bluuebunny/crossref_metadata_2025 huggingface dataset:
Manatee position estimation by passive acoustic localization
Authors: Buaka Muanke Paulin , Niezrecki Christopher
Published: April 2007

Passive sound source localization with sensor arrays is based on the estimation of the time difference of arrival (TDOA), and precise TDOA is required to achieve accurate position estimation. For a majority of practical localization systems (based on TDOA estimation with four sensors in two dimensions), only three time delays are computed to determine the location of interest. This paper presents an approach to determine the position of a manatee by using four hydrophones and all the combinations of the TDOAs available. With four hydrophones, six TDOAs are computed and then combined three by three to get 20 possible points for each position to estimate. Experimental results using the Hilbert envelope peak technique to estimate the TDOAs and the least square method to estimate the position are presented. For the tests conducted it is shown that for a manatee call having a high signal-to-noise ratio, the individual position estimated for each of the 20 combinations of TDOAs lies on a straight line, providing a good estimation of the direction of arrival approximately 85% of the time. However, a good estimation of the position is obtained for a manatee near the hydrophone array approximately 55% of the time.
Wave propagation along transversely periodic structures
Authors: Predoi Mihai V. , Castaings Michel , Hosten Bernard , Bacon Christophe
Published: April 2007

The dispersion curves for guided waves have been of constant interest in the last decades, because they constitute the starting point for NDE ultrasonic applications. This paper presents an evolution of the semianalytical finite element method, and gives examples that illustrate new improvements and their importance for studying the propagation of waves along periodic structures of infinite width. Periodic boundary conditions are in fact used to model the infinite periodicity of the geometry in the direction normal to the direction of propagation. This method allows a complete investigation of the dispersion curves and of displacement ∕ stress fields for guided modes in anisotropic and absorbing periodic structures. Among other examples, that of a grooved aluminum plate is theoretically and experimentally investigated, indicating the presence of specific and original guided modes.
Noise within the social context: Annoyance reduction through fair procedures
Authors: Maris Eveline , Stallen Pieter J. , Vermunt Riel , Steensma Herman
Published: April 2007

The social context of noise exposure is a codeterminant of noise annoyance. The present study shows that fairness of the exposure procedure (sound management) can be used as an instrument to reduce noise annoyance. In a laboratory experiment (N=117) participants are exposed to aircraft sound of different sound pressure level (SPL: 50 vs 70dBA)—which is experienced as noise—while they work on a reading task. The exposure procedure (fair versus neutral) is modeled in line with findings from social justice theory. In the fair condition, participants can voice their preference for a certain sound sample, although they cannot deduce whether their preference is granted. In the neutral condition, participants are not asked to voice their preference. Results show the predicted interaction effect of sound pressure level and procedure on annoyance: Annoyance ratings are significantly lower in the fair condition than in the neutral condition, but this effect is found only in the 70dB condition. When the SPL is considerably disturbing, fair procedures reduce noise annoyance. Consequences of the reported findings for both theory and practice are discussed.
Finite-bandwidth Kramers-Kronig relations for acoustic group velocity and attenuation derivative applied to encapsulated microbubble suspensions
Authors: Mobley Joel
Published: April 2007

Kramers-Kronig (KK) analyses of experimental data are complicated by the conflict between the inherently bandlimited data and the requirement of KK integrals for a complete infinite spectrum of input information. For data exhibiting localized extrema, KK relations can provide accurate transforms over finite bandwidths due to the local-weighting properties of the KK kernel. Recently, acoustic KK relations have been derived for the determination of the group velocity (cg) and the derivative of the attenuation coefficient (α′) (components of the derivative of the acoustic complex wave number). These relations are applicable to bandlimited data exhibiting resonant features without extrapolation or unmeasured parameters. In contrast to twice-subtracted finite-bandwidth KK predictions for phase velocity and attenuation coefficient (components of the undifferentiated wave number), these more recently derived relations for cg and α′ provide stricter tests of causal consistency because the resulting shapes are invariant with respect to subtraction constants. The integrals in these relations can be formulated so that they only require the phase velocity and attenuation coefficient data without differentiation. Using experimental data from suspensions of encapsulated microbubbles, the finite-bandwidth KK predictions for cg and α′ are found to provide an accurate mapping of the primary wave number quantities onto their derivatives.
Sensitivity of a continuum vocal fold model to geometric parameters, constraints, and boundary conditions
Authors: Cook Douglas D. , Mongeau Luc
Published: April 2007

The influence of key dimensional parameters, motion constraints, and boundary conditions on the modal properties of an idealized, continuum model of the vocal folds was investigated. The Ritz method and the finite element method were used for the analysis. The model’s vibratory modes were determined to be most sensitive to changes in the anterior-posterior length of the vocal fold model, due to the influence of three-dimensional stress components acting in the transverse plane. Anterior/posterior boundary conditions were found to have a significant influence on the vibratory response. Overestimation of modal frequencies resulted when vibration of the structure was restricted to the transverse plane. The overestimation of each modal frequency was proportional to the ratio of longitudinal to transverse Young’s modulus, and was significant for ratio values less than 20.
Time reversal imaging for sensor networks with optimal compensation in time
Authors: Derveaux Grégoire , Papanicolaou George , Tsogka Chrysoula
Published: April 2007

Using extensive numerical simulations, several distributed sensor imaging algorithms for localized damage in a structure are analyzed. Given a configuration of ultrasonic transducers, a full response matrix for the healthy structure is assumed known. It is used as a basis for comparison with the response matrix that is recorded when there is damage. Numerical simulations are done with the wave equation in two dimensions. The healthy structure contains many scatterers. The aim is to image point-like defects with several regularly distributed sensors. Because of the complexity of the environment, the recorded traces have a lot of delay spread and travel time migration does not work so well. Instead, the traces are back propagated numerically assuming that there is some knowledge of the background. Since the time at which the back propagated field will focus on the defects is unknown, the Shannon entropy or the bounded variation norm of the image is computed and the time where it is minimal is picked. This imaging method performs well because it produces a tight image near the location of the defects at the time of refocusing. When there are several defects, the singular value decomposition of the response matrix is also carried out.
Sensitivity to binaural timing in bilateral cochlear implant users
Authors: van Hoesel Richard J. M.
Published: April 2007

Various measures of binaural timing sensitivity were made in three bilateral cochlear implant users, who had demonstrated moderate-to-good interaural time delay (ITD) sensitivity at 100pulses-per-second (pps). Overall, ITD thresholds increased at higher pulse rates, lower levels, and shorter durations, although intersubject differences were evident. Monaural rate-discrimination thresholds, using the same stimulation parameters, showed more substantial elevation than ITDs with increased rate. ITD sensitivity with 6000pps stimuli, amplitude-modulated at 100Hz, was similar to that with unmodulated pulse trains at 100pps, but at 200 and 300Hz performance was poorer than with unmodulated signals. Measures of sensitivity to binaural beats with unmodulated pulse-trains showed that all three subjects could use time-varying ITD cues at 100pps, but not 300pps, even though static ITD sensitivity was relatively unaffected over that range. The difference between static and dynamic ITD thresholds is discussed in terms of relative contributions from initial and later arriving cues, which was further examined in an experiment using two-pulse stimuli as a function of interpulse separation. In agreement with the binaural-beat data, findings from that experiment showed poor discrimination of ITDs on the second pulse when the interval between pulses was reduced to a few milliseconds.
Speaker-independent factors affecting the perception of foreign accent in a second language
Authors: Levi Susannah V. , Winters Stephen J. , Pisoni David B.
Published: April 2007

Previous research on foreign accent perception has largely focused on speaker-dependent factors such as age of learning and length of residence. Factors that are independent of a speaker’s language learning history have also been shown to affect perception of second language speech. The present study examined the effects of two such factors—listening context and lexical frequency—on the perception of foreign-accented speech. Listeners rated foreign accent in two listening contexts: auditory-only, where listeners only heard the target stimuli, and auditory+orthography, where listeners were presented with both an auditory signal and an orthographic display of the target word. Results revealed that higher frequency words were consistently rated as less accented than lower frequency words. The effect of the listening context emerged in two interactions: the auditory+orthography context reduced the effects of lexical frequency, but increased the perceived differences between native and non-native speakers. Acoustic measurements revealed some production differences for words of different levels of lexical frequency, though these differences could not account for all of the observed interactions from the perceptual experiment. These results suggest that factors independent of the speakers’ actual speech articulations can influence the perception of degree of foreign accent.
Semantic and phonetic enhancements for speech-in-noise recognition by native and non-native listeners
Authors: Bradlow Ann R. , Alexander Jennifer A.
Published: April 2007

Previous research has shown that speech recognition differences between native and proficient non-native listeners emerge under suboptimal conditions. Current evidence has suggested that the key deficit that underlies this disproportionate effect of unfavorable listening conditions for non-native listeners is their less effective use of compensatory information at higher levels of processing to recover from information loss at the phoneme identification level. The present study investigated whether this non-native disadvantage could be overcome if enhancements at various levels of processing were presented in combination. Native and non-native listeners were presented with English sentences in which the final word varied in predictability and which were produced in either plain or clear speech. Results showed that, relative to the low-predictability-plain-speech baseline condition, non-native listener final word recognition improved only when both semantic and acoustic enhancements were available (high-predictability-clear-speech). In contrast, the native listeners benefited from each source of enhancement separately and in combination. These results suggests that native and non-native listeners apply similar strategies for speech-in-noise perception: The crucial difference is in the signal clarity required for contextual information to be effective, rather than in an inability of non-native listeners to take advantage of this contextual information per se.
Consonant and vowel confusions in speech-weighted noise
Authors: Phatak Sandeep A. , Allen Jont B.
Published: April 2007

This paper presents the results of a closed-set recognition task for 64 consonant-vowel sounds (16C×4V, spoken by 18 talkers) in speech-weighted noise (−22,−20,−16,−10,−2[dB]) and in quiet. The confusion matrices were generated using responses of a homogeneous set of ten listeners and the confusions were analyzed using a graphical method. In speech-weighted noise the consonants separate into three sets: a low-scoring set C1 (/f/, /θ/, /v/, /ð/, /b/, /m/), a high-scoring set C2 (/t/, /s/, /z/, /ʃ/, /ʒ/) and set C3 (/n/, /p/, /g/, /k/, /d/) with intermediate scores. The perceptual consonant groups are C1: { /f/-/θ/, /b/-/v/-/ð/, /θ/-/ð/ }, C2: { /s/-/z/, /ʃ/-/ʒ/ }, and C3: /m/-/n/, while the perceptual vowel groups are /ɑ/-/æ/ and /ε/-/ɪ/. The exponential articulation index (AI) model for consonant score works for 12 of the 16 consonants, using a refined expression of the AI. Finally, a comparison with past work shows that white noise masks the consonants more uniformly than speech-weighted noise, and shows that the AI, because it can account for the differences in noise spectra, is a better measure than the wideband signal-to-noise ratio for modeling and comparing the scores with different noise maskers.
Age, sex, and vowel dependencies of acoustic measures related to the voice source
Authors: Iseli Markus , Shue Yen-Liang , Alwan Abeer
Published: April 2007

The effects of age, sex, and vocal tract configuration on the glottal excitation signal in speech are only partially understood, yet understanding these effects is important for both recognition and synthesis of speech as well as for medical purposes. In this paper, three acoustic measures related to the voice source are analyzed for five vowels from 3145 CVC utterances spoken by 335 talkers (8–39years old) from the CID database [Miller et al., Proceedings of ICASSP, 1996, Vol. 2, pp. 849–852]. The measures are: the fundamental frequency (F0), the difference between the “corrected” (denoted by an asterisk) first two spectral harmonic magnitudes, H1*−H2* (related to the open quotient), and the difference between the “corrected” magnitudes of the first spectral harmonic and that of the third formant peak, H1*−A3* (related to source spectral tilt). The correction refers to compensating for the influence of formant frequencies on spectral magnitude estimation. Experimental results show that the three acoustic measures are dependent to varying degrees on age and vowel. Age dependencies are more prominent for male talkers, while vowel dependencies are more prominent for female talkers suggesting a greater vocal tract-source interaction. All talkers show a dependency of F0 on sex and on F3, and of H1*−A3* on vowel type. For low-pitched talkers (F0⩽175Hz), H1*−H2* is positively correlated with F0 while for high-pitched talkers, H1*−H2* is dependent on F1 or vowel height. For high-pitched talkers there were no significant sex dependencies of H1*−H2* and H1*−A3*. The statistical significance of these results is shown.
Temporal limits of level dominance in a sample discrimination task
Authors: Turner Matthew D. , Berg Bruce G.
Published: April 2007

Level dominance refers to the effect where attention is automatically directed to the loudest part of an auditory display. In a sample discrimination task, the frequencies of five 50ms tones were sampled from normal distributions with means of 1000 and 1100Hz and presented sequentially, with the tones alternating in intensity. Observers decide from which distribution the sample was drawn. The informativeness of the even numbered tones (d′=2) was greater than the informativeness of the odd numbered tones (d′=1). Estimates of decision weights and performance levels (d′) show that when the more informative tones were less intense, observers attended to the louder tones rather than the more informative tones. This effect extends well beyond the temporal limits expected from forward masking studies.
Using cross correlations of turbulent flow-induced ambient vibrations to estimate the structural impulse response. Application to structural health monitoring
Authors: Sabra Karim G. , Winkel Eric S. , Bourgoyne Dwayne A. , Elbing Brian R. , Ceccio Steve L. , Perlin Marc , Dowling David R.
Published: April 2007

It has been demonstrated theoretically and experimentally that an estimate of the impulse response (or Green’s function) between two receivers can be obtained from the cross correlation of diffuse wave fields at these two receivers in various environments and frequency ranges: ultrasonics, civil engineering, underwater acoustics, and seismology. This result provides a means for structural monitoring using ambient structure-borne noise only, without the use of active sources. This paper presents experimental results obtained from flow-induced random vibration data recorded by pairs of accelerometers mounted within a flat plate or hydrofoil in the test section of the U.S. Navy’s William B. Morgan Large Cavitation Channel. The experiments were conducted at high Reynolds number (Re>50 million) with the primary excitation source being turbulent boundary layer pressure fluctuations on the upper and lower surfaces of the plate or foil. Identical deterministic time signatures emerge from the noise cross-correlation function computed via robust and simple processing of noise measured on different days by a pair of passive sensors. These time signatures are used to determine and/or monitor the structural response of the test models from a few hundred to a few thousand Hertz.
How to take deontological concerns seriously in risk–cost–benefit analysis: a re-interpretation of the precautionary principle
Authors: John S D
Published: March 2007

In this paper the coherence of the precautionary principle as a guide to public health policy is considered. Two conditions that any account of the principle must meet are outlined, a condition of practicality and a condition of publicity. The principle is interpreted in terms of a tripartite division of the outcomes of action (good outcomes, normal bad outcomes and special bad outcomes). Such a division of outcomes can be justified on either “consequentialist” or “deontological” grounds. In the second half of the paper, it is argued that the precautionary principle is not necessarily opposed to risk–cost–benefit analysis, but, rather, should be interpreted as suggesting a lowering of our epistemic standards for assessing evidence that there is a link between some policy and “special bad” outcomes. This suggestion is defended against the claim that it mistakes the nature of statistical testing and against the charge that it is unscientific or antiscientific, and therefore irrational.
Consent gained from patients after breast surgery for the use of surplus tissue in research: an exploration: Table 1
Authors: Hamilton S , Hepper J , Hanby A , Hewison J
Published: March 2007

Objectives:(1) To investigate the quality of consent gained for the use in research of tissue that is surplus after surgery. (2) To compare the use of two consent forms: a simple locally introduced form and a more complex centrally instigated form. (3) To discuss the attitudes of patients towards the use of their surplus tissue in research.

Design:Data were collected through interviews and analysed with a combination of quantitative and qualitative analytical techniques.

Participants and setting:Patients of the breast care unit at a teaching hospital were interviewed at home or in a quiet room at the hospital.

Results:57 people were interviewed out of 81 approached, between October 2003 and March 2004. Most participants had a poor level of knowledge about the consent they had given, but reported being happy about having given it. The patients who had signed the locally introduced form had considerably more knowledge than those who had signed the centrally instigated form (z = −2.56; p<0.05). Participants considered being well informed to be less important than believing that their opinions were valued and respected.

Conclusions:The findings suggest that traditional models of informed consent are not universally applicable and, in this case, seem to overstate what people wish to know. The simple consent form achieved a better quality of informed consent and provided a better model of practice than the complex form, and it seemed that a focused approach to consent seeking is more effective and acceptable than more complex approaches.
A good death certificate: improved performance by simple educational measures
Authors: Selinger Christian P , Ellis Robert A , Harrington Mary G
Published: April 2007

Background and aims

The initial aim of this audit was to determine whether information on death certificates is correct and all legal requirements are met. As shortcomings were found, educational measures were undertaken and the effect of those was measured by a re-audit.

Method

All death certificates issued during a 4-month period within the elderly care department of a district general hospital were retrospectively audited. A re-audit was performed later the same year over a 3-month period.

Results

19 (13.6%) of 140 certificates issued during the initial 4-month period could not be shown to meet the statutory criteria, as no evidence was found that these patients were attended by the issuing medical officer. Minor errors and omissions were found in 58.6% of certificates. Following education about these problems, there was a significant improvement in death certification. Only 2 (2.4%) of 85 certificates issued in the re-audit period did not meet the statutory criteria (p = 0.01) and minor errors and omissions occurred in 20%.

Conclusion

The incidence of unsatisfactory death certificates within a hospital setting is high. Increased education and better documentation leads to improvements in accuracy and legitimacy.
Sociodemographic and psychosocial correlates of smoking-induced deprivation and its effect on quitting: findings from the International Tobacco Control Policy Evaluation Survey
Authors: Siahpush Mohammad , Borland Ron , Yong Hua-Hie
Published: March 2007

Aims:To determine the prevalence and characteristics of smokers who experience smoking-induced deprivation (SID), and to examine its effect on quit attempts, relapse and cessation.

Methods:Waves 2 and 3 (2003–5) of the International Tobacco Control Policy Evaluation Survey were used, which is a prospective study of a cohort of smokers in the US, Canada, UK and Australia. SID was measured with the question “In the last six months, have you spent money on cigarettes that you knew would be better spent on household essentials like food?” A total of 7802 smokers participated in the survey in wave 2, of whom 5408 were also interviewed in wave 3.

Findings:The proportion of smokers who reported SID was highest in Australia (33%) and lowest in the UK (20%). Younger age, minority status and low income were associated with a higher probability of SID. Some of the other factors related to a higher probability of SID were higher level of nicotine dependence, having an intention to quit, and smoking to help one socialise or control weight. The relationship between SID and quit attempt was mediated by having an intention to quit and worrying that smoking would damage health and reduce the quality of life. The relationship between SID and relapse was mediated by perceived stress. SID was not associated with successful cessation.

Conclusions:Many smokers experience deprivation that is the result of their smoking. Strategies to reduce the prevalence of smoking probably effect a general improvement in standards of living and reduction in deprivation.
TOPOLOGICAL STRUCTURE AND EVOLUTION OF SPACE–TIME DISLOCATIONS AND DISCLINATIONS
Authors: DUAN Y. S. , ZHAO L.
Published: April 2007

By making use of the gauge potential decomposition theory and ϕ-mapping theory, the topological structure and the topological quantization of dislocations and disclinations are studied in the framework of Riemann–Cartan space–time manifold. The evolution of dislocation strings and disclination points is also studied from the topological properties of the order parameter field. The dislocations and disclinations are found generating or annihilating at the limit points and encountering, splitting, or merging at the bifurcation points of the order parameter field.
DUAL PERTURBATION EXPANSION FOR A CLASSICAL λϕ4 FIELD THEORY
Authors: FRASCA MARCO
Published: April 2007

We prove the existence of a strong coupling expansion for a classical λϕ4 field theory in agreement with the duality principle in perturbation theory put forward in a paper: M. Frasca, Phys. Rev. A58, 3439 (1998). The leading order solution is a snoidal wave taking the place of plane waves of the free theory. We compute the first-order correction and show that higher-order terms do renormalize the leading order solution.
THE ASSOCIATION OF SCAPHO-TRAPEZIO-TRAPEZOID OSTEOARTHROSIS AND SCAPHOLUNATE DISSOCIATION
Authors: Roberts C. , Porter M. , Wines A. P. , Shadbolt B.
Published: April 2007

There are two parts to this paper. In the first part we report 18 cases of bilateral scapho-trapezio-trapezoid osteoarthrosis associated with uni- or bilateral scapholunate dissociation. This case series was followed prospectively using repeat clinical assessments and radiographs. We were able to document the progression of both the clinical manifestations and radiographic features of the scapholunate dissociation in these patients. In the second part of the paper we compared the radiographic indices of scapholunate dissociation seen in our series, that is, the scapholunate angle and interval, with those of a control group over time, to determine if there was a significant difference. The control group differed from our series principally by being devoid of any clinical or radiographic evidence of scapho-trapezio-trapezoid osteoarthrosis. We found that our case series already had some radiographic evidence of scapholunate attrition at presentation and that at follow-up the scapholunate dissociation became more pronounced both clinically and radiographically relative to the controls. The authors propose a theory to explain the association and temporal relationship between the two conditions.
β-2-Microglobulin Is an Androgen-Regulated Secreted Protein Elevated in Serum of Patients with Advanced Prostate Cancer
Authors: Gross Mitchell , Top Irina , Laux Isett , Katz Jonathan , Curran John , Tindell Charles , Agus David
Published: April 2007

Purpose: A better understanding of secreted proteins may lead to the discovery of new biomarkers, which, along with prostate-specific antigen (PSA), may be useful in the diagnosis and treatment of prostate cancer patients.

Experimental Design: Conditioned medium was collected from LNCaP cells following stimulation with methyltrienolone (R1881), 17β-estradiol (estradiol), or interleukin-6 and analyzed for differential protein expression with surface-enhanced laser desorption/ionization-time of flight mass spectrometry. Quantitative reverse transcription-PCR, immunoblots, and ELISA were used to measure β-2-microglobulin (B2M) message and protein levels in cells, conditioned medium, and serum.

Results: Surface-enhanced laser desorption/ionization-time of flight revealed that many peaks were induced or repressed following stimulation with R1881 or estradiol. A peak of interest centered at 11.8 kDa was chosen for additional analysis. Immunodepletion identified the peak of interest as B2M. Reverse transcription-PCR and immunoblots confirmed that PSA and B2M were induced by R1881. However, unlike PSA, B2M was not increased on stimulation with estradiol or interleukin-6. Human B2M is identified in the serum of mice bearing human prostate cancer xenograft. B2M is expressed in human prostate cancer cell lines and tissues. Serum B2M levels are elevated in patients with metastatic, androgen-independent prostate cancer.

Conclusions: B2M is a secreted protein expressed in prostate cancer, which is more specific for androgen stimulation than PSA under the conditions tested. Additional studies are warranted to explore if B2M is as useful marker for prostate cancer. Identification of proteins secreted from cancer cells in preclinical models may be a useful strategy for biomarker discovery.
The Therapeutic and Preventive Effect of RRR-α-Vitamin E Succinate on Prostate Cancer via Induction of Insulin-Like Growth Factor Binding Protein-3
Authors: Yin Yi , Ni Jing , Chen Ming , DiMaggio Matthew A. , Guo Yinglu , Yeh Shuyuan
Published: April 2007

Purpose: Insulin-like growth factor binding protein-3 (IGFBP-3) is a well-known antiproliferative and proapoptotic molecule in prostate cancer, suggesting that targeting IGFBP-3 might produce clinical benefits. In prostate cancer cells, RRR-α-vitamin E succinate (VES) inhibits cell proliferation and induces apoptosis, yet the mechanisms remain to be elucidated. We hypothesize that the protective effects of VES in prostate cancer are mediated by IGFBP-3 up-regulation. Using prostate cancer models, the involvement of IGFBP-3 in the anticancer effect of VES was investigated.

Experimental Design: IGFBP-3 mRNA and protein were determined by real-time PCR and Western blotting in prostate cancer cells, xenografted tumors of nude mice, and prostate tumors of transgenic adenocarcinoma mouse prostate (TRAMP) mice. The serum levels of IGFBP-3 were assessed by ELISA. The importance of IGFBP-3 in VES-mediated antitumor effects was confirmed by small interfering RNA knockdown strategy.

Results: We found that VES induced IGFBP-3 mRNA and protein levels in human prostate cancer cell lines. Knockdown of IGFBP-3 by small interfering RNA attenuated VES-induced IGFBP-3 expression and VES-mediated antiproliferative and proapoptotic functions. Furthermore, administration of VES resulted in a significant therapeutic effect on LNCaP and PC3 xenografts and a preventive effect on tumorigenic progression in the TRAMP model without overt toxicity. Notably, the therapeutic and preventive efficacy of VES correlated with increased accumulation of IGFBP-3 in mouse serum as well as in the xenograft tumors and TRAMP prostate samples. Consequently, reduced proliferation and induced apoptosis were witnessed.

Conclusions: VES mediates its therapeutic and preventive effects against prostate cancer at least partially through up-regulating IGFBP-3, which inhibits cell proliferation and promotes cell apoptosis.
A Phase I Pharmacokinetic and Pharmacodynamic Study of S-3304, a Novel Matrix Metalloproteinase Inhibitor, in Patients with Advanced and Refractory Solid Tumors
Authors: Chiappori Alberto A. , Eckhardt S. Gail , Bukowski Ronald , Sullivan Daniel M. , Ikeda Minoru , Yano Yoshitaka , Yamada-Sawada Takuko , Kambayashi Yoshikaze , Tanaka Kazushige , Javle Milind M. , Mekhail Tarek , O'Bryant Cindy L. , Creaven Patrick J.
Published: April 2007

Purpose: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers.

Experimental Design: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival.

Results: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean Cmax and AUC0-8 increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase.

Conclusion: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.
The Therapeutic Potential of Hepatocyte Growth Factor to Sensitize Ovarian Cancer Cells to Cisplatin and Paclitaxel In vivo
Authors: Bardella Chiara , Dettori Daniela , Olivero Martina , Coltella Nadia , Mazzone Massimiliano , Di Renzo Maria Flavia
Published: April 2007

Purpose: Advanced ovarian cancers are initially responsive to combinatorial chemotherapy with platinum drugs and taxanes but, in most cases, develop drug resistance. We recently showed that, in vitro, hepatocyte growth factor (HGF) enhances death of human ovarian cancer cell lines treated with cisplatin (CDDP) and paclitaxel. The present study addresses whether in vivo HGF makes ovarian carcinoma cells more responsive to these chemotherapeutics.

Experimental Design: Using Lentiviral vectors carrying the HGF transgene, we transduced SK-OV-3 and NIH:OVCAR-3 ovarian carcinoma cell lines to obtain stable autocrine and paracrine HGF receptor activation. In vitro, we assayed growth, motility, invasiveness, and the response to CDDP and paclitaxel of the HGF-secreting bulk unselected cell populations. In vivo, we tested the cytotoxic effects of the drugs versus s.c. tumors formed by the wild-type and HGF-secreting cells in immunocompromised mice. Tumor-bearing mice were treated with CDDP (i.p.) and paclitaxel (i.v.), combined in different schedules and doses.

Results: In vitro, HGF-secreting cells did not show altered proliferation rates and survival but were strongly sensitized to the death triggered by CDDP and paclitaxel, alone or in combination. In vivo, we found a therapeutic window in which autocrine/paracrine HGF made tumors sensitive to low doses of the drugs, which were ineffective on their own.

Conclusions: These data provide the proof-of-concept that in vivo gene therapy with HGF might be competent in sensitizing ovarian cancer cells to conventional chemotherapy.
Tumor-Infiltrating Foxp3−CD4+CD25+ T Cells Predict Poor Survival in Renal Cell Carcinoma
Authors: Siddiqui Sameer A. , Frigola Xavier , Bonne-Annee Sandra , Mercader Maria , Kuntz Susan M. , Krambeck Amy E. , Sengupta Shomik , Dong Haidong , Cheville John C. , Lohse Christine M. , Krco Christopher J. , Webster W. Scott , Leibovich Bradley C. , Blute Michael L. , Knutson Keith L. , Kwon Eugene D.
Published: April 2007

Purpose: Regulatory T cells (Tregs) have been implicated as inhibitors of antitumoral immunity, and evidence suggests that elimination of Tregs may augment natural and pharmacologic immunity. We tested for the presence of putative Tregs within renal cell carcinoma (RCC) tumors.

Experimental Design: We identified 170 patients who underwent radical or partial nephrectomy for clear cell RCC between 2000 and 2002. Specimens were stained with anti-CD4, anti-CD25, and anti-Foxp3 antibodies and examined using confocal microscopy. Associations of CD4+CD25+Foxp3− and CD4+CD25+Foxp3+ T cells with death from RCC were evaluated using Cox proportional hazards regression models.

Results: At last follow-up, 46 of 170 patients had died; of these, 37 died from RCC at a median of 1.4 years following nephrectomy (range, 0-4.4). Among the 124 remaining patients, median follow-up was 3.7 years (range, 0-5.7). Forty-three (25.3%) tumors harbored CD4+CD25+Foxp3+ T cells. The presence of Foxp3+ T cells was not significantly associated with RCC death univariately. One hundred forty-three (84.1%) tumors harbored CD4+CD25+Foxp3− T cells. The indicator for ≥10% CD4+CD25+Foxp3− T cells was significantly associated with RCC death univariately [risk ratio (RR), 2.60; 95% confidence interval (95% CI), 1.35-4.98; P = 0.004], after adjusting for tumor B7-H1 expression (RR, 2.53; 95% CI, 1.32-4.85; P = 0.005) and lymphocytic infiltration (RR, 2.53; 95% CI, 1.32-4.87; P = 0.005).

Conclusions: Increased presence of CD4+CD25+Foxp3+ T cells was not significantly associated with RCC death. In contrast, CD4+CD25+Foxp3− T cells, which may represent a unique set of Tregs or activated helper T cells, was significantly associated with outcome.
Loss of the Mismatch Repair Protein MSH6 in Human Glioblastomas Is Associated with Tumor Progression during Temozolomide Treatment
Authors: Cahill Daniel P. , Levine Kymberly K. , Betensky Rebecca A. , Codd Patrick J. , Romany Candice A. , Reavie Linsey B. , Batchelor Tracy T. , Futreal P. Andrew , Stratton Michael R. , Curry William T. , Iafrate A. John , Louis David N.
Published: April 2007

Purpose: Glioblastomas are treated by surgical resection followed by radiotherapy [X-ray therapy (XRT)] and the alkylating chemotherapeutic agent temozolomide. Recently, inactivating mutations in the mismatch repair gene MSH6 were identified in two glioblastomas recurrent post-temozolomide. Because mismatch repair pathway inactivation is a known mediator of alkylator resistance in vitro, these findings suggested that MSH6 inactivation was causally linked to these two recurrences. However, the extent of involvement of MSH6 in glioblastoma is unknown. We sought to determine the overall frequency and clinical relevance of MSH6 alterations in glioblastomas.

Experimental Design: The MSH6 gene was sequenced in 54 glioblastomas. MSH6 and O6-methylguanine methyltransferase (MGMT) immunohistochemistry was systematically scored in a panel of 46 clinically well-characterized glioblastomas, and the corresponding patient response to treatment evaluated.

Results: MSH6 mutation was not observed in any pretreatment glioblastoma (0 of 40), whereas 3 of 14 recurrent cases had somatic mutations (P = 0.015). MSH6 protein expression was detected in all pretreatment (17 of 17) cases examined but, notably, expression was lost in 7 of 17 (41%) recurrences from matched post–XRT + temozolomide cases (P = 0.016). Loss of MSH6 was not associated with O6-methylguanine methyltransferase status. Measurements of in vivo tumor growth using three-dimensional reconstructed magnetic resonance imaging showed that MSH6-negative glioblastomas had a markedly increased rate of growth while under temozolomide treatment (3.17 versus 0.04 cc/mo for MSH6-positive tumors; P = 0.020).

Conclusions: Loss of MSH6 occurs in a subset of post–XRT + temozolomide glioblastoma recurrences and is associated with tumor progression during temozolomide treatment, mirroring the alkylator resistance conferred by MSH6 inactivation in vitro. MSH6 deficiency may therefore contribute to the emergence of recurrent glioblastomas during temozolomide treatment.
Stromal Myofibroblasts Predict Disease Recurrence for Colorectal Cancer
Authors: Tsujino Tadashi , Seshimo Iwao , Yamamoto Hirofumi , Ngan Chew Yee , Ezumi Koji , Takemasa Ichiro , Ikeda Masataka , Sekimoto Mitsugu , Matsuura Nariaki , Monden Morito
Published: April 2007

Purpose: Myofibroblasts, which are specifically differentiated fibroblasts, are thought to play a central role in the desmoplastic reaction, a dynamic stromal change closely associated with cancer development. Although fundamental studies suggest that myofibroblasts may either facilitate or inhibit cancer progression, cumulative evidence supports their role in promoting tumor progression. The aim of this study was to assess the value of myofibroblasts in the cancer stroma as an indicator of disease recurrence after colorectal cancer surgery.

Experimental Design: Using computer-assisted image analysis, we quantified myofibroblasts in the cancer-associated stroma of 192 colorectal cancers using α-smooth muscle actin as a marker.

Results: The cancer-associated stroma contained various numbers of myofibroblasts (0.35-19.0%; mean, 5.55 ± 3.85%). Tumors with abundant myofibroblasts were associated with shorter disease-free survival rate (P = 0.001) for stage II and III colorectal cancer. Multivariate analysis indicated that α-smooth muscle actin was a significant prognostic factor comparable with lymph node metastasis and superior to other tumor and stromal components, including histology of the tumor invasive front, peritumoral lymphocytic infiltration, and Crohn's-like lymphoid reaction. Moreover, colorectal cancers with synchronous liver metastasis generally displayed an active desmoplastic reaction, which was retained in the metastatic lesion to a similar extent.

Conclusions: The results suggest that the abundance of myofibroblasts in cancer-associated stroma may be a useful indicator of disease recurrence after curative colorectal cancer surgery.
Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth by Suppressing Cyclin D1 Expression through Inhibition of Nuclear Factor κB Activation
Authors: Ozaki Iwata , Zhang Hao , Mizuta Toshihiko , Ide Yasushi , Eguchi Yuichiro , Yasutake Tsutomu , Sakamaki Toshiyuki , Pestell Richard G. , Yamamoto Kyosuke
Published: April 2007

Purpose: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2–induced growth inhibition of HCC cells.

Experimental Design: HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor κB (NF-κB) activation was investigated by a NF-κB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IκB, and an in vitro kinase assay for IκB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1.

Results: Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-κB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)–, TNF-α–, and interleukin (IL)-1–induced activation of NF-κB binding and transactivation. Concomitant with the suppression of NF-κB activation, vitamin K2 also inhibited the phosphorylation and degradation of IκBα and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment.

Conclusion: Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IκB/NF-κB pathway and might therefore be useful for treatment of HCC.
5-Aza-2′-Deoxycytidine Delays Androgen-Independent Disease and Improves Survival in the Transgenic Adenocarcinoma of the Mouse Prostate Mouse Model of Prostate Cancer
Authors: Zorn Christoph S. , Wojno Kirk J. , McCabe Michael T. , Kuefer Rainer , Gschwend Juergen E. , Day Mark L.
Published: April 2007

Purpose: We have previously shown that 5-aza-2′-deoxycytidine (5-aza) is an effective chemopreventive agent capable of preventing early disease progression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) model. The purpose of this study was to determine the effect of 5-aza on preexisting TRAMP prostate cancers and prevention of androgen-independent prostate cancer.

Experimental Design: TRAMP mice with established prostate cancers were treated with 5-aza, castration, castration + 5-aza, or vehicle control (PBS). One cohort of 22 mice per treatment was euthanized after 10 weeks of treatment, whereas a second cohort of 14 mice per group was followed until death to determine survival. Histologic sections of prostate, pelvic lymph nodes, lung, and liver were blinded and analyzed by a certified genitourinary pathologist (K.J.W.).

Results: Combined treatment (castration + 5-aza) provided significant survival benefits over either single treatment (combined versus castration P = 0.029, combined versus 5-aza P = 0.036). At 24 weeks of age, 86% of mice within the PBS cohort exhibited histologic evidence of prostate cancer, whereas only 47% of the combined cohort exhibited malignant disease (P < 0.0001). Additionally, whereas 43% of the PBS treatment group exhibited lymph node metastases, these were only observed in 21% of the combined treatment mice.

Conclusions: This is the first study to examine the effect of 5-aza and combined castration + 5-aza on preexisting prostate cancer in an animal model. Based on these preclinical findings, we suggest that 5-aza treatment may prolong the time to an androgen-independent status and thus survival in a hormone-deprived setting in prostate cancer.
Morin (3,5,7,2′,4′-Pentahydroxyflavone) Abolishes Nuclear Factor-κB Activation Induced by Various Carcinogens and Inflammatory Stimuli, Leading to Suppression of Nuclear Factor-κB–Regulated Gene Expression and Up-regulation of Apoptosis
Authors: Manna Sunil K. , Aggarwal Rishi S. , Sethi Gautam , Aggarwal Bharat B. , Ramesh Govindarajan T.
Published: April 2007

Purpose: Morin is a flavone that exhibits antiproliferative, antitumor, and anti-inflammatory effects through a mechanism that is not well understood. Because of the role of transcription factor nuclear factor-κB (NF-κB) in the control of cell survival, proliferation, tumorigenesis, and inflammation, we postulated that morin mediates its effects by modulating NF-κB activation.

Experimental Design: We investigated the effect of morin on NF-κB pathway activated by inflammatory agents, carcinogens, and tumor promoters. The effect of this flavone on expression of NF-κB–regulated gene products involved in cell survival, proliferation, and invasion was also examined.

Results: We showed by DNA-binding assay that NF-κB activation induced by tumor necrosis factor (TNF), phorbol 12-myristate 13-acetate, lipopolysaccharide, ceramide, interleukin-1, and H2O2 was suppressed by morin; the suppression was not cell type specific. The suppression of NF-κB by morin was mediated through inhibition of IκBα (inhibitory subunit of NF-κB) kinase, leading to suppression of phosphorylation and degradation of IκBα and consequent p65 nuclear translocation. Morin also inhibited the NF-κB–dependent reporter gene expression activated by TNF, TNF receptor (TNFR) 1, TNFR1-associated death domain, TNFR-associated factor 2, NF-κB–inducing kinase, IκB kinase, and the p65 subunit of NF-κB. NF-κB–regulated gene products involved in cell survival [inhibitor of apoptosis (IAP) 1, IAP2, X chromosome-linked IAP, Bcl-xL, and survivin], proliferation (cyclin D1 and cyclooxygenase-2), and invasion (matrix metalloproteinase-9) were down-regulated by morin. These effects correlated with enhancement of apoptosis induced by TNF and chemotherapeutic agents.

Conclusion: Overall, our results indicate that morin suppresses the activation of NF-κB and NF-κB–regulated gene expression, leading to enhancement of apoptosis. This may provide the molecular basis for the ability of morin to act as an anticancer and anti-inflammatory agent.