conditions driving the re-adsorption to other mineral surfaces. This detailed evaluation has shown that the long-term evolution of the site and subsequent reactions are a function of the biological processes that the waste was exposed to. The controlling factors for long-term pollutant release are therefore related to the substantial primary organic content degraded.
Geology and geochemical aspects of lode gold mineralization at Dimako–Mboscorro, SE Cameroon
Authors: Suh C.E. , Lehmann B. , Mafany G.T.
Published: October 2006

The Dimako–Mboscorro lode gold deposit has two styles of mineralization: quartz veins (4.5–54 ppm Au) and altered wallrock (up to 2.6 ppm Au). The veins occur in steeply dipping brittle–ductile shear zones in a foliated biotite metagranite. The alteration envelop around the gold-bearing quartz veins shows lateral zoning comprising a silicified/ ferruginized and mylonitic zone (SFZ) at the centre, through a transitional sericite zone (SZ), to an outer, slightly sheared, but mineralogically less altered, though bleached, metagranite zone (BZ) at the shear zone boundaries. Hydrothermal alteration in these zones is characterized by silicification (SFZ, SZ), hematite formation (SFZ), alkali metasomatism with muscovite/sericite formation (SFZ, SZ, to a much lesser extent BZ), and pyritization (SFZ, SZ). The auriferous quartz veins are concordant to the host structure but discordant to the foliation in the metagranite. The main ore minerals in the veins and in the SFZ and SZ zones are gold, hydrothermal hematite, sphalerite, galena, pyrite, chalcopyrite, arsenopyrite, chalcocite, covellite and colloidal supergene hematite. Gold occurs as inclusions in sphalerite (15.7±0.4 wt% Ag; 83.6±0.2 wt% Au), as coarse grains associated with euhedral hematite pseudomorphs (18.5±1.0 wt% Ag; 82.0±1.1 wt% Au), as stringers within fractures in quartz (13.3±0.1 wt% Ag; 87.1±0.5 wt% Au), as well as fine to coarse grains related to limonite, goethite and colloidal hematite (8.1±1.8 wt% Ag; 92.1±2.2 wt% Au). A hydrothermal metal association of Ag, Au, As, Ba, Pb, V, W, and Zn is identified in the wallrock and quartz veins. These metals, together with K-enrichment, are potential pathfinder elements for wider lithogeochemical exploration in this region, especially when combined with the lateral wallrock zonation pattern. Preliminary fluid inclusion data from the auriferous quartz vein samples indicate that gold was probably deposited from low salinity (<1 to 8 wt% eq. NaCl, with mean at 5.52 wt% eq. NaCl) H
2
O–CO
2
fluids that have total homogenization temperatures of 263–335°C.
On the special application of Thompson–Howarth error analysis to geochemical variables exhibiting a nugget effect
Authors: Stanley Clifford R.
Published: October 2006

Thompson–Howarth error analysis is based on the assumption that measurement error is normally distributed. As a result, geochemical variables that are not normally distributed, such as those containing rare nuggets, cannot be statistically evaluated using Thompson–Howarth error analysis unless a modification to the procedure, involving use of the group root mean square (RMS) standard deviations, is implemented that makes it independent of the normality assumption. This modification prevents samples exhibiting a positively skewed error distribution, such as that produced by a ‘nugget effect’, from having their measurement errors underestimated (biased) using conventional Thompson–Howarth error analysis.

A consequence of the duplicate error analysis of ‘nuggety’ samples is that the maximum feasible relative error (of 141.2%; one standard deviation divided by the mean) may be observed in some samples. Maximum feasible relative errors for
n
replicates are equal to √
n
.
Maximum relative errors may be observed because Poisson probabilities of obtaining zero nuggets in one duplicate and one or several nuggets in another are not negligible, and thus very large grade disparities can be obtained in duplicate samples simply due to natural sampling variability. As a result, an abundance of samples exhibiting this maximum relative error is not necessarily an analytical or sample numbering error, but rather an expected consequence of sampling geological materials exhibiting large nugget effects, and may reflect relative measurement error that is larger than the maximum exhibited by duplicate samples. Consequently, if a large number of duplicate samples exhibit relative errors close to the maximum, it is likely that Thompson–Howarth error analysis of duplicate samples will underestimate the actual relative error in the data. As a result, replicate samples (where
n
>2) that have higher maximum relative error limits should be used to ensure that relative error estimates derived from such a Thompson–Howarth error analysis are not biased low (underestimated).
Geochemistry and mineralogy of the regolith profile over the Aries kimberlite pipe, Western Australia
Authors: Singh Balbir , Cornelius Matthias
Published: October 2006

Residual regolith over the Aries kimberlite pipe, situated in the central Kimberley Block of Western Australia, consists of lateritic duricrust, mottled zone, upper saprolite, lower saprolite and saprock. Duricrust and mottled zone are dominated by goethite and kaolinite while saprolite consists mostly of smectite with minor amounts of mica and serpentine. Most kimberlite indicator minerals except chromite have been weathered. Kimberlitic rock fabric is preserved in the regolith up to the top of saprolite.

Chromium, Ni, Co, Cu, Nb, Zr, Ti, P and rare earth elements (REE) are significantly enriched in the mottled zone and duricrust relative to the saprolite and fresh kimberlite. Vanadium, Sb, As, Mo and U, derived from the sediments and basaltic rocks around the pipe, are also enriched. Goethite partly hosts Cr, Ni, and Co, and Nb and REE are associated with anatase. The clay fractions of the mottled zone and saprolite contain significant quantities of Cr, Co, Cu, Ni, Zr, Ga, Ti, Nb, Zn and REE. A suite of six trace elements comprising those associated with ultramafic rocks (Cr and Co) and felsic rocks (Nb, La, Sm and P) can readily distinguish the kimberlitic laterite from that derived from ultramafic or felsic rocks.
A preliminary investigation of the release of oil from contaminated clays and other fine-grained sediments during consolidation
Authors: Thornley D.M. , Wilkinson W.B. , Parker A.
Published: October 2006

Fine-grained sediments on land, or in a freshwater or marine environment, may become contaminated with a wide range of pollutants including hydrocarbons. This paper is concerned with preliminary studies of the mobilization and transportation of hydrocarbons, during the process of consolidation, to adjacent sediments or water bodies. A modified Rowe Cell was used to measure the consolidation properties of prepared kaolinite and bentonite clay–water slurries, with and without the addition of oil, along with hydrocarbon-bearing drill-cuttings samples taken from the sea-bed adjacent to two North Sea oil-well platforms. The consolidation properties of the kaolinite and bentonite clay slurries were little altered by the addition of oil, which was present at concentrations of between 8073 and 59 572 mg kg
−1
. During each consolidation stage, samples of the expelled pore-fluids were collected and analysed for oil content. These values were very low in comparison with the original oil concentration in the samples and changed little between each consolidation stage. Analysis of the slurry samples both before and after consolidation confirms that, proportionally, little oil is removed as a result of consolidation. The implication of these results is that, for the range of samples tested, the very high hydraulic gradients and particle rearrangements that occur during the process of consolidation are capable of releasing only proportionally small amounts of oil bound to the fine-grained clay and silt particles.
Installation of a lime injection barrier for the remediation of acid sulphate soil problems
Authors: Indraratna B. , Golab A.N. , Banasiak L.J.
Published: October 2006

Oxidation of naturally occurring pyrite (FeS
2
) in certain low-lying clayey soils generates sulphuric acid, hence the term acid sulphate soils. A horizontal alkaline barrier was installed by radial grouting, for the purpose of remediating leachate from acid sulphate soils and preventing further oxidation. The current research relates to a large-scale field trial of this technique and the effect on the groundwater composition. In coastal Australia, a pyritic layer commonly exists in the soil at shallow depth that is at risk of oxidation, hence the main objective was to inject the barrier above the pyritic layer to (1) stop infiltration of oxygen to the pyritic layer and (2) neutralize any acidity stored in the soil. Two fine-grained alkaline materials, lime and fly ash, were assessed in this study. Lime was selected for its neutralizing capacity, and the fly ash was selected to accompany the lime to enhance the pozzolanic reactions. The optimum mix ratio of lime, fly ash and water to form an ideal slurry and the optimum depth and pressure of injection were experimentally determined. For the large-scale field trial, the slurry was injected into a systematic grid of 22 holes to form the reactive barrier. The groundwater composition was monitored in a network of observation holes across the study site to determine the effectiveness of the barrier. The average groundwater pH was 3.25 prior to installation of the barrier, and it rose to 4.6 after the barrier was installed. The influence of the barrier on the groundwater pH was greater in observation holes close to the barrier than in those further away. The concentrations of aluminium and iron decreased in the groundwater after the installation of the alkaline barrier. The ratio of Cl/SO
4
in the groundwater increased after the barrier was installed, which confirmed that the barrier had successfully controlled the subsequent pyrite oxidation in the soil.
The slip surface in the D Zone of the Barton Clay
Authors: Barton M.E. , Hillier S. , Watson G.V.R.
Published: October 2006

The most dominant of the preferred bedding plane surfaces of shearing in the Eocene Barton Clay coastal cliffs of the Hampshire Basin is that near the base of the D Zone. This is utilized as the basal surface of compound landslides virtually throughout its 2.3 km outcrop from near the cliff top to beach level, an elevation change of nearly 30 m. The shear zone is located along a thin seam of dark chocolate brown clay, which has been investigated by X-ray powder diffraction mineralogical analysis, X-ray fluorescence chemical analysis, scanning electron microscope study of the microfabric and ring shear tests. The dark seam is slightly more clay rich and has a slightly lower value of residual shear strength than the ambient D Zone clay. The reason for its preference during landsliding is discussed. The available evidence suggests that although some previous shear displacement by flexural slip during folding may have occurred, the main displacement results from the lateral rebound response to coastal recession, involving a reorientation of any previous clay particle alignment. Lateral rebound initiates progressive failure, which leads to the compound landsliding of the
in situ
clay slopes.
Pharmacokinetic-Pharmacodynamic Relationships of Imatinib and Its Main Metabolite in Patients with Advanced Gastrointestinal Stromal Tumors
Authors: Delbaldo Catherine , Chatelut Etienne , Ré Micheline , Deroussent Alain , Séronie-Vivien Sophie , Jambu Aurore , Berthaud Patrice , Le Cesne Axel , Blay Jean-Yves , Vassal Gilles
Published: October 2006

Purpose: This study explored factors affecting the pharmacokinetic variability of imatinib and CGP 74588, and the pharmacokinetic-pharmacodynamic correlations in patients with advanced gastrointestinal stromal tumors.

Experimental Design: Thirty-five patients with advanced gastrointestinal stromal tumors received 400 mg of imatinib daily. Six blood samples were drawn: before intake, during 1- to 3- and 6- to 9-hour intervals after intake on day 1, and before intake on days 2, 30, and 60. Plasma imatinib and CGP 74588 concentrations were quantified by reverse-phase high-performance liquid chromatography coupled with tandem mass spectrometry, and analyzed by the population pharmacokinetic method (NONMEM program). The influence of 17 covariates on imatinib clearance (CL) and CGP 74588 clearance (CLM/fm) was studied. These covariates included clinical and biological variables and occasion (OCC = 0 for pharmacokinetic data corresponding to the first administration, or OCC = 1 for the day 30 or 60 administrations).

Results: The best regression formulas were: CL (L/h) = 7.97 (AAG/1.15)−0.52, and CLM/fm (L/h) = 58.6 (AAG/1.15)−0.60 × 0.55OCC, with the plasma α1-acid glycoprotein (AAG) levels indicating that both clearance values decreased at a higher AAG level. A significant time-dependent decrease in CLM/fm was evidenced with a mean (+SD) CGP 74588/imatinib area under the curve (AUC) ratio of 0.25 (±0.07) at steady state, compared with 0.14 (±0.03) on day 1. Hematologic toxicity was correlated with pharmacokinetic variables: the correlation observed with the estimated unbound imatinib AUC at steady-state (r = 0.56, P < 0.001) was larger than that of the total imatinib AUC (r = 0.32, NS).

Conclusions: The plasma AAG levels influenced imatinib pharmacokinetics. A protein-binding phenomenon needs to be considered when exploring the correlations between pharmacokinetics and pharmacodynamics.
Bcl-2 Expression as a Predictive Marker of Hormone-Refractory Prostate Cancer Treated with Taxane-Based Chemotherapy
Authors: Yoshino Tateki , Shiina Hiroaki , Urakami Shinji , Kikuno Nobuyuki , Yoneda Tatsuaki , Shigeno Kazushi , Igawa Mikio
Published: October 2006

Purpose: Bcl-2 inhibits apoptosis, and its overexpression is associated with hormone refractory prostate cancer (HRPC). Bak and Bax are in the Bcl-2 family and counteract the antiapoptotic function of Bcl-2. Taxane-induced (paclitaxel and its analogue docetaxel) phosphorylation of Bcl-2 abolishes the potential antiapoptotic effect of Bcl-2. We hypothesized that (a) survival benefit in HRPC patients treated with taxanes is determined by the presence of Bcl-2 protein and (b) altered expression of Bak and Bax protein caused by genetic mutation is associated with biological aggressiveness of prostate cancer.

Experimental Design: Forty localized prostate cancer and 30 HRPC cases were used in this study. Surgical specimens of localized prostate cancer and biopsy specimens of HRPC were used for immunostaining of Bcl-2, Bak, and Bax as well as DNA extraction. Mutations in the Bak and Bax genes were screened by single-strand conformational polymorphism, and confirmed by direct DNA sequencing.

Results: Bcl-2–positive HRPC showed longer cause-specific survival in comparison with the counterparts. Multivariate analysis revealed that the level of Bcl-2 expression before treatment with taxane-based chemotherapy was an independent predictor for cause-specific survival (P < 0.01) and baseline prostate-specific antigen level was an independent predictor for progression-free survival (P < 0.01). Bax gene mutation was found in only one HRPC specimen.

Conclusions: Bcl-2 expression in addition to prostate-specific antigen measurement before treatment could identify HRPC patients who may benefit from taxane-based chemotherapy. Mutation of the Bak and Bax genes is a rare event in prostate cancer.
The p53 Pathway and Outcome among Patients with T1G3 Bladder Tumors
Authors: López-Knowles Elena , Hernández Silvia , Kogevinas Manolis , Lloreta Josep , Amorós Alex , Tardón Adonina , Carrato Alfredo , Kishore Sirish , Serra Consol , Malats Núria , Real Francisco X. ,   on behalf of the EPICURO Study Investigators
Published: October 2006

Purpose: The aim was to analyze Tp53 and HDM2 in T1G3 bladder tumors and to determine the prognostic value of their alterations.

Experimental Design: Tumors (n = 119) were extracted from a prospective study of 1,356 bladder cancers. Tp53 mutations (exons 4-9) were assessed by sequencing of PCR products. HDM2 dose was assessed by quantitative PCR. p53, HDM2, and the products of p53 target genes were analyzed by immunohistochemistry. Cases were distributed in three categories. The association with prognosis was determined using Kaplan-Meier and Cox analyses.

Results: Eighty-five percent of tumors harbored alterations in Tp53 or HDM2. In group 1 (n = 77), 69 tumors had inactivating Tp53 mutations (58%), and 8 had HDM2 gains (7%). Group 2 (n = 24) comprised tumors overexpressing p53 in the absence of mutations (20%). Group 3 tumors (n = 18) had no alterations. HDM2 gains were associated to HDM2 overexpression and to wild-type Tp53. Expression of type 1 insulin-like growth factor receptor, 14-3-3 σ, and cyclooxygenase-2 was similar in groups 1 and 2 and significantly different from group 3. Survivin was expressed in the majority of tumors regardless of p53 pathway status. Taking group 3 as reference, the hazard ratios (HR) for recurrence, progression, and death were not significantly different in the other patient groups. HRs for recurrence were 1.13 for group 1 [95% confidence interval (95% CI), 0.25-5.03] and 1.40 for group 2 (95% CI, 0.27-7.20). HRs for progression were 0.50 for group 1 (95% CI, 0.18-1.40) and 0.25 for group 2 (95% CI, 0.05-1.29).

Conclusions: The p53 pathway is inactivated in most T1G3 bladder tumors. These genetic alterations do not independently predict patient's prognosis.
Erlotinib for Frontline Treatment of Advanced Non–Small Cell Lung Cancer: a Phase II Study
Authors: Giaccone Giuseppe , Gallegos Ruiz Marielle , Le Chevalier Thierry , Thatcher Nick , Smit Egbert , Rodriguez Jose Antonio , Janne Pasi , Oulid-Aissa Dalila , Soria Jean-Charles
Published: October 2006

Purpose: Erlotinib has proven activity in pretreated patients with advanced non–small cell lung cancer (NSCLC). We evaluated erlotinib in the frontline treatment of advanced NSCLC and assessed biological predictors of outcome.

Experimental Design: In this phase II study, chemotherapy-naive patients with stage IIIB/IV NSCLC received oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity occurred. Tumor response was assessed every 6 weeks, and samples were analyzed for potential molecular markers of treatment response and survival. The primary end point was the proportion of patients without disease progression after 6 weeks of treatment.

Results: Fifty-three patients were eligible. The overall rate of nonprogression at 6 weeks was 52.8% (28 of 53 patients). Tumor response rate was 22.7%, with 1 complete response, 11 partial responses, and 16 cases of stable disease. Responses were seen across most patient clinical characteristics. The median duration of tumor response was 333 days; median overall survival was 391 days; and median time to disease progression was 84 days. Erlotinib was well tolerated, the main treatment-related adverse events being mild-to-moderate rash and diarrhea. Histologic material for biological studies was available in 29 cases. Four of five responders and one patient with stable disease had a classic epidermal growth factor receptor tyrosine kinase mutation. Two progressing patients exhibited epidermal growth factor receptor point mutations (one with T790M mutation), and K-ras mutations were detected in 10 nonresponders.

Conclusions: Erlotinib shows significant antitumor activity in the first-line treatment of advanced NSCLC and may be a viable alternative to chemotherapy. Patient selection cannot easily be based on clinical or biological variables.
Identification of a Gene Signature for Rapid Screening of Oral Squamous Cell Carcinoma
Authors: Ziober Amy F. , Patel Kirtesh R. , Alawi Faizan , Gimotty Phyllis , Weber Randall S. , Feldman Michael M. , Chalian Ara A. , Weinstein Gregory S. , Hunt Jennifer , Ziober Barry L.
Published: October 2006

Purpose: Oral cancer is a major health problem worldwide and in the U.S. The 5-year survival rate for oral cancer has not improved significantly over the past 20 years and remains at ∼50%. Patients diagnosed at an early stage of the disease typically have an 80% chance for cure and functional outcome, however, most patients are identified when the cancer is advanced. Thus, a convenient and an accurate way to detect oral cancer early will decrease patient morbidity and mortality. The ability to noninvasively monitor oral cancer onset, progression, and treatment outcomes requires two prerequisites: identification of specific biomarkers for oral cancers as well as noninvasive access to and monitoring of these biomarkers that could be conducted at the point of care (i.e., practitioner's or dentist's office) by minimally trained personnel.

Experimental Design: Here, we show that DNA microarray gene expression profiling of matched tumor and normal specimens can identify distinct anatomic site expression patterns and a highly significant gene signature distinguishing normal from oral squamous cell carcinoma (OSCC) tissue.

Results: Using a supervised learning algorithm, we generated a 25-gene signature for OSCC that can classify normal and OSCC specimens. This 25-gene molecular predictor was 96% accurate on cross-validation, averaging 87% accuracy using three independent validation test sets and failing to predict non–oral tumors.

Conclusion: Identification and validation of this tissue-specific 25-gene molecular predictor in this report is our first step towards developing a new, noninvasive, microfluidic-based diagnostic technology for mass screening, diagnosis, and treatment of pre-OSCC and OSCC.
Preclinical Antitumor Activity of BMS-599626, a pan-HER Kinase Inhibitor That Inhibits HER1/HER2 Homodimer and Heterodimer Signaling
Authors: Wong Tai W. , Lee Francis Y. , Yu Chiang , Luo Feng R. , Oppenheimer Simone , Zhang Hongjian , Smykla Richard A. , Mastalerz Harold , Fink Brian E. , Hunt John T. , Gavai Ashvinikumar V. , Vite Gregory D.
Published: October 2006

Purpose: The studies described here are intended to characterize the ability of BMS-599626, a small-molecule inhibitor of the human epidermal growth factor receptor (HER) kinase family, to modulate signaling and growth of tumor cells that depend on HER1 and/or HER2.

Experimental Design: The potency and selectivity of BMS-599626 were assessed in biochemical assays using recombinant protein kinases, as well as in cell proliferation assays using tumor cell lines with varying degrees of dependence on HER1 or HER2 signaling. Modulation of receptor signaling was determined in cell assays by Western blot analyses of receptor autophosphorylation and downstream signaling. The ability of BMS-599626 to inhibit receptor heterodimer signaling in tumor cells was studied by receptor coimmunoprecipitation. Antitumor activity of BMS-599626 was evaluated using a number of different xenograft models that represent a spectrum of human tumors with HER1 or HER2 overexpression.

Results: BMS-599626 inhibited HER1 and HER2 with IC50 of 20 and 30 nmol/L, respectively, and was highly selective when tested against a broad panel of diverse protein kinases. Biochemical studies suggested that BMS-599626 inhibited HER1 and HER2 through distinct mechanisms. BMS-599626 abrogated HER1 and HER2 signaling and inhibited the proliferation of tumor cell lines that are dependent on these receptors, with IC50 in the range of 0.24 to 1 μmol/L. BMS-599626 was highly selective for tumor cells that depend on HER1/HER2 and had no effect on the proliferation of cell lines that do not express these receptors. In tumor cells that are capable of forming HER1/HER2 heterodimers, BMS-599626 inhibited heterodimerization and downstream signaling. BMS-599626 had antitumor activity in models that overexpress HER1 (GEO), as well as in models that have HER2 gene amplification (KPL4) or overexpression (Sal2), and there was good correlation between the inhibition of receptor signaling and antitumor activity.

Conclusions: BMS-599626 is a highly selective and potent inhibitor of HER1 and HER2 kinases and inhibits tumor cell proliferation through modulation of receptor signaling. BMS-599626 inhibits HER1/HER2 receptor heterodimerization and provides an additional mechanism of inhibiting tumors in which receptor coexpression and heterodimerization play a major role in driving tumor growth. The preclinical data support the advancement of BMS-599626 into clinical development for the treatment of cancer.
Wnt Antagonism in Multiple Myeloma: A Potential Cause of Uncoupled Bone Remodeling
Authors: Pearse Roger N.
Published: October 2006

Bone disease in patients with multiple myeloma (MM) is characterized by uncoupled bone remodeling, evident as enhanced osteolytic resorption and decreased rather than increased bone formation. MM-triggered osteolysis follows deregulation of the receptor activator of nuclear factor κB ligand (RANKL)/osteoprotegerin cytokine axis. Inhibition of bone formation may result from the ability of MM to inhibit the function of Wnts, secreted glycoproteins critical to osteoblast development. Recent studies show how these processes may be linked.
Skeletal Complications of Breast Cancer Therapies
Authors: Hirbe Angela , Morgan Elizabeth A. , Uluçkan Özge , Weilbaecher Katherine
Published: October 2006

Nonsurgical treatment options, such as hormonal therapy, chemotherapy, radiation, and bisphosphonate therapy, are undoubtedly improving outcomes for women with breast cancer; however, these therapies also carry significant skeletal side effects. For example, adjuvant hormonal treatments, such as aromatase inhibitors that disrupt the estrogen-skeleton axis, have the potential to cause decreased bone mineral density. Similarly, chemotherapy often induces primary ovarian failure in premenopausal women, resulting in decreased levels of circulating estrogen and subsequent osteopenia. In both cases, women receiving these therapies are at an increased risk for the development of osteoporosis and skeletal fracture. Furthermore, women undergoing radiation therapy to the upper body may have an increased incidence of rib fracture, and those receiving bisphosphonates may be vulnerable to the development of osteonecrosis of the jaw. Therefore, women with breast cancer who are undergoing any of these therapies should be closely monitored for bone mineral loss and advised of skeletal health maintenance strategies.
Treatment for Myeloma Bone Disease
Authors: Yeh Howard S. , Berenson James R.
Published: October 2006

Multiple myeloma (MM) is a B cell malignancy characterized by enhanced bone loss commonly associated with diffuse osteopenia, focal lytic lesions, pathologic fractures, hypercalcemia, and bony pain. Bone destruction in MM results from asynchronous bone turnover wherein increased osteoclastic bone resorption is not accompanied by a comparable increase in bone formation. Consequently, patients with MM frequently require radiation therapy, surgery, and analgesic medications. The recent development of minimally invasive surgical procedures such as kyphoplasty allows patients with myeloma with vertebral compression fractures to have immediate improvement in their quality of life with shorter hospital stays. Bisphosphonates are specific inhibitors of osteoclastic activity, and these agents have been evaluated in patients with MM with bone disease during the past 15 years. Monthly i.v. infusions of either pamidronate or zoledronic acid have reduced the skeletal complications among patients with MM and are now a mainstay of myeloma therapy. Orally administered bisphosphonates, in contrast, have shown little ability to slow the development of skeletal complications in these patients. Although preclinical studies suggest that nitrogen-containing bisphosphonates have potent antitumor effects, clinical trials will be necessary, probably at higher doses given more slowly, to establish their possible antitumor effects clinically. Moreover, recent advances in the use of bone-seeking radiopharmaceuticals make these attractive therapeutic candidates to combine with bisphosphonates or radiosensitizing drugs (e.g., bortezomib) to achieve a synergistic effect. As our understanding of the pathophysiology of myeloma bone disease continues to grow, new target therapies will continue to emerge, offering new and more advanced options for the management of myeloma bone disease.
Glucocorticoids Suppress Tumor Lymphangiogenesis of Prostate Cancer Cells
Authors: Yano Akihiro , Fujii Yasuhisa , Iwai Aki , Kawakami Satoru , Kageyama Yukio , Kihara Kazunori
Published: October 2006

Purpose: Glucocorticoids such as prednisone, hydrocortisone, and dexamethasone are known to provide some clinical benefit for patients with hormone-refractory prostate cancer. However, the underlying mechanisms by which glucocorticoids affect hormone-refractory prostate cancer progression are not well established as yet. Our previous study has shown that glucocorticoids inhibit tumor angiogenesis possibly by down-regulation of vascular endothelial growth factor (VEGF) and interleukin 8. Here, we hypothesized that the therapeutic effect of dexamethasone on hormone-refractory prostate cancer can be partly attributed to a direct inhibition of lymphangiogenesis through the glucocorticoid receptor by down-regulating a major lymphangiogenic factor, VEGF-C.

Experimental Design: The effects of dexamethasone on the expression of VEGF-C and its receptor, VEGF receptor-3 (VEGFR-3), were examined using an androgen-independent human prostate cancer cell line, DU145, which expresses glucocorticoid receptor. The effects of dexamethasone on tumor-associated lymphangiogenesis in DU145 xenografts were determined by analyzing VEGF-C gene expression, lymphatic vessel density, and relative lymphatic vessel area.

Results: Dexamethasone significantly down-regulated VEGF-C gene expression and protein production by 48% (P = 0.003) and 44% (P = 0.002), respectively, under normoxic condition. Similarly, hydrocortisone down-regulated VEGF-C gene expression. The effects of dexamethasone were completely reversed by the glucocorticoid receptor antagonist RU486. Even under hypoxia-like conditions, dexamethasone inhibited VEGF-C gene expression. In DU145 xenografts, dexamethasone significantly down-regulated VEGF-C gene expression and decreased lymphangiogenesis. Dexamethasone did not affect VEGFR-3 gene expression in vitro and in vivo.

Conclusion: Glucocorticoids suppressed tumor-associated lymphangiogenesis by down-regulating VEGF-C through glucocorticoid receptor in androgen-independent prostate cancer cells in vivo.
High-Linear Energy Transfer Irradiation Targeted to Skeletal Metastases by the α-Emitter 223Ra: Adjuvant or Alternative to Conventional Modalities?
Authors: Bruland Øyvind S. , Nilsson Sten , Fisher Darrell R. , Larsen Roy H.
Published: October 2006

The bone-seeking, α-particle-emitting radiopharmaceutical Alpharadin, 223RaCl2 (half-life = 11.4 days), is under clinical development as a novel treatment for skeletal metastases from breast and prostate cancer. This article summarizes the current status of preclinical and clinical research on 223RaCl2. Potential advantages of 223Ra to that of external beam irradiation and registered β-emitting bone seekers are discussed. Published data of 223Ra dosimetry in mice and a therapeutic study in a skeletal metastases model in nude rats have indicated significant therapeutic potential of bone-seeking α-emitters. This article provides short-term and long-term results from the first clinical single dosage trial. We also present data from a repeated dosage study of five consecutive injections of 50 kBq/kg body weight, once every 3rd week, or two injections of 125 kBq/kg body weight, 6 weeks apart. Furthermore, interim results are described for a randomized phase 2 trial involving 64 patients with hormone-refractory prostate cancer and painful skeletal metastases who received four monthly injections of 223Ra or saline as an adjuvant to external beam radiotherapy. Lastly, we present preliminary dose estimates for 223Ra in humans. Results indicate that repeated dosing is feasible and toxicity is low, and that opportunities are available for combined treatment strategies.
New Potential Targets for Treating Myeloma Bone Disease
Authors: Roodman G. David
Published: October 2006

Purpose: Myeloma bone disease results in severe pain and pathologic fractures in >80% of patients. Myeloma bone disease is characterized by both increased osteoclast activity and suppressed new bone formation. The basis for both the increased bone destruction and decreased bone formation has been a topic of extensive investigation during the last several years.

Experimental Design: Marrow samples from patients with myeloma were screened by both molecular biological and gene expression profiling techniques to identify factors that may be responsible for the enhanced bone destruction and suppressed bone formation in patients with the disease.

Results: Several novel factors have been identified that directly stimulate osteoclastic bone destruction in myeloma. These include receptor activator of NF-κB ligand, macrophage inflammatory peptide 1α, and interleukin (IL)-3. All of these factors are increased in most patients with myeloma. Furthermore, osteoprotegerin levels are markedly suppressed, further driving osteoclast formation. In addition, four novel inhibitors of osteoblast differentiation or activity have been identified. These include two inhibitors of the Wnt signaling pathway, DKK1 and soluble frizzled protein 2. The Wnt signaling pathway is critical for osteoblast differentiation. Two cytokines, IL-3 and IL-7, have also been reported that directly or indirectly inhibit osteoblast differentiation in patients with myeloma. Interestingly, increased macrophage inflammatory peptide 1α, IL-3, and IL-7 result from abnormal transcriptional regulation of these genes by increased levels of acute myelogenous leukemia-1 to acute myelogenous leukemia-1B transcription factors.

Conclusions: The recent identification of novel stimulators of osteoclast activity and inhibitors of osteoblast differentiation provide new therapeutic targets for treating this devastating bone disease in patients with myeloma.
Src Inhibitors in Metastatic Bone Disease
Authors: Boyce Brendan F. , Xing Lianping , Yao Zhenqiang , Yamashita Teruhito , Shakespeare William C. , Wang Yihan , Metcalf Chester A. , Sundaramoorthi Raji , Dalgarno David C. , Iuliucci John D. , Sawyer Tomi K.
Published: October 2006

Src tyrosine kinase was the first gene product shown to have an essential function in bone using recombinant DNA technology after its expression was knocked out in mice ∼15 years ago. Since then, our understanding of the regulation of bone catabolism has advanced significantly with the identification of other key enzymes that regulate osteoclast formation, activation, and survival after their knockout in mice or recognition of mutations in them in humans. This led to the discovery or development of specific inhibitors of some of these key enzymes, including Src, as proof-of-concept lead compounds or potential clinical candidates for the prevention of diseases associated with increased bone resorption, such as osteoporosis and metastatic bone disease. Although bisphosphonates have been prescribed with proven and improving efficacy for the prevention of bone loss for >30 years, adverse effects, such as upper gastrointestinal tract symptoms, and the requirement to take them at least 2 hours before food have limited patient compliance. Thus, with growing knowledge of the pathways regulating osteoclast function and the appreciation that some of these are active also in tumor cells, drug companies have made efforts to identify small-molecular lead compounds for development into new therapeutic agents for the prevention of bone loss with efficacy that matches or supersedes that of bisphosphonates. In this article, we review our current understanding of the signaling pathways that regulate osteoclast formation, activation, and survival with specific reference to the role of Src tyrosine kinase and downstream signaling and highlight in a variety of models of increased bone resorption the effects of Src kinase inhibitors that have been targeted to bone to limit potential adverse effects on other cells.
The Use of a Tropism-Modified Measles Virus in Folate Receptor–Targeted Virotherapy of Ovarian Cancer
Authors: Hasegawa Kosei , Nakamura Takafumi , Harvey Mary , Ikeda Yasuhiro , Oberg Ann , Figini Mariangela , Canevari Silvana , Hartmann Lynn C. , Peng Kah-Whye
Published: October 2006

Purpose: Attenuated measles viruses are promising experimental anticancer agents currently being evaluated in a phase I dose escalation trial for ovarian cancer patients. Virus attachment, entry, and subsequent intercellular fusion between infected and uninfected neighboring cells are mediated via the two measles receptors (CD46 and SLAM). To minimize potential toxicity due to measles virus–associated immunosuppression and infection of nontarget tissues, we sought to develop an ovarian cancer exclusive fully retargeted measles virus.

Experimental Design and Results: Interactions of measles virus with its natural receptors were ablated, and a single-chain antibody (scFv) specific for α-folate receptor (FRα), a target overexpressed on 90% of nonmucinous ovarian cancer, was genetically engineered on the viral attachment protein (MV-αFR). Specificity of virus tropism was tested on tumor and normal cells. Biodistribution of measles virus infection was evaluated in measles-susceptible CD46 transgenic mice, whereas antitumor activity was monitored noninvasively by bioluminescence imaging in xenograft models. Tropism and fusogenic activity of MV-αFR was redirected exclusively to FRα without compromise to virus infectivity. In contrast to the parental virus, MV-αFR has no background infectivity on normal human cells. The antitumor activity of MV-αFR, as assessed by tumor volume reduction and overall survival increase, was equal to the parental virus in two models of human ovarian cancer (s.c. and i.p.).

Conclusions: A FR-exclusive ovarian cancer targeted oncolytic virus was generated and shown to be therapeutically effective, thus introducing a new modality for FR targeting and a candidate measles virus for clinical testing.
Basic Mechanisms Responsible for Osteolytic and Osteoblastic Bone Metastases
Authors: Guise Theresa A. , Mohammad Khalid S. , Clines Gregory , Stebbins Elizabeth G. , Wong Darren H. , Higgins Linda S. , Vessella Robert , Corey Eva , Padalecki Susan , Suva Larry , Chirgwin John M.
Published: October 2006

Certain solid tumors metastasize to bone and cause osteolysis and abnormal new bone formation. The respective phenotypes of dysregulated bone destruction and bone formation represent two ends of a spectrum, and most patients will have evidence of both. The mechanisms responsible for tumor growth in bone are complex and involve tumor stimulation of the osteoclast and the osteoblast as well as the response of the bone microenvironment. Furthermore, factors that increase bone resorption, independent of tumor, such as sex steroid deficiency, may contribute to this vicious cycle of tumor growth in bone. This article discusses mechanisms and therapeutic implications of osteolytic and osteoblastic bone metastases.