bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-language perception of Russian plain/palatalized laterals and rhotics.
Authors: Kochetov Alexei , Smith James
Published: October 2009

A number of studies investigating factors in non-native speech perception have focused on discrimination and identification of English /l/ and /r/ by listeners whose native languages do not have the relevant phonemic contrast. Relatively little work, however, has been done on non-native perception of lateral/rhotic contrasts in other languages and particularly on the perception of palatalized laterals or rhotics. This paper presents results of an AX discrimination experiment where 84 listeners, native speakers of Cantonese, English, Japanese, Korean, Mandarin, and Russian, were presented with stimuli containing intervocalic consonants /l/, /lj/, /r/, and /rj/ produced by a Russian native speaker. The results revealed significant differences in the perception of the lateral/rhotic contrasts across the listener groups, with relatively good discrimination of the contrasts by Korean and English listeners (yet less accurate compared to Russian listeners), and much poorer discrimination by the other groups of non-native listeners. All the groups, including native speakers, performed better with the more acoustically distinct plain /l/ and /r/ contrast than with the palatalized /lj/ and /rj/ contrast. The results suggest that presence or absence of similar native phonemic categories does not fully predict listeners’ performance, underscoring the importance of sub-phonemic gestural/acoustic detail in non-native perception.
Consonant intelligibility of English-, Chinese-, and Korean-native talkers.
Authors: Liu Chang , Jin Su-Hyun , Kamdar Sangeeta
Published: October 2009

Sixteen American-English consonants were recorded in a phonetic context of /aCa/ from young English-, Chinese-, and Korean-native talkers with normal speech and hearing functions. The Chinese and Korean talkers were bilingual with their US residency up to 6 years. The intelligibility of these consonants was examined for seven American-English listeners. Results showed that average consonant intelligibility for all three groups of listeners was well above 90% with English-native speakers having slightly higher intelligibility than the other two groups. Combined with our previous study on vowel intelligibility, there results indicate that the lower-than-native speech intelligibility for Chinese- and Korean-native speakers may be mainly due to the reduced vowel intelligibility, implying that speech training for these non-native speakers may need to focus on vowel production.
Manipulating within-speaker variation in non-native speech perception.
Authors: de Marneffe Marie , Sumner Meghan
Published: October 2009

Research in speech perception and L2 learning has shown that exposure to multiple speakers is generally beneficial [B. Sommers (2005); B. Bent (2008); Winters et al. (2005)]. Exactly what is driving these effects remains unclear. We examine whether varying a particular within-speaker cue improves perception. Specifically, we study perception by native English speakers of French-accented speech and concentrate on final obstruent devoicing: Are listeners better at perceiving final stops when a constant non-English V/C ratio is used by the speaker or does hearing variable ratios help? We used a click-on paradigm, with 20 pairs of pictures representing words featuring voiced and voiceless final stops (e.g., rope-robe) in two conditions: (1) constant V/C ratios (average) and (2) variable V/C ratios (short, average, long). We used modified natural tokens using the average variance from 11 native French speakers. Our results show that across items, accuracy rates for both conditions are the same, but variation yields slower RTs. Considering accuracy alone these are not different from each other, but listeners are either more cautious or processing is slowed with increased variation. Additionally, differences in accuracy surface by place of articulation, but only for the alveolar place of articulation.
A comparison of phonological errors made by native and non-native listeners.
Authors: Meyer Lindsay E. , McDonald Janet L.
Published: October 2009

Previous studies have shown that listeners have difficulty recognizing non-native words in noise [Mayo et al. (1997)] and affective prosody in quiet [Dromey et al. (2005)]. Difficulty increases with less L2 ability. Findings from the current study support these results while indicating that non-native listeners have additional difficulty identifying prosodic patterns (i.e., those indicating sentence type) and using semantic information under high levels of background noise. Participants heard sentences presented in −2, −4, −6, and −8-dB S/N. Target words were semantically predictable or unpredictable. Participant identification of sentence type and target words was recorded and analyzed. Both groups were affected by increasing levels of noise, but non-natives more strongly. Semantics aided native speakers under high levels of noise, but non-native speakers under low levels of noise. Analysis of phonological errors shows that the most frequent phonological error was on the onset and vowel, but this was not related to age of exposure. Later age of exposure for non-native listeners was correlated to fewer total phonologically correct words and they were more likely to give phonologically related forms that matched on the onset and coda. Therefore, age of exposure may affect the vowel whether in perception or production.
Effects of speechreading and signal-to-noise ratio on understanding mainstream American English by American and Indian adults.
Authors: Kanekama Yori , Downs David
Published: October 2009

The purpose of this study was to measure effects of speechreading and signal-to-noise ratio (SNR) on understanding mainstream American English (MAE) heard by 30 Indian adults compared to 30 American adults. Participants listened to a recording of a female speaker of MAE saying ten lists of ten different everyday speech sentences per list. Participants heard sentences from a TV loudspeaker at a 65 dB sound pressure level, while a four-talker babble played through two surrounding loudspeakers at various SNRs under auditory-visual and auditory modalities. Each participant’s speechreading performance at each SNR was computed as the difference in words correctly heard through auditory-visual versus auditory modalities. Consistent with most previous research, American participants benefited significantly more from speechreading at poorer SNRs than at favorable SNRs. The novel finding of this study, however, was that Indian participants benefited less from speechreading than American participants at poorer SNRs, but benefited more from speechreading than American participants at favorable SNRs. Linguistic (and, possibly, nonlinguistic) variables may have accounted for these findings, including an increased need for Indian participants to integrate more auditory cues with visual cues to benefit from speechreading, presumably because they only spoke English as a second language.
Spatial variability of density gradients in the transition layer from Bayesian inference of seabed reflection data.
Authors: Dettmer Jan , Dosso Stan E. , Holland Charles W.
Published: October 2009

This paper considers Bayesian inference of seabed reflection-coefficient data for geoacoustic models of the transition layer (i.e., uppermost low-velocity, water-saturated sediments) at several sites along a track, with the goal of studying spatial variability. Geoacoustic models are parametrized in terms of nonlinear density and linear sound-velocity gradients. Rigorous uncertainty estimation is of key importance to resolve spatial variability between measurement sites from the inherent inversion uncertainties. Geoacoustic uncertainty estimation is carried out including comprehensive estimation of data error statistics. Model parametrization is addressed by choosing gradient parameters that allow for a large variety of profile shapes. Metropolis–Hastings sampling is used to compute posterior probability densities. Several experimental sites are considered along a track located on the Malta Plateau, Mediteranean Sea, where the transition layer is expected to change with increasing distance from shore due to changes in the sedimentation processes. Differences between sites that exceed the estimated geoacoustic uncertainties are interpreted as spatial variability of the seabed. Density and sound-velocity gradients are clearly resolved by the reflectivity data and agree well with core measurements within the credibility bounds.
Intra-procedural aneurysm rupture treated with n-butyl cyanoacrylate embolization: technical note: Figure 1
Authors: Patsalides A , Smith M , Gobin Y P
Published: October 2009

A case is described of utilizing liquid polymer and stent placement to treat a procedural rupture of intracranial aneurysm during coil embolization. Although this technique is challenging, it seals the rupture immediately and can be used when additional coil placement is not possible.
Practical aspects of in situ measurements of material damping with the seismic cone penetration test
Authors: Stewart W. P. , Campanella R. G.
Published: October 2009

The downhole seismic cone penetration test (SCPT) procedure has been extended to allow the measurement of material damping at small strains at minimum expense while one is measuring shear wave velocity. The nature of damping, the required equipment characteristics, and the recommended procedure and calculation methodology are presented in a practical way. SCPT results from four different sites give results that are in general agreement with laboratory measurements of damping for sands and clays and with values recommended by other authors. It appears, however, that previously reported measurements of damping by borehole methods are higher, by a factor of two or more, when compared with SCPT and laboratory results. Key words : in situ, damping, seismic, shear wave, cone penetrometers, procedures.
Effect of freeze–thaw on the hydraulic conductivity and morphology of compacted clay
Authors: Othman Majdi A. , Benson Craig H.
Published: October 2009

Several studies have shown that freeze–thaw causes changes in the hydraulic conductivity of compacted clays. Cracks formed by ice lensing and shrinkage cause the hydraulic conductivity to increase. In this paper, changes in hydraulic conductivity are related to changes in morphology. Photographs of thin sections of frozen specimens show that ice lenses form in compacted clay during freezing in a closed system. Photographs also show that similar ice structures are obtained for one- and three-dimensional freezing, which explains why similar hydraulic conductivities are obtained for both conditions. The photographs also show that a significant network of cracks forms in a single cycle of freeze–thaw. With additional cycles, new ice lenses are created and thus the hydraulic conductivity continues to increase. However, after about three cycles the number of new ice lenses becomes negligible and hence further changes in hydraulic conductivity cease. The temperature gradient and state of stress affect morphology and hydraulic conductivity of compacted clays subjected to freeze–thaw. At larger temperature gradients, more ice lenses form and hence the hydraulic conductivity increases. In contrast, application of overburden pressure inhibits the formation of ice lenses and reduces the size of the cracks remaining when lenses thaw. As a result, the hydraulic conductivity is reduced. Key words : compacted clay, hydraulic conductivity, clay liners, soil liners, freeze-thaw, ice lenses, structure.
Compression characteristics and index properties of tills and intertill clays in southern Saskatchewan, Canada
Authors: Sauer E. Karl , Egeland Anne K. , Christiansen E. A.
Published: October 2009

Compression characteristics and index properties of unweathered tills and clays from repeated glaciations follow a predictable pattern at 10 sites along a 1300-km transect across southern Saskatchewan. A surface ablation melt-out till of the Battleford Formation is normally consolidated, a basal melt-out till of the Battleford Formation is moderately overconsolidated (σp′ = 400–750 kPa), and the older (pre-Battleford) tills and intertill clays are heavily overconsolidated (1800 ± 200 kPa). Variation in lithology, as indicated by Atterberg limits, is small within formations which reflected in the compression index. The older tills of the Sutherland Group are highly plastic compared with the younger tills of the Saskatoon Group. The in situ dry density of the youngest (Battleford) till is slightly above 100% maximum Proctor density. The in situ dry density of the older (pre-Battleford) tills is at or above the 100% maximum modified Proctor density. At these high densities the in situ degree of saturation is 94.5 ± 4.8%; as compared with Proctor optimums at 80.3 ± 3.8%. It is not practical to increase bearing capacity of the tills by compaction. Disturbance by compaction equipment could cause a decrease in density. Key words : preconsolidation, tills, intertill clays, Proctor density, multiple glaciations.
Mining-induced deformation in potash yield pillars, Vanscoy, Saskatchewan
Authors: Chen Rui , Brisbin W. C. , Stimpson B.
Published: October 2009

Mining-induced deformation of potash yield pillars in the Cominco potash mine at Vanscoy, Saskatchewan, has been documented by mapping deformational structures, determining changes in pillar width and in thicknesses of potash and interbedded clay layers, and analyses of rock fabrics in samples collected from three yield pillars. Pillar deformation over a period of 8 years can be shown to have involved progressive bulk rock flattening, followed by development of shear zones at pillar corners, development of shear wedges at pillar margins, and detachment of these wedges into adjacent rooms. Furthermore, this sequence appears to be repetitive. Strain in halite involves fracturing and displacement and rotation of fragments, strain in sylvite is continuous, and grain boundary sliding has been an important mechanism in the deformation. Although the fabric anisotropy cannot be used to assess total bulk rock strain, the component of strain related to sylvite shape change has been examined during progressive failure of the pillars. The values of strain in the principal strain directions based on sylvite shape are estimated as 42% shortening in the subvertical direction, 37% subhorizontal elongation perpendicular to the original openings, and 25% subhorizontal elongation parallel to the original openings. Key words : yield pillar, potash, fabric analysis, induced deformation.
A finite element study of the pressuremeter test in sand using a nonlinear elastic plastic model
Authors: Fahey Martin , Carter John P.
Published: October 2009

The stress–strain behaviour of sands is highly nonlinear, even at stresses well below the peak strength of the sand. The hyperbolic model is a reasonable conceptual model for representing the stress–strain behaviour of sand, but some empirical curve fitting is required to obtain a more realistic model for calculation purposes. This can readily be performed for reconstituted samples of sand using laboratory tests. Recent evidence shows that the stiffness of natural sands is often much greater than that of the same sand when reconstituted at the same density and stress state in the laboratory, and it is therefore necessary to use in situ testing methods to determine the stress–strain behaviour of such sands. In this paper, the finite element method is used to simulate pressuremeter tests in a soil modelled using a hyperbolic-type model. It concentrates on the behaviour in unload-reload loops, which are often included in pressuremeter tests to measure shear modulus. The effect on the whole unload-reload loop of varying some of the model parameters is examined. The results are compared with a high-quality pressuremeter test in sand. It is concluded that, though the results to date are encouraging, some further experimental work is required to verify some of the features of the model. Key words : pressuremeter test, hyperbolic model, nonlinear behaviour, initial shear modulus, sand behaviour.
Interaction of lateritic soil and steel grid reinforcement
Authors: Bergado D. T. , Macatol K. C. , Amin N. U. , Chai J. C. , Alfaro M. C. , Anderson L. R.
Published: October 2009

Laboratory and field pullout tests were carried out to study the interaction of welded steel grid reinforcements embedded in lateritic residual soil backfill. The laboratory pullout tests were conducted on various reinforcement sizes, mesh geometries, normal pressures, and compaction conditions of the backfill material. Field pullout tests were conducted at representative overburden, field-moisture, and density conditions. From the test results, it was found that the longitudinal members yielded frictional resistance from 8 to 15% of the total grid pullout resistance. Thus, the major contribution to the pullout resistance of grid reinforcements consists of the passive resistance mobilized in front of the transverse members. The maximum pullout resistance is shown by a bilinear curve which displayed similarity with the failure envelope from direct shear tests of the backfill material. This bilinear envelope reinforced the previous observation regarding the effect of particle breakage phenomenon inherent to lateritic residual soils subjected to high normal pressures. Comparisons between laboratory and field pullout resistances and between the predicted passive resistance and the laboratory test data are also presented. Key words : reinforcement, laboratory test, earthfill, compaction, friction resistance.
BLIND SOURCE SEPARATION: AN APPLICATION TO THE MT. MERAPI VOLCANO, INDONESIA
Authors: CABRAS GIUSEPPE , CARNIEL ROBERTO , WASSERMANN JOACHIM
Published: October 2009

Independent Component Analysis (ICA) is an emerging new technique in the blind identification of signals recorded in a variety of different fields. ICA tries to find the most statistically independent sources from an observable random vector, with the only restriction that all sources but at most one are non-Gaussian; no other a priori information on sources and mixing dynamic system are needed. The applications of these techniques to the analysis of volcanic time series are relatively few to date. In this paper we show that ICA is a suitable technique to separate a volcanic source component from ocean microseisms background noise in a seismic dataset recorded at the Mt. Merapi volcano, Indonesia. The encouraging results obtained with this methodology in the presented case study support their wider applicability in volcano seismology.
INVESTIGATING THE TEMPORAL FLUCTUATIONS IN PARTICULATE MATTER DATA
Authors: TELESCA LUCIANO , CAGGIANO ROSA , LAPENNA VINCENZO , LOVALLO MICHELE , TRIPPETTA SERENA , MACCHIATO MARIA
Published: October 2009

The temporal fluctuations of particulate matter time series of three reference European stations have been investigated, by using the power spectrum analysis. Our results point out to the presence in particulate matter of annual periodicities superimposed on a scaling behaviour with exponent ranging between ~1.4 and ~1.6, indicating quite high persistent correlations. Furthermore, a crossover timescale at about 1 month, evidenced in all the signals analysed, could be linked with chemical-physical processes in which aerosol particles are involved during their atmospheric lifetimes.
Pigment epithelium-derived factor suppresses adipogenesis via inhibition of the MAPK/ERK pathway in 3T3-L1 preadipocytes
Authors: Wang Min , Wang Joshua J. , Li Jingming , Park Kyoungmin , Qian Xiaoxian , Ma Jian-xing , Zhang Sarah X.
Published: October 2009

We previously reported that circulating levels of pigment epithelium-derived factor (PEDF), a newly identified adipokine, are increased in patients with type 2 diabetes, correlating with body mass index. However, the role of PEDF in adipogenesis remains elusive. In the present study, we have investigated the effects and mechanisms of PEDF on adipocyte differentiation in 3T3-L1 preadipocytes. Differentiation of 3T3-L1 preadipocytes was induced in the presence or absence of human recombinant PEDF protein. The effects of PEDF on adipogenic gene expression, mitotic clonal expansion (MCE), and MAPK activation were investigated. Physiological concentrations of human PEDF protein inhibited adipocyte differentiation, evidenced by decreased lipid accumulation, downregulation of adipocyte markers, and inhibition of master adipogenic transcription factors such as C/EBP-α and PPARγ. The antiadipogenic effects of PEDF were observed only when PEDF was added to the cells on day 0, but not on day 3 during differentiation, suggesting that PEDF targets some early adipogenic events. Similarly, overexpression of PEDF by adenovirus attenuated adipocyte differentiation. Further studies revealed that PEDF, or U-0126, a specific MAPK/ERK inhibitor, sequentially inhibited the early activation of ERK and MCE. Moreover, PEDF attenuated expression and the phosphorylation of C/EBP-β at Thr188, an essential step for transcriptional activation of C/EBP-β. In addition, PEDF expression was decreased significantly in the first 24 h during adipocyte differentiation, suggesting that downregulation of PEDF may be essential for the initiation of MCE and adipogenesis. We conclude that PEDF inhibits adipogenesis in 3T3-L1 preadipocytes partially because of inhibition of the MAPK/ERK signaling pathway and MCE.
Quantification of pancreatic islet distribution in situ in mice
Authors: Kilimnik German , Kim Abraham , Jo Junghyo , Miller Kevin , Hara Manami
Published: October 2009

Tracing changes of specific cell populations in health and disease is an important goal of biomedical research. Precisely monitoring pancreatic β-cell proliferation and islet growth is a challenging area of research. We have developed a method to capture the distribution of β-cells in the intact pancreas of transgenic mice with fluorescence-tagged β-cells with a macro written for ImageJ (rsb.info.nih.gov/ij/). Total β-cell area and islet number and size distribution are quantified with reference to specific parameters and location for each islet and for small clusters of β-cells. The entire distribution of islets can now be plotted in three dimensions, and the information from the distribution on the size and shape of each islet allows a quantitative and a qualitative comparison of changes in overall β-cell area at a glance.
Exercise, sex, menstrual cycle phase, and 17β-estradiol influence metabolism-related genes in human skeletal muscle
Authors: Fu Ming-hua H. , Maher Amy C. , Hamadeh Mazen J. , Ye Changhua , Tarnopolsky Mark A.
Published: October 2009

Higher fat and lower carbohydrate and amino acid oxidation are observed in women compared with men during endurance exercise. We hypothesized that the observed sex difference is due to estrogen and that menstrual cycle phase or supplementation of men with 17β-estradiol (E2) would coordinately influence the mRNA content of genes involved in lipid and/or carbohydrate metabolism in skeletal muscle. Twelve men and twelve women had muscle biopsies taken before and immediately after 90 min of cycling at 65% peak oxygen consumption (V̇o2peak). Women were studied in the midfollicular (Fol) and midluteal (Lut) phases, and men were studied after 8 days of E2or placebo supplementation. Targeted RT-PCR was used to compare mRNA content for genes involved in transcriptional regulation and lipid, carbohydrate, and amino acid metabolism. Sex was the greatest predictor of substrate metabolism gene content. Sex affected the mRNA content of FATm, FABPc, SREBP-1c, mtGPAT, PPARδ, PPARα, CPTI, TFP-α, GLUT4, HKII, PFK, and BCOADK ( P < 0.05). E2administration significantly ( P < 0.05) affected the mRNA content of PGC-1α, PPARα, PPARδ, TFP-α, CPTI, SREBP-1c, mtGPAT, GLUT4, GS-1, and AST. Acute exercise increased the mRNA abundance for PGC-1α, HSL, FABPc, CPTI, GLUT4, HKII, and AST ( P < 0.05). Menstrual cycle had a small effect on PPARδ, GP, and glycogenin mRNA content. Overall, women have greater mRNA content for several genes involved in lipid metabolism, which is partially due to an effect of E2.
Global Stability for a Delayed Predator‐Prey System with Stage Structure for the Predator
Authors: Zhang Xiao , Xu Rui , Gan Qintao
Published: October 2009

A delayed predator‐prey system with stage structure for the predator is investigated. By analyzing the corresponding characteristic equations, the local stability of equilibria of the system is discussed. The existence of Hopf bifurcation at the positive equilibrium is established. By using an iteration technique and comparison argument, respectively, sufficient conditions are derived for the global stability of the positive equilibrium and two boundary equilibria of the
system. Numerical simulations are carried out to illustrate the theoretical results.
Treatment with Mycophenolat Mofetil of Steroid-Dependent Asthma—One Case of Severe Asthma
Authors: Backer V. , Hjardem E. , Karlsmark T.
Published: October 2009

Background. Some patients with severe nonallergic asthma can be difficult to treat with conventional therapy. Mycophenolat Mofetil (MMF) is an immunosuppressive drug with multiple mechanisms. There is theoretical support of specific effect of MMF on severe asthma, in “difficult to treat” patients. The aim of the present case was to explore whether MMF had an effect in one case of severe refractory asthma. The patient. This case deals with one patient with very severe nonallergic treatment refractory asthma who experienced treatment failure on ordinary antiasthmatic treatment and severe adverse events to conventional immunosupressive treatment. She was then treated with MMF. Results. The patient experienced a gain in FEV1 and a reduction in the need for oral glucocorticosteroids as well as seldom need of when needed bronchodilator both during daytime and night. It therefore seems very interesting to examine the use of MMF for severe refractory asthma with further clinical studies and basic cellular trials.
Transcriptional Activity of Human Epidermal Growth Factor Receptor Family and Angiogenesis Effectors in Locoregionally Recurrent Head and Neck Squamous Cell Carcinoma and Correlation with Patient Outcome
Authors: Pentheroudakis George , Angouridakis Nikolaos , Wirtz Ralph , Nikolaou Angelos , Kalogeras Konstantine T. , Pavlidis Nicholas , Fountzilas George
Published: October 2009

Locoregional recurrence is the most common failure pattern in patients with head and neck squamous cell carcinoma (HNSCC). We retrospectively identified 41 HNSCC patients with locoregional relapse and used kinetic reverse transcription-polymerase chain reaction (kRT-PCR) in order to study fresh-frozen tumour messenger RNA (mRNA) levels of the Human Epidermal growth factor family members HER1-4, the Vascular Endothelial Growth Factors (VEGFs) A, B, C, D, and their receptors VEGFR1, 2, 3. High VEGF-C and VEGFR3 tumour mRNA expression correlated with relapse beyond the primary locus (neck nodes or soft tissues,P<.05). Tumours with regional nodal involvement at diagnosis more often exhibited high transcriptional activity of VEGFR1 and VEGFR3 at the time of relapse (P<.05). At a median follow-up of 52 months from the time of locoregional recurrence, patients with high VEGF-C tumours at relapse had significantly poorer postrelapse progression-free survival (R-PFS, 5 versus 47 months, log-rankP=.052) and a trend for inferior postrelapse overall survival (R-OS, 22 versus 44 months, log-rankP=.076) in comparison to low VEGF-C tumours. Similar association with dismal outcome was seen for its receptor, VEGFR3 tumoural mRNA levels (log-rankP=.060). In contrast, suppressed tumour transcription of VEGF-D was associated with poorer post-relapse survival, though statistical significance was not reached. Active transcription of the VEGF-C/VEGFR3 axis in recurrent HNSCC is associated with failure at neck soft tissues/lymph nodes and inferior survival post-relapse.
Inhibition of Tumor Cell Growth, Invasion, and Metastasis by EXEL-2880 (XL880, GSK1363089), a Novel Inhibitor of HGF and VEGF Receptor Tyrosine Kinases
Authors: Qian Fawn , Engst Stefan , Yamaguchi Kyoko , Yu Peiwen , Won Kwang-Ai , Mock Lillian , Lou Tracy , Tan Jenny , Li Connie , Tam Danny , Lougheed Julie , Yakes F. Michael , Bentzien Frauke , Xu Wei , Zaks Tal , Wooster Richard , Greshock Joel , Joly Alison H.
Published: October 2009

The Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), are overexpressed and/or activated in a wide variety of human malignancies. Vascular endothelial growth factor (VEGF) receptors are expressed on the surface of vascular endothelial cells and cooperate with Met to induce tumor invasion and vascularization. EXEL-2880 (XL880, GSK1363089) is a small-molecule kinase inhibitor that targets members of the HGF and VEGF receptor tyrosine kinase families, with additional inhibitory activity toward KIT, Flt-3, platelet-derived growth factor receptor β, and Tie-2. Binding of EXEL-2880 to Met and VEGF receptor 2 (KDR) is characterized by a very slow off-rate, consistent with X-ray crystallographic data showing that the inhibitor is deeply bound in the Met kinase active site cleft. EXEL-2880 inhibits cellular HGF-induced Met phosphorylation and VEGF-induced extracellular signal-regulated kinase phosphorylation and prevents both HGF-induced responses of tumor cells and HGF/VEGF-induced responses of endothelial cells. In addition, EXEL-2880 prevents anchorage-independent proliferation of tumor cells under both normoxic and hypoxic conditions. In vivo, these effects produce significant dose-dependent inhibition of tumor burden in an experimental model of lung metastasis. Collectively, these data indicate that EXEL-2880 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of invasion and angiogenesis mediated by HGF and VEGF receptors. [Cancer Res 2009;69(20):8009–16]
A Novel Experimental Heme Oxygenase-1–Targeted Therapy for Hormone-Refractory Prostate Cancer
Authors: Alaoui-Jamali Moulay A. , Bismar Tarek A. , Gupta Ajay , Szarek Walter A. , Su Jie , Song Wei , Xu Yingjie , Xu Bin , Liu Guoan , Vlahakis Jason Z. , Roman Gheorghe , Jiao Jinsong , Schipper Hyman M.
Published: October 2009

Heme oxygenase-1 (HO-1), a member of the heat shock protein family, plays a key role as a sensor and regulator of oxidative stress. Herein, we identify HO-1 as a biomarker and potential therapeutic target for advanced prostate cancer (PCA). Immunohistochemical analysis of prostate tissue using a progression tissue microarray from patients with localized PCA and across several stages of disease progression revealed a significant elevation of HO-1 expression in cancer epithelial cells, but not in surrounding stromal cells, from hormone-refractory PCA (HRPCA) compared with hormone-responsive PCA and benign tissue. Silencing the ho-1 gene in HRPCA cells decreased the HO-1 activity, oxidative stress, and activation of the mitogen-activated protein kinase–extracellular signal-regulated kinase/p38 kinase. This coincided with reduced cell proliferation, cell survival, and cell invasion in vitro, as well as inhibition of prostate tumor growth and lymph node and lung metastases in vivo. The effect of ho-1 silencing on these oncogenic features was mimicked by exposure of cells to a novel selective small-molecule HO-1 inhibitor referred to as OB-24. OB-24 selectively inhibited HO-1 activity in PCA cells, which correlated with a reduction of protein carbonylation and reactive oxygen species formation. Moreover, OB-24 significantly inhibited cell proliferation in vitro and tumor growth and lymph node/lung metastases in vivo. A potent synergistic activity was observed when OB-24 was combined with Taxol. Together, these results establish HO-1 as a potential therapeutic target for advanced PCA. [Cancer Res 2009;69(20):8017–24]
Height, Body Mass Index, and Physical Activity in Relation to Glioma Risk
Authors: Moore Steven C. , Rajaraman Preetha , Dubrow Robert , Darefsky Amy S. , Koebnick Corinna , Hollenbeck Albert , Schatzkin Arthur , Leitzmann Michael F.
Published: October 2009

Whether energy balance during early life and/or adulthood is related to glioma risk is unknown. We therefore investigated height, body mass index (BMI), and physical activity in relation to glioma risk in the prospective NIH-AARP Diet and Health Study. Participants completed a baseline questionnaire (sent in 1995-1996) inquiring about height, weight, and potential confounders. A second questionnaire (sent in 1996) inquired about physical activity during ages 15 to 18, 19 to 29, and 35 to 39 years and the past 10 years and body weight at ages 18, 35, and 50 years. During follow-up from 1995/1996 to 2003, we documented 480 cases of glioma among 499,437 respondents to the baseline questionnaire and 257 cases among 305,681 respondents to the second questionnaire. Glioma risk among tall persons (≥1.90 m) was twice that of short persons [<1.60 m; multivariate relative risk (RR), 2.12; 95% confidence interval (95% CI), 1.18-3.81; Ptrend = 0.006]. Risk among participants who were obese (BMI 30.0-34.9 kg/m2) at age 18 years was nearly four times that of persons of normal weight (BMI 18.5-24.9 kg/m2) at age 18 years (RR, 3.74; 95% CI, 2.03-6.90; Ptrend = 0.003); 11 cases were obese at age 18 years. Risk among participants who were active during ages 15 to 18 years was 36% lower than that of persons who were inactive during ages 15 to 18 years (RR, 0.64; 95% CI, 0.44-0.93; Ptrend = 0.02). BMI and physical activity after age 18 years were unrelated to glioma risk. Adult height, BMI during adolescence, and physical activity during adolescence were each associated with glioma risk, supporting a role for early-life energy balance in glioma carcinogenesis. [Cancer Res 2009;69(21):8349–55]
Sox11 Prevents Tumorigenesis of Glioma-Initiating Cells by Inducing Neuronal Differentiation
Authors: Hide Takuichiro , Takezaki Tatsuya , Nakatani Yuka , Nakamura Hideo , Kuratsu Jun-ichi , Kondo Toru
Published: October 2009

Recent findings have shown that malignant tumors contain cancer-initiating cells (CIC), which self-renew and are tumorigenic. However, CICs have not been characterized properly due to lack of specific markers. We recently established a mouse glioma cell line, NSCL61, by overexpressing an oncogenic HRasL61 in p53-deficient neural stem cells. Using limiting dilution assays, we show that only 2 of 24 NSCL61 clones retained their tumorigenicity in vivo, although the others also expressed oncogenic HRasL61 and could proliferate in culture. A comparison of the gene expression profiles of tumorigenic and nontumorigenic clones showed that the tumorigenic clones had lost Sox11 expression. We show that overexpression of sox11 prevented tumorigenesis of NSCL61s by inducing their neuronal differentiation accompanied with decreased levels of plagl1. We also show that overexpression of plagl1 abolished neuronal commitment of nontumorigenic cells and induced them to become tumorigenic. Moreover, we show that human glioma-initiating cells lost sox11 expression, and overexpression of sox11 prevented their tumorigenesis in vivo. Together with the clinical evidence showing that downregulation of sox11 mRNA correlates with a significant decrease in survival, these findings suggest that Sox11 prevents gliomagenesis by blocking the expression of oncogenic plagl1. [Cancer Res 2009;69(20):7953–9]
Dose-Ranging Study of Metronomic Oral Vinorelbine in Patients with Advanced Refractory Cancer
Authors: Briasoulis Evangelos , Pappas Periklis , Puozzo Christian , Tolis Christos , Fountzilas George , Dafni Urania , Marselos Marios , Pavlidis Nicholas
Published: October 2009

Aim: To determine the safe dose range and pharmacokinetics of metronomic oral vinorelbine and obtain preliminary data on biomarkers and efficacy in patients with advanced cancer.

Methods: Successive cohorts of patients received escalated doses of oral vinorelbine given thrice a week until disease progression, unacceptable toxicity (UT), or consent withdrawal. UT was any grade 4 toxicity, or grade 2 or 3 toxicity that would result to longer than 2-week break during the first 2 months of treatment. Blood samples were collected for pharmacokinetics and quantification of angiogenesis regulatory proteins.

Results: Sixty-two patients (median age, 60 years) enrolled at six dose levels from 20 to 70 mg and received treatment for median 12.25 weeks (range, 2-216+). Unacceptable toxicity occurred in two of six patients treated at 60 mg (leucopenia grade 4 and epistaxis grade 2) and in one at 70 mg (leucopenia grade 2). The upper metronomic dose was 50 mg. Objective antitumor response documented in eight cases and 32% of patients experienced disease stability for minimum 6 months. Three responders (renal cancer, medullary thyroid carcinoma, and Kaposi sarcoma) received nonstop treatment for over 3 years without overt toxicity. Low pretreatment levels of circulating interleukin-8, vascular endothelial growth factor, and basic fibroblast growth factor were found predictors of efficacy. Steady-state concentrations of vinorelbine and its active metabolite ranged from 0.5 to 1.5 ng/mL.

Conclusions: Metronomic administration of oral vinorelbine is feasible at doses up to 50 mg thrice a week and can yield sustainable antitumor activity without overt toxicity, probably through antiangiogenic mechanism. Further clinical investigation is warranted. (Clin Cancer Res 2009;15(20):6454–61)
An Embryonic Stem Cell–Like Signature Identifies Poorly Differentiated Lung Adenocarcinoma but not Squamous Cell Carcinoma
Authors: Hassan Khaled A. , Chen Guoan , Kalemkerian Gregory P. , Wicha Max S. , Beer David G.
Published: October 2009

Purpose: An embryonic stem cell (ESC) profile correlates with poorly differentiated breast, bladder, and glioma cancers. In this article, we assess the correlation between the ESC profile and clinical variables in lung cancer.

Experimental Design: Microarray gene expression analysis was done using Affymetrix Human Genome U133A on 443 samples of human lung adenocarcinoma and 130 samples of squamous cell carcinoma (SCC). To identify gene set enrichment patterns, we used the Genomica software.

Results: Our analysis showed that an increased expression of the ESC gene set and a decreased expression of the Polycomb target gene set identified poorly differentiated lung adenocarcinoma. In addition, this gene expression signature was associated with markers of poor prognosis and worse overall survival in lung adenocarcinoma. However, there was no correlation between this ESC gene signature and any histologic or clinical variable assessed in lung SCC.

Conclusions: This work suggests that not all poorly differentiated non–small cell lung cancers exhibit a gene expression profile similar to that of ESC, and that other characteristics may play a more important role in the determination of differentiation and survival in SCC of the lung. (Clin Cancer Res 2009;15(20):6386–90)
Identification of Novel Kinase Targets for the Treatment of Estrogen Receptor–Negative Breast Cancer
Authors: Speers Corey , Tsimelzon Anna , Sexton Krystal , Herrick Ashley M. , Gutierrez Carolina , Culhane Aedin , Quackenbush John , Hilsenbeck Susan , Chang Jenny , Brown Powel
Published: October 2009

Purpose: Previous gene expression profiling studies of breast cancer have focused on the entire genome to identify genes differentially expressed between estrogen receptor (ER) α–positive and ER-α–negative cancers.

Experimental Design: Here, we used gene expression microarray profiling to identify a distinct kinase gene expression profile that identifies ER-negative breast tumors and subsets ER-negative breast tumors into four distinct subtypes.

Results: Based on the types of kinases expressed in these clusters, we identify a cell cycle regulatory subset, a S6 kinase pathway cluster, an immunomodulatory kinase–expressing cluster, and a mitogen-activated protein kinase pathway cluster. Furthermore, we show that this specific kinase profile is validated using independent sets of human tumors and is also seen in a panel of breast cancer cell lines. Kinase expression knockdown studies show that many of these kinases are essential for the growth of ER-negative, but not ER-positive, breast cancer cell lines. Finally, survival analysis of patients with breast cancer shows that the S6 kinase pathway signature subtype of ER-negative cancers confers an extremely poor prognosis, whereas patients whose tumors express high levels of immunomodulatory kinases have a significantly better prognosis.

Conclusions: This study identifies a list of kinases that are prognostic and may serve as druggable targets for the treatment of ER-negative breast cancer. (Clin Cancer Res 2009;15(20):6327–40)
Phase I Study of Ipilimumab, an Anti–CTLA-4 Monoclonal Antibody, in Patients with Relapsed and Refractory B-Cell Non–Hodgkin Lymphoma
Authors: Ansell Stephen M. , Hurvitz Sara A. , Koenig Patricia A. , LaPlant Betsy R. , Kabat Brian F. , Fernando Donna , Habermann Thomas M. , Inwards David J. , Verma Meena , Yamada Reiko , Erlichman Charles , Lowy Israel , Timmerman John M.
Published: October 2009

Purpose: The growth of non–Hodgkin lymphomas can be influenced by tumor–immune system interactions. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative regulator of T-cell activation that serves to dampen antitumor immune responses. Blocking anti–CTLA-4 monoclonal antibodies improves host resistance to immunogenic tumors, and the anti–CTLA-4 antibody ipilimumab (MDX-010) has clinical activity against melanoma, prostate, and ovarian cancers.

Experimental Design: We did a phase I trial of ipilimumab in patients with relapsed/refractory B-cell lymphoma to evaluate safety, immunologic activity, and potential clinical efficacy. Treatment consisted of ipilimumab at 3 mg/kg and then monthly at 1 mg/kg × 3 months (dose level 1), with subsequent escalation to 3 mg/kg monthly × 4 months (dose level 2).

Results: Eighteen patients were treated, 12 at the lower dose level and 6 at the higher dose level. Ipilimumab was generally well tolerated, with common adverse events attributed to it, including diarrhea, headache, abdominal pain, anorexia, fatigue, neutropenia, and thrombocytopenia. Two patients had clinical responses; one patient with diffuse large B-cell lymphoma had an ongoing complete response (>31 months), and one with follicular lymphoma had a partial response lasting 19 months. In 5 of 16 cases tested (31%), T-cell proliferation to recall antigens was significantly increased (>2-fold) after ipilimumab therapy.

Conclusions: Blockade of CTLA-4 signaling with the use of ipilimumab is well tolerated at the doses used and has antitumor activity in patients with B-cell lymphoma. Further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted. (Clin Cancer Res 2009;15(20):6446–53)
In vivoeffects of targeting CD79b with antibodies and antibody-drug conjugates
Authors: Zheng Bing , Fuji Reina N. , Elkins Kristi , Yu Shang-Fan , Fuh Franklin K. , Chuh Josefa , Tan Christine , Hongo Jo-Anne , Raab Helga , Kozak Katherine R. , Williams Marna , McDorman Elena , Eaton Dan , Ebens Allen , Polson Andrew G.
Published: October 2009

Antibodies directed against B cells are in use for the treatment of non-Hodgkin's lymphoma and autoimmune disorders. The B-cell–restricted surface antigen CD79b, a signaling component of the B-cell receptor, has been shown as a promising antibody target in mouse efficacy models of systemic lupus erythematosus. Anti-CD79b antibody-drug conjugates (ADC), cytotoxic drugs linked through specialized chemical linkers to antibodies, are effective in mouse xenograft models of non-Hodgkin's lymphoma. We were interested in evaluating the systemic effects of anti-CD79b antibodies and ADCs in normal animals as a step toward the development of these molecules as therapeutics. As we were unable to identify any cell surface binding anti-human CD79b antibodies that were cross-reactive to other species, we developed an antibody to cynomolgus monkey (Macaca fascicularis) CD79b (anti-cyCD79b). The anti-cynomolgus antibody, anti-cyCD79b (10D10), and the maytansine (tubulin inhibitor)–conjugated ADC, anti-cyCD79b (10D10)-MCC-DM1, were administered to cynomolgus monkeys at ∼30 mg/kg (6,000 μg DM1/m2) for two doses 3 weeks apart. Anti-cyCD79b and anti-cyCD79b-MCC-DM1 resulted in peripheral blood B-cell depletion of ∼65% and ∼94%, respectively. In addition, anti-cyCD79b-MCC-DM1 resulted in near-complete absence of splenic germinal centers, an observation supporting an effect on dividing B cells. Both molecules were well tolerated, with minimal findings for the antibody and findings for the ADC limited to the lymphoid and hematopoietic systems, liver, and peripheral nerves. These preclinical data suggest that targeting CD79b with antibodies or ADCs may provide safe and effective therapies for B-cell malignancies and autoimmune diseases. [Mol Cancer Ther 2009;8(10):2937–46]
Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion
Authors: Golding Sarah E. , Rosenberg Elizabeth , Valerie Nicholas , Hussaini Isa , Frigerio Mark , Cockcroft Xiaoling F. , Chong Wei Yee , Hummersone Marc , Rigoreau Laurent , Menear Keith A. , O'Connor Mark J. , Povirk Lawrence F. , van Meter Timothy , Valerie Kristoffer
Published: October 2009

Ataxia telangiectasia (A-T) mutated (ATM) is critical for cell cycle checkpoints and DNA repair. Thus, specific small molecule inhibitors targeting ATM could perhaps be developed into efficient radiosensitizers. Recently, a specific inhibitor of the ATM kinase, KU-55933, was shown to radiosensitize human cancer cells. Herein, we report on an improved analogue of KU-55933 (KU-60019) with Ki and IC50 values half of those of KU-55933. KU-60019 is 10-fold more effective than KU-55933 at blocking radiation-induced phosphorylation of key ATM targets in human glioma cells. As expected, KU-60019 is a highly effective radiosensitizer of human glioma cells. A-T fibroblasts were not radiosensitized by KU-60019, strongly suggesting that the ATM kinase is specifically targeted. Furthermore, KU-60019 reduced basal S473 AKT phosphorylation, suggesting that the ATM kinase might regulate a protein phosphatase acting on AKT. In line with this finding, the effect of KU-60019 on AKT phosphorylation was countered by low levels of okadaic acid, a phosphatase inhibitor, and A-T cells were impaired in S473 AKT phosphorylation in response to radiation and insulin and unresponsive to KU-60019. We also show that KU-60019 inhibits glioma cell migration and invasion in vitro, suggesting that glioma growth and motility might be controlled by ATM via AKT. Inhibitors of MEK and AKT did not further radiosensitize cells treated with KU-60019, supporting the idea that KU-60019 interferes with prosurvival signaling separate from its radiosensitizing properties. Altogether, KU-60019 inhibits the DNA damage response, reduces AKT phosphorylation and prosurvival signaling, inhibits migration and invasion, and effectively radiosensitizes human glioma cells. [Mol Cancer Ther 2009;8(10):2894–902]