bluuebunny/crossref_metadata_2025 huggingface dataset:
Wideband nonlinear time reversal seismo-acoustic method for landmine detection
Authors: Sutin Alexander , Libbey Brad , Fillinger Laurent , Sarvazyan Armen
Published: April 2009

Acoustic and seismic waves provide a method to localize compliant mines by vibrating the top plate and a thin soil layer above the mine. This vibration is mostly linear, but also includes a small nonlinear deviation. The main goal of this paper is to introduce a method of processing that uses phase-inversion to observe nonlinear effects in a wide frequency band. The method extracts a nonlinear part of surface velocity from two similar broadcast signals of opposite sign by summing and canceling the linear components and leaving the nonlinear components. This phase-inversion method is combined with time reversal focusing to provide increased seismic vibration and enhance the nonlinear effect. The experiments used six loudspeakers in a wood box placed over sand in which inert landmines were buried. The nonlinear surface velocity of the sand with a mine compared to the sand without a mine was greater as compared to a linear technique.
Speech intelligibility in background noise with ideal binary time-frequency masking
Authors: Wang DeLiang , Kjems Ulrik , Pedersen Michael S. , Boldt Jesper B. , Lunner Thomas
Published: April 2009

Ideal binary time-frequency masking is a signal separation technique that retains mixture energy in time-frequency units where local signal-to-noise ratio exceeds a certain threshold and rejects mixture energy in other time-frequency units. Two experiments were designed to assess the effects of ideal binary masking on speech intelligibility of both normal-hearing (NH) and hearing-impaired (HI) listeners in different kinds of background interference. The results from Experiment 1 demonstrate that ideal binary masking leads to substantial reductions in speech-reception threshold for both NH and HI listeners, and the reduction is greater in a cafeteria background than in a speech-shaped noise. Furthermore, listeners with hearing loss benefit more than listeners with normal hearing, particularly for cafeteria noise, and ideal masking nearly equalizes the speech intelligibility performances of NH and HI listeners in noisy backgrounds. The results from Experiment 2 suggest that ideal binary masking in the low-frequency range yields larger intelligibility improvements than in the high-frequency range, especially for listeners with hearing loss. The findings from the two experiments have major implications for understanding speech perception in noise, computational auditory scene analysis, speech enhancement, and hearing aid design.
The masking of interaural delays
Authors: Kolarik Andrew J. , Culling John F.
Published: April 2009

Four experiments measured discrimination of interaural time delay (ITD) thresholds for broadband noise in the presence of masking noise of the same bandwidth as the target (0.1–3 kHz for experiments 1–3 and 0–10 kHz for experiment 4). In experiments 1–3, listeners performed interaural two–interval two–alternative forced–choice (2I-2AFC) delay discrimination tasks with stimuli composed of delayed and masking noises mixed in proportions of delayed noise ranging between 1 and 0.05. Experiments 1–3 employed interaurally correlated, anticorrelated, and uncorrelated maskers, respectively. Experiment 4 measured centering accuracy for continuous noise with a range of interaural coherences (equivalent to proportion of delayed noise) obtained by mixing delayed and interaurally uncorrelated noises. Results indicate that in the presence of an interaurally correlated masker ITD thresholds doubled for every halving of the proportion of delayed noise power in the stimulus. This function became steeper as the masking noise changed from interaurally correlated, to uncorrelated, to anticorrelated. The results were compared to thresholds predicted by a model based on variations in the distribution of interaural phase differences of the stimulus components.
Estimating vowel formant discrimination thresholds using a single-interval classification task
Authors: Oglesbee Eric , Kewley-Port Diane
Published: April 2009

Previous research estimating vowel formant discrimination thresholds in words and sentences has often employed a modified two-alternative-forced-choice (2AFC) task with adaptive tracking. Although this approach has produced stable data, the length and number of experimental sessions, as well as the unnaturalness of the task, limit generalizations of results to ordinary speech communication. In this exploratory study, a typical identification task was used to estimate vowel formant discrimination thresholds. Specifically, a signal detection theory approach was used to develop a method to estimate vowel formant discrimination thresholds from a quicker, more natural single-interval classification task. In experiment 1 “classification thresholds” for words in isolation and embedded in sentences were compared to previously collected 2AFC data. Experiment 2 used a within-subjects design to compare thresholds estimated from both classification and 2AFC tasks. Due to instabilities observed in the experiment 1 sentence data, experiment 2 examined only isolated words. Results from these experiments show that for isolated words, thresholds estimated using the classification procedure are comparable to those estimated using the 2AFC task. These results, as well as an analysis of several aspects of the classification procedure, support the viability of this new approach for estimating discrimination thresholds for speech stimuli.
Trombone bore optimization based on input impedance targets
Authors: Braden Alistair C. P. , Newton Michael J. , Campbell D. Murray
Published: April 2009

Optimization methods based on input impedance target functions have been proposed for the design of brass musical instruments. Criteria for target functions in trombone bore optimization are discussed, drawing on experimental input impedance data from a variety of high-quality trombones of differing sizes. An “inharmonicity plot” is introduced and used to aid the interpretation of impedance curves. An efficient optimization technique is described and is shown to be capable of predicting bore changes which achieve specified modifications to the input impedance curve while maintaining a smoothly-flaring bell contour. Further work is required to clarify the relationship between input impedance targets and the preferences of professional players.
Maximal azimuthal resolution needed in measurements of head-related transfer functions
Authors: Zhong Xiao-Li , Xie Bo-Sun
Published: April 2009

The head-related transfer function (HRTF) is a continuous function of sound source position. Measurement of the HRTF can only be undertaken at discrete positions in space, however. Determination of angular resolutions so as to reconstruct HRTFs at unmeasured positions has been an open problem. Azimuthal Fourier analysis was proposed to analyze the variation in the HRTF in each elevation plane. As a result, an azimuthal sampling theorem and a corresponding interpolation formula were derived. It was proved that the maximal azimuthal resolution of measurements is 360°/(2Q+1), where Q represents the highest order in the truncation of the azimuthal Fourier expansion of the HRTF. The maximal azimuthal resolutions for the HRTF with and without arrival time correction were investigated. Results show that the arrival time correction can reduce the burden of measurements, since a larger azimuthal resolution is possible without introducing obvious interpolation error. A psychoacoustic experiment was also conducted to evaluate the proposed theorem.
An articulatory investigation of lingual coarticulatory resistance and aggressiveness for consonants and vowels in Catalan
Authors: Recasens Daniel , Espinosa Aina
Published: April 2009

Lingual movement data for Catalan vowel-consonant-vowel sequences reveal differences in contextual coarticulatory variability in tongue position at the middle of the consonant for ∕p∕>∕n∕>dark ∕l∕>∕s∕>∕ʃ∕>∕ɲ∕ and at vowel midpoint for ∕u∕>∕a∕>∕i∕. The velar stop /k/ exhibits a high degree of contextual variability in the horizontal dimension but not in the vertical dimension. These differences in coarticulatory sensitivity are attributed to differences in articulatory constraint, e.g., palatality and frication cause a higher degree of resistance in the consonant than laterality. A higher degree of contextual variability for dark /l/ than expected appears to be associated with speaker-dependent differences in darkness degree. Contextual variability is greater at regions not involved in closure or constriction formation, e.g., at the tongue dorsum than at the tongue front for alveolars. Coarticulatory resistance and coarticulatory aggressiveness are positively correlated: Phonetic segments, which are especially resistant to coarticulatory effects from the adjacent segments, exert maximal coarticulation on them. Consequently, highly constrained segments such as alveolopalatal consonants turn out to affect tongue position for less constrained segments such as back vowels rather than vice versa.
Acupuncture in a Rheumatology Clinic
Authors: Alexander Rosemary , White Adrian
Published: April 2009

An acupuncture clinic was established, for a limited period, within a rheumatology department of Barnet and Chase Farm Hospital Trust. Courses of six to eight sessions of traditional and trigger-point acupuncture were offered for a specified range of conditions. Pain and use of analgesics were measured routinely. A prospective observational study is presented of the outcome for a series of 41 patients, who had a mean age of 57 years and pain duration of 3 years. The mean score for daytime pain fell from 6.8 (SD 1.2) to 4.9 (2.5) points which is highly significant (p < 0.001). A total of 30 patients (73%) had reduction in pain of at least 33% and 22 patients (54%) had a reduction in pain of at least 50%. Analgesic intake (without distinguishing between different analgesic medication) was reduced from a mean of 17 (15.3) tablets per week to a mean of 6 (7.9). Patients with normal X-rays had a much better response to acupuncture than those whose X-rays showed significant degenerative changes. In response to these findings, financial support has been provided to continue the acupuncture clinic.
Role of Acupuncture in Thoracic Outlet Syndrome
Authors: Tariq M , Zahir Jawad , Saleem Salman Ahmad
Published: April 2009

This report describes a case of Thoracic Outlet Syndrome (TOS) which was successfully treated with acupuncture after failed conservative management with a variety of interventions.
Is There a Role for Acupuncture in Endometriosis Pain, Or ‘endometrialgia’?
Authors: Lundeberg Thomas , Lund Iréne
Published: April 2009

Endometriosis is a common cause of pelvic pain in women, many of whom suffer a progression of symptoms over their menstrual life. Symptoms may include combinations of abnormal visceral sensations and emotional distress. Endometriosis pain, or ‘endometrialgia’ often has a negative influence on the ability to work, on family relationships and sense of worth.

Endometrialgia is often considered to be a homogeneous sensory entity, mediated by a specialised high threshold sensory system, which extends from the periphery through the spinal cord, brain stem and thalamus to the cerebral cortex. However, multiple mechanisms have been detected in the nervous system responsible for the pain including peripheral sensitisation, phenotypic switches, central sensitisation, ectopic excitability, structural reorganisation, decreased inhibition and increased facilitation, all of which may contribute to the pain.

Although the causes of endometrialgia can differ (eg inflammatory, neuropathic and functional), they share some characteristics. Endometrialgia may be evoked by a low intensity, normally innocuous stimulus (allodynia), or it may be an exaggerated and prolonged response to a noxious stimulus (hyperalgesia). The pain may also be spontaneous in the absence of any apparent peripheral stimulus.

Oestrogens and prostaglandins probably play key modulatory roles in endometriosis and endometrialgia. Consequently many of the current medical treatments for the condition include oral drugs, like non-steroid anti-inflammatory drugs, contraceptives, progestogens, androgenic agents, gonadotrophin releasing hormone analogues, as well as laparoscopic surgical excision of the endometriosis lesions. However, management of pain in women with endometriosis is currently inadequate for many. Possibly acupuncture and cognitive therapy may be used as an adjunct.
FINDING PLANAR SURFACES IN KNOT- AND LINK-MANIFOLDS
Authors: JACO WILLIAM , RUBINSTEIN J. HYAM , SEDGWICK ERIC
Published: April 2009

It is shown that given any link-manifold, there is an algorithm to decide if the manifold contains an embedded, essential planar surface; if it does, the algorithm will construct one. Two similar results are obtained with added boundary conditions. Namely, given a link-manifold M, a component B of ∂M, and a slope γ on B, there is an algorithm to decide if there is an embedded punctured-disk in M with boundary γ and punctures in ∂M\B; and given a link-manifold M, a component B of ∂M, and a meridian slope μ on B, there is an algorithm to decide if there is an embedded punctured-disk with boundary a longitude on B and punctures in ∂M\B. In both cases, if there is one, the algorithm will construct one. The proofs introduce a number of new methods and differ from the classical proofs, using normal surfaces, as solutions may not be found among the fundamental solutions.
A DYNAMIC APPROACH TO THE MODELING OF CORRELATION CREDIT DERIVATIVES USING MARKOV CHAINS
Authors: DI GRAZIANO GIUSEPPE , ROGERS L. C. G.
Published: April 2009

The modeling of credit events is in effect the modeling of the times to default of various names. The distribution of individual times to default can be calibrated from CDS quotes, but for more complicated instruments, such as CDOs, the joint law is needed. Industry practice is to model this correlation using a copula/base correlation approach, which suffers significant deficiencies. We present a new approach to default correlation modeling, where defaults of different names are driven by a common continuous-time Markov process. Individual default probabilities and default correlations can be calculated in closed form. We provide semi-analytic formulas for the pricing of CDO tranches via Laplace-transform techniques which are both fast and easy to implement. The model calibrates to quoted tranche prices with a high degree of precision and allows one to price non-standard tranches in a consistent and arbitrage-free manner. The number of parameters of the model is flexible and can be adjusted to adapt to the set of market data one is calibrating to. More importantly, the model is dynamically consistent and can be used to price options on tranches and other exotic path-dependent products.
AN EXPLORATORY STUDY ON R&D PERFORMANCE MEASUREMENT PRACTICES: A SURVEY OF ITALIAN R&D-INTENSIVE FIRMS
Authors: CHIESA VITTORIO , FRATTINI FEDERICO , LAZZAROTTI VALENTINA , MANZINI RAFFAELLA
Published: April 2009

Although measuring the performance of a firm's R&D activities is a very challenging task, the critical role played by R&D in creating and sustaining a firm's competitive advantage has raised the need to adopt appropriate performance measurement systems (PMSs) in R&D units. Therefore, management scholars have been studying this issue and PMSs have diffused in the R&D departments of most R&D-intensive companies. Nevertheless, empirical investigations into the diffusion and practical use of PMSs in R&D units mainly concern Anglo-Saxon countries, where R&D information disclosure requirements have been in place for a long time. The purpose of this paper is to study the diffusion and practical use of PMSs in the R&D units of firms that are not subject to these types of external institutional influences. With this aim, the results of a survey on the R&D performance measurement practices adopted by a sample of Italian R&D-intensive firms are discussed. They allow to understand why and how R&D-intensive companies design and use a PMS in their R&D units for managerial purposes.
QUANTIFICATION OF RESPIRATORY SINUS ARRHYTHMIA USING HILBERT–HUANG TRANSFORM
Authors: KUO TERRY B. J. , YANG CHERYL C. H. , HUANG NORDEN E.
Published: April 2009

To investigate whether the first intrinsic mode function, obtained from Hilbert–Huang transform (HHT), of heart rate variability is respiratory related. Electrocardiogram and chest circumference signals were recorded from 10 healthy subjects at supine rest. The HHT was applied to both R-R interval and chest circumference signals to figure out their first intrinsic mode functions (C1RR and C1RESP, respectively) from which the instantaneous amplitude, phase, and frequency were calculated. Although the instantaneous amplitudes and frequencies of C1RR and C1RESP were variable, linear regression analysis indicated a phase lock between C1RR and C1RESP. Intake of 500 ml water significantly elevated the amplitude ratio of C1RR to C1RESP; however, the phase difference of C1RR to C1RESP was still unchanged. The data indicate that the first intrinsic mode function of heart rate variability is respiratory related and may be equivalent to respiratory sinus arrhythmia. As compared to fast Fourier transform, HHT of respiratory sinus arrhythmia provides a comparative spatial measurement with a much higher temporal resolution.
WHEN DO THREE LONGEST PATHS HAVE A COMMON VERTEX?
Authors: AXENOVICH MARIA
Published: April 2009

It is well known that any two longest paths in a connected graph share a vertex. It is also known that there are connected graphs where 7 longest paths do not share a common vertex. It was conjectured that any three longest paths in a connected graph have a vertex in common. In this note we prove the conjecture for outerplanar graphs and give sufficient conditions for the conjecture to hold in general.
ON PLANARITY OF DIRECT PRODUCT OF MULTIPARTITE COMPLETE GRAPHS
Authors: BEAUDOU LAURENT , DORBEC PAUL , GRAVIER SYLVAIN , JHA PRANAVA K.
Published: April 2009

The planarity of the direct product of two graphs has been widely studied in the past. Surprisingly, the missing part is the product with K2, which seems to be less predictible. In this piece of work, we characterize which subdivisions of multipartite complete graphs, have their direct product with K2 planar. This can be seen as a step towards the characterization of all such graphs.
Predictions of Phase-Locking in Excitatory Hybrid Networks: Excitation Does Not Promote Phase-Locking in Pattern-Generating Networks as Reliably as Inhibition
Authors: Sieling Fred H. , Canavier Carmen C. , Prinz Astrid A.
Published: April 2009

Phase-locked activity is thought to underlie many high-level functions of the nervous system, the simplest of which are produced by central pattern generators (CPGs). It is not known whether we can define a theoretical framework that is sufficiently general to predict phase-locking in actual biological CPGs, nor is it known why the CPGs that have been characterized are dominated by inhibition. Previously, we applied a method based on phase response curves measured using inputs of biologically realistic amplitude and duration to predict the existence and stability of 1:1 phase-locked modes in hybrid networks of one biological and one model bursting neuron reciprocally connected with artificial inhibitory synapses. Here we extend this analysis to excitatory coupling. Using the pyloric dilator neuron from the stomatogastric ganglion of the American lobster as our biological cell, we experimentally prepared 86 networks using five biological neurons, four model neurons, and heterogeneous synapse strengths between 1 and 10,000 nS. In 77% of networks, our method was robust to biological noise and accurately predicted the phasic relationships. In 3%, our method was inaccurate. The remaining 20% were not amenable to analysis because our theoretical assumptions were violated. The high failure rate for excitation compared with inhibition was due to differential effects of noise and feedback on excitatory versus inhibitory coupling and suggests that CPGs dominated by excitatory synapses would require precise tuning to function, which may explain why CPGs rely primarily on inhibitory synapses.
Structural and Functional Asymmetry in the Human Parietal Opercular Cortex
Authors: Jung Patrick , Baumgärtner Ulf , Stoeter Peter , Treede Rolf-Detlef
Published: April 2009

In this combined electroencephalographic and magnetic resonance imaging (MRI) study, the asymmetry of functional and structural measures in the human parietal operculum (PO) were investigated. Median nerve somatosensory evoked potential recordings showed maximum scalp potentials over contralateral (N80, N110) and ipsilateral (N100, N130) temporal electrode positions. In accordance, MRI-coregistered source analysis revealed two electrical sources in the contralateral (N80, N110) and two in the ipsilateral (N100, N130) PO. The dipole orientations of the contra- and ipsilateral sources with earlier peak activation, N80 and N100, were more tangential than those of the later peaking N110 and N130 sources. The most prominent contralateral N110 source exhibited pronounced left lateralized dipole strengths in the 80- to 120-ms latency range, in contrast to symmetrical N80 and ipsilateral source responses. The asymmetry of the N110 source activity explained both the asymmetry of N110 and N100 scalp potentials. Morphometric analysis demonstrated no interhemispheric differences in the sizes of the anterior PO (aPO), containing the cytoarchitectonic areas OP3 and OP4, but left lateralized sizes of the posterior PO (pPO), which encompasses the anatomically defined areas OP1 and OP2. The N110 source was located in the pPO and its asymmetry was significantly correlated with the structural pPO asymmetry but not with handedness and auditory lateralization. Thus both structural and functional asymmetries exist in the human PO and they are closely related to each other but not to measures of brain asymmetry in other functional systems, i.e., auditory lateralization and handedness.
Regulator of sex-limitation KRAB zinc finger proteins modulate sex-dependent and -independent liver metabolism
Authors: Krebs Christopher J. , Khan Shaema , MacDonald James W. , Sorenson Meredith , Robins Diane M.
Published: April 2009

Krüppel-related zinc finger proteins (KRAB-zfps) comprise the largest mammalian transcription factor family, but their specific functions are largely unknown. Two KRAB-zfps, regulator of sex-limitation ( Rsl) 1 and Rsl2, repress expression of the mouse sex-limited protein ( Slp) gene, the hallmark of Rsl activity, as well as some other male-predominant liver genes. This phenotype suggests Rsl modifies sex-specific transcription. The scope of Rsl control was determined by expression profiling of liver RNA from wild-type (wt), rsl, and transgenic mice with hepatic overexpression of Rsl1 or Rsl2. About 7.5% of the liver transcriptome was Rsl-responsive. More genes in males than females were affected by the loss of Rsl (e.g., in rsl mice), whereas Rsl overexpression altered more transcripts in females than males. Rsl dramatically repressed some female-predominant genes, but most were modestly (1.25- to 2-fold) influenced. In males, most Rsl-responsive genes unexpectedly expressed at lower levels in rsl than wt, suggesting not all are direct targets of Rsl repression. Gene Ontology analysis showed Rsl targets enriched in pathways of cholesterol, steroid, and lipid metabolism, linking Rsl to energy balance. In accord with this, blood glucose levels were less in male rsl than wt mice, and less responsive to fasting and refeeding. rsl mice were also leaner than wt, consistent with their hepatic regulation of phosphoenolpyruvate carboxykinase 1 and stearoyl-Coenzyme A desaturase 1. Altogether, Rsl's effect on sexually dimorphic and metabolically sensitive liver gene expression suggests a role for KRAB-zfps as broad genetic modulators of individual adaptation.
A 15-Year-Old Boy with Anterior Chest Pain, Progressive Dyspnea, and Subcutaneous Emphysema of the Neck
Authors: Scichilone Nicola , Buttacavoli Maria , Camarda Gaetana , Marchese Margherita , Bellia Maria , Spatafora Mario
Published: April 2009

We describe the case of an adolescent who was admitted to the hospital because of sudden occurrence of chest pain, dyspnea and subcutaneous emphysema. On admission, physical examination revealed subcutaneous crepitations in the superior part of the rib cage, and auscultation of the chest showed widespread wheezing. The radiological assessment confirmed the diagnosis of pneumomediastinum and pneumothorax. A follow-up CT scan performed one week after the admission showed almost complete resolution of the radiological alterations. At the following visits, the patient was asymptomatic, but reported to have suffered from frequent episodes of rhinorrea, sneezing, nasal blockage, and sometimes, chest tightness, especially during exposure to pets and/or windy weather. Skin prick testing showed sensitivities to dermatophagoides pteronyssinus and farinae, grass pollen and dog dander. Spirometry documented significant improvement in lung function after short-acting bronchodilator, allowing for the diagnosis of asthma to be made. Although pneumomediastinum may be a complication of various respiratory diseases, including asthma, it has never been reported as the first presentation of underlying bronchial asthma. Herein, the physiopathological mechanisms, the diagnostic procedures and treatment of pneumomediastinum in asthma are discussed. We suggest that the diagnosis of asthma should be considered in the differential diagnosis of pneumomediastinum in adolescence.
Src-Induced Cisplatin Resistance Mediated by Cell-to-Cell Communication
Authors: Peterson-Roth Elizabeth , Brdlik Cathleen M. , Glazer Peter M.
Published: April 2009

Cisplatin-induced cell death can be triggered by cell-to-cell communication through gap junctions. Here, we show that activated src produces tyrosine phosphorylation of the gap junction protein connexin 43, decreases gap junction communication, and increases cell survival in response to cisplatin. Experiments with mixed cell populations show that src activity in one cell can confer increased cisplatin survival on neighboring cells, even when the neighboring cells lack such src activity. This work is the first demonstration that expression of an oncogene in one cell can affect the survival of a neighboring cell not expressing the oncogene in response to a chemotherapeutic drug. The trans-acting effect of activated src on neighboring cells can be blocked by inhibitors of src kinase or by siRNA-mediated knockdown of src expression, and it can be counteracted by forced up-regulation of connexin 43, via either gene transfer or proteasome inhibition. These results identify a novel pathway of cisplatin resistance that may be amenable to therapeutic intervention. [Cancer Res 2009;69(8):3619–24]
Combined Integrin Phosphoproteomic Analyses and Small Interfering RNA–Based Functional Screening Identify Key Regulators for Cancer Cell Adhesion and Migration
Authors: Chen Yanling , Lu Bingwen , Yang Qingkai , Fearns Colleen , Yates John R. , Lee Jiing-Dwan
Published: April 2009

Integrins interact with extracellular matrix (ECM) and deliver intracellular signaling for cell proliferation, survival, and motility. During tumor metastasis, integrin-mediated cell adhesion to and migration on the ECM proteins are required for cancer cell survival and adaptation to the new microenvironment. Using stable isotope labeling by amino acids in cell culture–mass spectrometry, we profiled the phosphoproteomic changes induced by the interactions of cell integrins with type I collagen, the most common ECM substratum. Integrin-ECM interactions modulate phosphorylation of 517 serine, threonine, or tyrosine residues in 513 peptides, corresponding to 357 proteins. Among these proteins, 33 key signaling mediators with kinase or phosphatase activity were subjected to small interfering RNA–based functional screening. Three integrin-regulated kinases, DBF4, PAK2, and GRK6, were identified for their critical role in cell adhesion and migration possibly through their regulation of actin cytoskeleton arrangement. Altogether, we not only depict an integrin-modulated phosphorylation network during cell-ECM protein interactions but also reveal novel regulators for cell adhesion and migration. [Cancer Res 2009;69(8):3713–20]
Non–Small Cell Lung Cancer Exhibits Transcript Overexpression of Genes Associated with Homologous Recombination and DNA Replication Pathways
Authors: Saviozzi Silvia , Ceppi Paolo , Novello Silvia , Ghio Paolo , Lo Iacono Marco , Borasio Piero , Cambieri Alberto , Volante Marco , Papotti Mauro , Calogero Raffaele A. , Scagliotti Giorgio V.
Published: April 2009

Genes involved in DNA repair and replication have been recently investigated as predictive markers of response to chemotherapy in non–small cell lung cancer (NSCLC). However, few data on the expression of these genes in tumor compared with corresponding normal lung are available. The aim of this study was to evaluate differential mRNA levels of 22 DNA repair genes of five different DNA repair pathways: direct, base excision, nucleotide excision (NER), double-strand break (DSBR), and postreplicative repair. In addition, six genes involved in DNA replication (REP) and three telomere maintenance genes were investigated. Total RNAs extracted from fresh-frozen tumors and corresponding normal tissues of 50 consecutive chemo-naïve resected NSCLC patients were analyzed. Transcript levels were quantified by real-time PCR. A significant overexpression was detected in 20 of 30 (67%) genes, mostly belonging to DSBR pathways, whereas others (XPA, XPC, and UBE2N; 10%) were significantly underexpressed. For 7 of 30 (23%) genes, mostly belonging to NER pathway, no significant difference between paired tumor and normal samples was observed. Transcript overexpression of DSBR and REP genes was significantly higher in poorly differentiated carcinomas and DSBR levels were higher in men compared with women. The transcriptional overexpression of four genes (XRCC5, TOP3B, TYMS, and UNG) showed significant correlation with a shorter patients' outcome at the univariate, whereas only stage of disease appeared as an independent factor affecting prognosis, as assessed by multivariate analysis. In conclusion, genes belonging to DNA repair/replication pathways are overexpressed in NSCLC and are associated with a more aggressive phenotype. [Cancer Res 2009;69(8):3390–6]
Suppression of Human Solid Tumor Growth in Mice by Intratumor and Systemic Inoculation of Histidine-Rich and pH-Dependent Host Defense–like Lytic Peptides
Authors: Makovitzki Arik , Fink Avner , Shai Yechiel
Published: April 2009

Previously, we reported that intratumor or systemic inoculation of a cationic 15-mer, innate immunity-like lytic peptide composed of d- and l-amino acids ([D]-K6L9) caused growth arrest of 22RV1 prostate carcinoma xenografts in a mouse model. However, despite its therapeutic potential, this peptide has significant systemic toxicity at concentrations slightly higher than the therapeutic one. Here, we used the acidic environment created by solid tumors as a trigger to activate anticancer lytic peptides by making them cationic only at low pH levels. We achieved this selectivity by substituting lysines (pKa, ∼10.5) for histidines (pKa, ∼6.1) in the parental peptide [D]-K6L9. Histidine is protonated below pH 7. For that purpose, we replaced either three or all six lysines in the parental peptide with histidines to obtain the peptides [D]-K3H3L9 and [D]-H6L9. Interestingly, in vitro experiments showed pH-dependent activity only with [D]-H6L9 mainly toward cancer cell lines. However, both peptides showed reduced systemic toxicity compared with the parental peptide. Intratumor and systemic inoculation of these peptides resulted in a significant decrease in the 22RV1 prostate cancer tumor volume and systemic secretion of prostate-specific antigen in a xenograft mice model. Moreover, histologic modifications revealed a significant reduction in new blood vessels selectively in tumor tissues after treatment with the peptides compared with the untreated tumors. The lytic mode of action of these new peptides, which makes it difficult for the cancer cells to develop resistance, and their selective and pH-dependent activity make them potential candidates for treatment of solid cancer tumors. [Cancer Res 2009;69(8):3458–63]
Akt Phosphorylation of Merlin Enhances Its Binding to Phosphatidylinositols and Inhibits the Tumor-Suppressive Activities of Merlin
Authors: Okada Masashi , Wang Yanru , Jang Sung-Wuk , Tang Xiaoling , Neri Luca M. , Ye Keqiang
Published: April 2009

The NF2 tumor suppressor gene encodes an intracellular membrane-associated protein, called merlin, which belongs to the band 4.1 family of cytoskeleton-associated proteins that link cell surface glycoproteins to the actin cytoskeleton. Merlin suppresses phosphatidylinositol 3-kinase (PI3K)/Akt signaling by directly binding and inhibiting the stimulatory activity of PIKE-L on PI3K. Akt feeds back and phosphorylates merlin and provokes its polyubiquitination and degradation. Here, we show that Akt phosphorylation and PI(3,4,5)P3 binding mediate the tumor-suppressive activity of merlin. The extreme NH2 terminus of merlin directly interacts with phosphatidylinositols, for which the unfolded conformation is required. Moreover, Akt phosphorylation enhances merlin binding affinity to phosphatidylinositols and inhibits its proapoptotic actions. Furthermore, Akt phosphorylation and phosphatidylinositols increase merlin binding to CD44. Epidermal growth factor treatment and Akt phosphorylation provoke merlin to aggregate in the ruffled plasma membrane and promote cell migration. Thus, these results suggest that PI3K signaling regulates the tumor-suppressive activity of merlin via both Akt phosphorylation and phosphatidylinositol lipids binding to merlin. [Cancer Res 2009;69(9):4043–51]
PTEN Loss Contributes to Erlotinib Resistance in EGFR-Mutant Lung Cancer by Activation of Akt and EGFR
Authors: Sos Martin L. , Koker Mirjam , Weir Barbara A. , Heynck Stefanie , Rabinovsky Rosalia , Zander Thomas , Seeger Jens M. , Weiss Jonathan , Fischer Florian , Frommolt Peter , Michel Kathrin , Peifer Martin , Mermel Craig , Girard Luc , Peyton Michael , Gazdar Adi F. , Minna John D. , Garraway Levi A. , Kashkar Hamid , Pao William , Meyerson Matthew , Thomas Roman K.
Published: April 2009

Clinical resistance to epidermal growth factor receptor (EGFR) inhibition in lung cancer has been linked to the emergence of the EGFR T790M resistance mutation or amplification of MET. Additional mechanisms contributing to EGFR inhibitor resistance remain elusive. By applying combined analyses of gene expression, copy number, and biochemical analyses of EGFR inhibitor responsiveness, we identified homozygous loss of PTEN to segregate EGFR-dependent and EGFR-independent cells. We show that in EGFR-dependent cells, PTEN loss partially uncouples mutant EGFR from downstream signaling and activates EGFR, thereby contributing to erlotinib resistance. The clinical relevance of our findings is supported by the observation of PTEN loss in 1 out of 24 primary EGFR-mutant non–small cell lung cancer (NSCLC) tumors. These results suggest a novel resistance mechanism in EGFR-mutant NSCLC involving PTEN loss. [Cancer Res 2009;69(8):3256–61]
The Role of microRNA-221 and microRNA-222 in Androgen-Independent Prostate Cancer Cell Lines
Authors: Sun Tong , Wang Qianben , Balk Steven , Brown Myles , Lee Gwo-Shu Mary , Kantoff Philip
Published: April 2009

Androgen-dependent prostate cancer typically progresses to castration-resistant prostate cancer (CRPC) after the androgen deprivation therapy. MicroRNAs (miR) are noncoding small RNAs (19-25nt) that play an important role in the regulation of gene expression. Recent studies have shown that miR expression patterns are significantly different in normal and neoplastic prostate epithelial cells. However, the importance of miRs in the development of CRPC has not yet been explored. By performing genome-wide expression profiling of miRs, we found that expression levels of several miRs, in particular miR-221 and miR-222, were significantly increased in CRPC cells (the LNCaP-derived cell line LNCaP-Abl), compared with those in the androgen-dependent prostate cancer cell line (LNCaP). Overexpression of miR-221 or miR-222 in LNCaP or another androgen-dependent cell line, LAPC-4, significantly reduced the level of the dihydrotestosterone (DHT) induced up-regulation of prostate-specific antigen (PSA) expression and increased androgen-independent growth of LNCaP cells. Knocking down the expression level of miR-221 and miR-222 with antagonist miRs in the LNCaP-Abl cell line restored the response to the DHT induction of PSA transcription and also increased the growth response of the LNCaP-Abl cells to the androgen treatment. Changing the expression level of p27/kip1, a known target of miR-221 and miR-222, alone in LNCaP cells affected the DHT-independent cell growth but did not significantly influence the response of PSA transcription to the DHT treatment. In conclusion, our data suggest the involvement of miR-221 and miR-222 in the development or maintenance of the CRPC phenotype. [Cancer Res 2009;69(8):3356–63]
Characterization of the HDAC1 Complex That Regulates the Sensitivity of Cancer Cells to Oxidative Stress
Authors: Kato Takuya , Shimono Yohei , Hasegawa Masaki , Jijiwa Mayumi , Enomoto Atsushi , Asai Naoya , Murakumo Yoshiki , Takahashi Masahide
Published: April 2009

Histone deacetylases (HDAC) are involved in carcinogenesis through their regulation of cell proliferation, differentiation, and survival. The inhibitors of HDAC exhibit profound synergistic effects in cancer treatment when combined with other anticancer drugs. However, the molecular mechanisms underlying this synergy are not fully understood. Here, we show that HDAC1 increases the resistance of cancer cells to oxidative stress by negatively regulating the expression of thioredoxin binding protein 2 (TBP-2). We found that the recruitment of HDAC1 to the TBP-2 promoter is mediated by a protein complex consisting of RET finger protein (RFP; also called TRIM27) and the trimeric transcription factor NF-Y. Accordingly, RNA interference–mediated depletion of RFP led to the disruption of the protein complex and a marked increase in the sensitivity of cancer cells to cisplatin, a potent inducer of oxidative stress. Furthermore, high levels of RFP expression correlated with down-regulation of TBP-2 in human colon cancers and were associated with poor clinical outcome. These findings reveal the diverse cancer-promoting activities of HDAC1 and identify RFP as a key regulator that provides cancer cells with resistance to anticancer drugs. [Cancer Res 2009;69(8):3597–604]
Folate Intake, Methylenetetrahydrofolate Reductase Polymorphisms, and Breast Cancer Risk in Women from the Malmö Diet and Cancer Cohort
Authors: Ericson Ulrika , Sonestedt Emily , Ivarsson Malin I.L. , Gullberg Bo , Carlson Joyce , Olsson Håkan , Wirfält Elisabet
Published: April 2009

Background: Single nucleotide polymorphisms (SNP) of the folate-metabolizing enzyme methylenetetrahydrofolate reductase (MTHFR) may modify associations between folate intake and breast cancer. We examined if the association between tertiles of dietary folate equivalents (DFE) and breast cancer was different in subgroups according to genotypes of the MTHFR 677 C>T (rs1801133) and 1298A>C (rs1801131) SNPs and if the polymorphisms per se were associated with breast cancer.

Methods: This nested case-control study included 544 incident cases with invasive breast cancer and 1,088 controls matched on age and blood sampling date from the population-based Malmö Diet and Cancer cohort. Genotyping of the MTHFR SNPs was done with PCR-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Odds ratios (OR) were obtained by unconditional logistic regression.

Results: DFE was positively associated with breast cancer in MTHFR 677CT/TT−1298AA women (P for trend = 0.01) but inversely associated in compound heterozygous women (P for trend = 0.01). Interaction was observed between DFE and the 1298C allele (P = 0.03). The 677T allele was associated with increased breast cancer risk in women above 55 years [multivariate adjusted OR, 1.34; 95% confidence interval (95% CI), 1.01-1.76] and an interaction was observed between the T allele and age (P = 0.03). Homozygosis for the 1298C allele was associated with increased risk in women between 45 and 55 years (multivariate adjusted OR, 1.89; 95% CI, 1.09-3.29).

Conclusion: In conclusion, a positive association between DFE and breast cancer was observed in MTHFR 677CT/TT−1298AA women but an inverse association was observed in 677CT−1298AC women. The 677T allele was associated with higher breast cancer risk in women above 55 years of age. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1101–10)
Cardiorespiratory Fitness and Digestive Cancer Mortality: Findings from the Aerobics Center Longitudinal Study
Authors: Peel J. Brent , Sui Xuemei , Matthews Charles E. , Adams Swann A. , Hébert James R. , Hardin James W. , Church Timothy S. , Blair Steven N.
Published: April 2009

Although higher levels of physical activity are inversely associated with risk of colon cancer, few prospective studies have evaluated overall digestive system cancer mortality in relation to cardiorespiratory fitness (CRF). The authors examined this association among 38,801 men ages 20 to 88 years who performed a maximal treadmill exercise test at baseline in the Aerobics Center Longitudinal Study (Dallas, TX) during 1974 to 2003. Mortality was assessed over 29 years of follow-up (1974-2003). Two hundred eighty-three digestive system cancer deaths occurred during a mean 17 years of observation. Age-adjusted mortality rates per 10,000 person-years according to low, moderate, and high CRF groups were 6.8, 4.0, and 3.3 for digestive system cancer (Ptrend < 0.001). After adjustment for age, examination year, body mass index, smoking, drinking, family history of cancer, personal history of diabetes, hazard ratios (95% confidence intervals) for overall digestive cancer deaths for those in the middle and upper 40% of the distribution of CRF relative to those in the lowest 20% were 0.66 (0.49-0.88) and 0.56 (0.40-0.80), respectively. Being fit (the upper 80% of CRF) was associated with a lower risk of mortality from colon [0.61 (0.37-1.00)], colorectal [0.58 (0.37-0.92)], and liver cancer [0.28 (0.11-0.72)] compared with being unfit (the lowest 20% of CRF). These findings support a protective role of CRF against total digestive tract, colorectal, and liver cancer deaths in men. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1111–7)
Association of CYP1B1 Haplotypes and Breast Cancer Risk in Caucasian Women
Authors: Huang Yifan , Trentham-Dietz Amy , García-Closas Montserrat , Newcomb Polly A. , Titus-Ernstoff Linda , Hampton John M. , Chanock Stephen J. , Haines Jonathan L. , Egan Kathleen M.
Published: April 2009

CYP1B1 is a key enzyme involved in estrogen metabolism and may play an important role in the development and progression of breast cancer. In a population-based case-control study, we examined eight CYP1B1 haplotype-tagging single nucleotide polymorphisms in relation to invasive breast cancer risk. Analyses were based on 1,655 cases and 1,470 controls; all women were Caucasian. Among the individual single nucleotide polymorphisms, one (rs9341266) was associated with increased risk of breast cancer (Ptrend = 0.021), although the association was no longer significant after adjusting for multiple tests. A marginally significant haplotype effect was identified (Pglobal = 0.015), with significant associations identified for 2 uncommon haplotypes comprising 4% of the controls. Results suggest that genetic variation in CYP1B1 has at most a minor influence on breast cancer susceptibility among Caucasian women. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1321–3)
Prospective Study of Plasma Vitamin B6 and Risk of Colorectal Cancer in Men
Authors: Lee Jung Eun , Li Haojie , Giovannucci Edward , Lee I-Min , Selhub Jacob , Stampfer Meir , Ma Jing
Published: April 2009

Vitamin B6 may lower risk of colorectal cancer by preventing aberrations in one-carbon metabolism or by anti-inflammatory effects. We prospectively evaluated the association between plasma levels of pyridoxal 5′-phosphate (PLP; the active form of vitamin B6) and risk of colorectal cancer in a nested case-control study within the Physicians' Health Study. Among 14,916 men who provided blood specimens in 1982 to 1984, we identified 197 incident colorectal cancer cases through 2000 and individually matched them to 371 controls by age and smoking status. Plasma PLP levels were positively correlated with cold cereal intake and plasma levels of folate and vitamin B12 (age- and smoking-adjusted partial correction r = 0.28-0.48) and slightly inversely correlated with body mass index (r = −0.11) and plasma levels of homocysteine, C-reactive protein, tumor necrosis factor-α receptor 2, and interleukin-6 (r = −0.23 to −0.14). With control for these factors and known risk factors for colorectal cancer, plasma PLP levels were significantly inversely associated with risk of colorectal cancer; compared with men in the lowest quartile, those with PLP in quartiles 2 to 4 had relative risks (95% confidence interval) of 0.92 (0.55-1.56), 0.42 (0.23-0.75), and 0.49 (0.26-0.92; Ptrend = 0.01), respectively. In conclusion, vitamin B6 may protect against colorectal cancer independent of other one-carbon metabolites and inflammatory biomarkers. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1197–202)
Heritable Variation ofERBB2and Breast Cancer Risk
Authors: Breyer Joan P. , Sanders Melinda E. , Airey David C. , Cai Qiuyin , Yaspan Brian L. , Schuyler Peggy A. , Dai Qi , Boulos Fouad , Olivares Maria G. , Bradley Kevin M. , Gao Yu-Tang , Page David L. , Dupont William D. , Zheng Wei , Smith Jeffrey R.
Published: April 2009

Amplification of the epithelial growth factor receptor gene ERBB2 (HER2, NEU) in breast cancer is associated with a poor clinical prognosis. In mammary gland development, this receptor plays a role in ductal and lobuloalveolar differentiation. We conducted a systematic investigation of the role of genetic variation of the ERBB2 gene in breast cancer risk in a study of 842 histologically confirmed invasive breast cancer cases and 1,108 controls from the Shanghai Breast Cancer Study. We observed that the ERBB2 gene resides within a locus of high linkage disequilibrium, composed of three major ancestral haplotypes in the study population. These haplotypes are marked by simple tandem repeat and single nucleotide polymorphisms, including the missense variants I655V and P1170A. We observed a risk-modifying effect of a highly polymorphic simple tandem repeat within an evolutionarily conserved region, 4.4 kb upstream from the ERBB2 transcription start site. Under a dominant genetic model, the age-adjusted odds ratio was 1.74 (95% confidence interval, 1.27-2.37). Its association with breast cancer, and with breast cancer stratified by histology, by histologic grade, and by stage, remained significant after correction for multiple comparisons. In contrast, we observed no association of ERBB2 single nucleotide polymorphism haplotypes with breast cancer predisposition. (Cancer Epidemiol Biomarkers Prev 2009;18(4):1252–8)