bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling plasma loudspeakers
Authors: Béquin Ph. , Castor K. , Herzog Ph. , Montembault V.
Published: April 2007

This paper deals with the acoustic modeling and measurement of a needle-to-grid plasma loudspeaker using a negative Corona discharge. In the first part, we summarize the model described in previous papers, where the electrode gap is divided into a charged particle production region near the needle and a drift region which occupies most of the inter-electrode gap. In each region, interactions between charged and neutral particles in the ionized gas lead to a perturbation of the surrounding air, and thus generate an acoustic field. In each region, viewed as a separate acoustic source, an acoustical model requiring only a few parameters is proposed. In the second part of the paper, an experimental setup is presented for measuring acoustic pressures and directivities. This setup was developed and used to study the evolution of the parameters with physical properties, such as the geometrical and electrical configuration and the needle material. In the last part of this paper, a study on the electroacoustic efficiency of the plasma loudspeaker is described, and differences with respect to the design parameters are analyzed. Although this work is mainly aimed at understanding transduction phenomena, it may be found useful for the development of an audio loudspeaker.
Azimuthal sound localization using coincidence of timing across frequency on a robotic platform
Authors: Calmes Laurent , Lakemeyer Gerhard , Wagner Hermann
Published: April 2007

An algorithm for localizing a sound source with two microphones is introduced and used in real-time situations. This algorithm is inspired by biological computation of interaural time difference as occurring in the barn owl and is a modification of the algorithm proposed by Liu et al. [J. Acoust. Soc. Am. 110, 3218–3231 (2001)] in that it creates a three-dimensional map of coincidence location. This eliminates localization artifacts found during tests with the original algorithm. The source direction is found by determining the azimuth at which the minimum of the response in an azimuth-frequency matrix occurs. The system was tested with a pan-tilt unit in real-time in an office environment with signal types ranging from broadband noise to pure tones. Both open loop (pan-tilt unit stationary) and closed loop experiments (pan-tilt unit moving) were conducted. In real world situations, the algorithm performed well for all signal types except pure tones. Subsequent room simulations showed that localization accuracy decreases with decreasing direct-to-reverberant ratio.
The perception of phonemic contrasts in a non-native dialect
Authors: Dufour Sophie , Nguyen Noël , Frauenfelder Ulrich Hans
Published: April 2007

This study examined the impact on speech processing of regional phonetic/phonological variation in the listener’s native language. The perception of the /e/-/ε/ and /o/-/ɔ/ contrasts, produced by standard but not southern French native speakers, was investigated in these two populations. A repetition priming experiment showed that the latter but not the former perceived words such as /epe/ and /epε/ as homophones. In contrast, both groups perceived the two words of /o/-/ɔ/ minimal pairs (/pom/-/pɔm/) as being distinct. Thus, standard-French words can be perceived differently depending on the listener’s regional accent.
Applying nonlinear resonant ultrasound spectroscopy to improving thermal damage assessment in concrete
Authors: Payan C. , Garnier V. , Moysan J. , Johnson P. A.
Published: April 2007

Nonlinear resonant ultrasound spectroscopy (NRUS) consists of evaluating one or more resonant frequency peak shifts while increasing excitation amplitude. NRUS exhibits high sensitivity to global damage in a large group of materials. Most studies conducted to date are aimed at interrogating the mechanical damage influence on the nonlinear response, applying bending, or longitudinal modes. The sensitivity of NRUS using longitudinal modes and the comparison of the results with a classical linear method to monitor progressive thermal damage (isotropic) of concrete are studied in this paper. In addition, feasibility and sensitivity of applying shear modes for the NRUS method are explored.
Experimental study on subharmonic and ultraharmonic acoustic waves in water-saturated sandy sediment
Authors: Kim Byoung-Nam , Lee Kang Il , Yoon Suk Wang
Published: April 2007

Experimental observations of the subharmonic and ultraharmonic acoustic waves in water-saturated sandy sediment are reported in this paper. Acoustic pressures of both nonlinear acoustic waves strongly depend on the driving acoustic pressure at a transducer. The first ultraharmonic wave reaches a saturation value as the driving acoustic pressure increases. The acoustic pressure levels of both nonlinear acoustic waves exhibit some fluctuations in comparison with that of the primary acoustic wave as the receiving distance of hydrophone increases in sediment. The subharmonic and the ultraharmonic phenomena in this study show close resemblance to those produced in bubbly water.
Acquisition of lexical stress by Mandarin learners
Authors: Lai Yuwen , Sereno Joan
Published: April 2007

Acoustic characteristics of stress were examined in second language learners’ productions of English lexical stress. Fourteen minimal pairs of disyllabic English nouns and verbs contrasting in stress pattern (trochees and iambs; e.g., OBject and obJECT) were recorded. Eighteen Chinese learners of English (NNSs) (nine advanced, nine basic) and ten native speakers of English (NSs) participated in the experiment. Preliminary results indicate that subjects in all groups use vowel duration, F0, and intensity to distinguish the nouns and verbs but the correlates were realized differently. In nouns, NSs and both groups of NNSs pattern similarly in their use of duration. However, both basic and advanced non-native learners use F0 and intensity to a lesser extent than NSs. For verbs, NSs differ from NNSs in the realization of duration and F0 but not intensity. In addition, basic learners have significantly smaller duration differences but greater F0 differences between stressed and unstressed syllables when compared to NSs while advanced learners pattern in between the basic and NS groups. These results are discussed with respect to how suprasegmental features of the native language affect the prosodic acquisition of a second language.
Resuscitation competencies in paediatric specialist registrars
Authors: Gemke Reinoud J B J , Weeteling Bianca , van Elburg Ruurd M
Published: April 2007

Background

Despite the increased availability of resuscitation courses and guidelines requiring optimal training for acute situations, little is known on the actual qualification of house staff with in-hospital on-call duties for critically ill newborns and children.

Objective

To assess (1) the characteristics of education and training; (2) the level of experience; and (3) factors that may hamper optimal performance of paediatric specialist registrars caring for acute critically ill newborns and children.

Methods

A structured questionnaire was completed by a national cohort of all paediatric specialist registrars in their fourth year (ie pre-final) of training.

Results

Important shortcomings in training and assessment of actual qualifications of resuscitation competencies were identified in paediatric specialist registrars. In 17 of 57 (30%) specialist registrars, competencies in acute care had never been assessed or reconfirmed when starting on-call duties while in the others, 40 (70%), substantial heterogeneity was found regarding the type of assessment of qualifications for on-call duties. In acute situations, occasionally untrained and unsupervised resuscitation procedures were performed. Individual responsibility was the most important stressor that may hamper optimal performance. Despite these findings, adequate reported levels of self-confidence were found; self confidence was higher in newborns as compared to children (7.8 and 7.0 respectively on scale 1–10, p<0.05).

Conclusions

Successful completion of a resuscitation course does not ensure adequate qualifications by on-call residents, unless regular refresher sessions are provided. Teaching hospitals should establish and implement uniform guidelines for training and assessment of competencies regarding acute care for critically ill children and newborns.
Tako-tsubo syndrome on the rise: a review of the current literature
Authors: Buchholz Stefan , Rudan George
Published: April 2007

Tako-tsubo syndrome (TTS) or stress-related acute reversible ventricular apical dysfunction is an emerging but seemingly under-recognised cardiomyopathy mimicking acute ST elevation myocardial infarction (STEMI) without concomitant epicardial coronary artery disease. Severe emotional stress is the most common trigger for this syndrome in the published series, but it can also be precipitated by severe intercurrent medical illness. Precise epidemiological data are not yet available, although TTS most commonly affects elderly women. The exact cause of this syndrome is undetermined, but proposed mechanisms include epicardial coronary artery vasospasm, impaired multivessel coronary microcirculation, calcium overload with direct myocyte damage and disrupted fatty acid metabolism with prolonged myocardial stunning. The time course of electrocardiographic changes is very similar to that of an acute STEMI due to an acute occlusion of the left anterior descending coronary artery. The left ventricular dysfunction typically displays an akinetic apical half of the left or both ventricles with hyperkinetic basal segments, although a variant with apical sparing has also been described recently. The ventricular dysfunction usually resolves within weeks and carries a generally favourable prognosis.
Classical diseases revisited: transient global amnesia
Authors: Owen D , Paranandi B , Sivakumar R , Seevaratnam M
Published: April 2007

Transient global amnesia usually affects patients between the ages of 40 and 80. Patients with this condition are often described – wrongly – as being confused. It presents classically with an abrupt onset of severe anterograde amnesia. It is usually accompanied by repetitive questioning. The patient does not have any focal neurological symptoms. Patients remain alert, attentive, and cognition is not impaired. However, they are disoriented to time and place. Attacks usually last for 1–8 h but should be less than 24 h. It is possible that it may result from different mechanisms such as venous congestion with valsalva-like activities before symptom onset, arterial thromboembolic ischaemia and vasoconstriction due to hyperventilation. Diagnosis may be made safely in the presence of a characteristic collateral history. No specific treatment is indicated for a typical episode.
Vitamin D in childhood and adolescence
Authors: Cashman Kevin D
Published: April 2007

It is well-established that prolonged and severe vitamin D deficiency leads to rickets in children and osteomalacia in adults. More marginal vitamin D deficiency is likely to be a significant contributing factor to osteoporosis risk. However, recent emerging data from studies of adults suggest that low vitamin D status (serum 25-hydroxyvitamin D levels <50 nmol/l) may be contributing to the development of various chronic diseases, including cardiovascular disease, hypertension, diabetes mellitus, some inflammatory and autoimmune diseases, and certain cancers. Adequacy of vitamin D status in children and adolescents has been the focus of a number of recent investigations, and these studies have shown a high prevalence of low vitamin D status during the winter (especially in adolescents), with lower prevalence during the summer. Therefore, consideration of potential corrective strategies to allow children and adolescents to maintain adequate vitamin D status throughout the year, even in the absence of adequate summer sun exposure, is warranted.
Islet cell transplantation
Authors: Srinivasan P , Huang G C , Amiel S A , Heaton N D
Published: April 2007

People with type 1 diabetes have normal exocrine pancreatic function, making islet cell rather than whole organ transplantation an attractive option. Achieving insulin independence in type 1 diabetes was the perceived goal of islet cell transplantation. The success of the Edmonton group in achieving this in a selected group of type 1 patients has led to renewed optimism that this treatment could eventually replace whole organ pancreas transplantation. However the long-term results of this treatment indicate that insulin independence is lost with time in a significant proportion of patients, although they may retain glycaemic stability. In this context, the indications for islet cell transplantation, which have evolved over the last 5 years, indicate that the patients who benefit most are those who experience severe hypoglycaemic reactions despite optimal insulin therapy. This review will summarise the history of islet cell transplantation, islet isolation techniques, the transplant procedure, immunosuppressive therapy, indications for islet cell transplantation, current clinical trials, the early UK islet cell transplant experience using the Edmonton protocol, and some of the challenges that lie ahead.
ELECTROWEAK–HIGGS UNIFICATION AND THE HIGGS BOSON MASS
Authors: ARANDA A. , DÍAZ-CRUZ J. L. , ROSADO A.
Published: April 2007

We propose an alternative unification scenario where the Higgs self-coupling (λ) is determined by imposing its unification with the electroweak gauge couplings. An attractive feature of models within this scenario is the possibility to determine the Higgs boson mass by evolving λ from the electroweak–Higgs unification scale M GH down to the electroweak scale. The unification condition for the gauge (g1, g2) and Higgs couplings is written as g1 = g2 = f(λ), where [Formula: see text] being the normalization constant. Two variants for the unification condition are discussed; scenario I is defined through the linear relation: g1 = g2 = kHλ(M GH ), while scenario II assumes a quadratic relation: [Formula: see text]. Fixing kH = O(1) and the standard normalization (kY = 5/3), we obtain a Higgs boson mass value mH ≃ 190 GeV , with similar results for other normalizations such as kY = 7/4 and 3/2. However, the unification scale M GH depends on the value of kY, going from 1.8 ×1012 GeV up to 4.9 ×1014 GeV for 7/4 > kY > 3/2. Possible tests of this idea at a future linear collider and its application for determining the Higgs spectrum in the two-Higgs doublet model are also discussed. We also elaborate on these unification scenarios within the context of a six-dimensional SU (3)c× SU (3)w Gauge–Higgs unified model, where the Higgs boson arises as the extra-dimensional components of the 6D gauge fields.
INFLATION IS PERHAPS THE GENERIC FEATURE OF PHANTOM FIELD, NOT THE BIG-RIP
Authors: SANYAL ABHIK KUMAR
Published: April 2007

A class of solutions for phantom field corresponding to a generalized k-essence Lagrangian has been presented, employing a simple method which provides the scope to explore many such. All the solutions having dynamical state parameter are found to touch the magic line w = -1 asymptotically. The solutions with constant equation of state can represent phantom, quitessence or an ordinary scalar field cosmologies depending on the choice of a couple of parameters of the theory. For w ≈ -1, quintessence and phantom models are indistinguishable through the Hubble parameter. Finally, it appears that inflation rather than big-rip is the generic feature of phantom cosmology.
TRANSDERMAL ANAESTHESIA FOR PERCUTANEOUS TRIGGER FINGER RELEASE
Authors: Yiannakopoulos Christos K. , Ignatiadis Ioannis A.
Published: April 2007

The purpose of this study was to evaluate the safety and efficiency of transdermal anaesthesia using eutectic mixture of lidocaine and prilocaine (EMLA) in patients undergoing percutaneous trigger finger release and to compare it with lidocaine infiltration.

In this prospective, randomised study percutaneous release of the A1 annular pulley was performed to treat stenosing tenosynovitis (trigger finger syndrome) in 50 patients (50 fingers). The procedure was performed either under transdermal anaesthesia using EMLA applied transcutaneously 120 minutes prior to the operation (Group A, n = 25) or using local infiltration anaesthesia using lidocaine (Group B, n = 25). Pain experienced during administration of anaesthesia and during the operation was assessed using a 10-point Visual Analogue Pain Scale (VAPS), while all patients rated the effectiveness of anaesthesia with a 5-point scale.

There were no significant differences between the two groups in the VAPS during the operation (1.33 ± 0.52 versus 1.59 ± 0.87) and the satisfaction scores (4.6 ± 0.2 versus 4.4 ± 0.3). The VAPS score during the administration of anaesthesia was statistically significantly less in the EMLA group (0 versus 5.96 ± 2.41). All patients were satisfied with the final result of the operation.

Percutaneous trigger finger release can be performed as an office procedure with the use of EMLA avoiding the use of injectable local infiltration anaesthesia.
Low-Power Fully Integrated CMOS DTV Tuner Front-End for ATSC Terrestrial Broadcasting
Authors: Xiao Jianhong , Zhang Guang , Li Tianwei , Silva-Martinez Jose
Published: April 2007

A low-cost low-power DTV tuner for current digital television application is described. In order to increase integration level and reduce power consumption for off-air DTV tuner application, an SAW-filterless tuner front-end architecture is adopted. As a part of the concept, key building blocks for this architecture are implemented on a main stream 0.35 μm CMOS technology. Experimental measurements for the prototype chip validate the system architecture; the prototype consumes 300 mw and achieves 45 dB of image rejection ratio within the entire 750 MHz frequency band.
Selective Killing of Cancer Cells by Leaf Extract of Ashwagandha: Identification of a Tumor-Inhibitory Factor and the First Molecular Insights to Its Effect
Authors: Widodo Nashi , Kaur Kamaljit , Shrestha Bhupal G. , Takagi Yasuomi , Ishii Tetsuro , Wadhwa Renu , Kaul Sunil C.
Published: April 2007

Purpose: Ashwagandha is regarded as a wonder shrub of India and is commonly used in Ayurvedic medicine and health tonics that claim its variety of health-promoting effects. Surprisingly, these claims are not well supported by adequate studies, and the molecular mechanisms of its action remain largely unexplored to date. We undertook a study to identify and characterize the antitumor activity of the leaf extract of ashwagandha.

Experimental Design: Selective tumor-inhibitory activity of the leaf extract (i-Extract) was identified by in vivo tumor formation assays in nude mice and by in vitro growth assays of normal and human transformed cells. To investigate the cellular targets of i-Extract, we adopted a gene silencing approach using a selected small hairpin RNA library and found that p53 is required for the killing activity of i-Extract.

Results: By molecular analysis of p53 function in normal and a variety of tumor cells, we found that it is selectively activated in tumor cells, causing either their growth arrest or apoptosis. By fractionation, purification, and structural analysis of the i-Extract constituents, we have identified its p53-activating tumor-inhibiting factor as withanone.

Conclusion: We provide the first molecular evidence that the leaf extract of ashwagandha selectively kills tumor cells and, thus, is a natural source for safe anticancer medicine.
Preclinical Studies of TW-37, a New Nonpeptidic Small-Molecule Inhibitor of Bcl-2, in Diffuse Large Cell Lymphoma Xenograft Model Reveal Drug Action on Both Bcl-2 and Mcl-1
Authors: Mohammad Ramzi M. , Goustin Anton Scott , Aboukameel Amro , Chen Ben , Banerjee Sanjeev , Wang Guoping , Nikolovska-Coleska Zaneta , Wang Shaomeng , Al-Katib Ayad
Published: April 2007

Purpose: Overexpression of Bcl-2 protein has been observed in more than 80% of B-cell lymphomas, including diffuse large cell lymphoma (DLCL), the most common subtype of non-Hodgkin's lymphoma. We have previously employed the natural product (−)-gossypol to test its therapeutic potential as a small-molecule inhibitor of Bcl-2 for the treatment of B-cell lymphomas.

Experimental Design: Recently, we have used a structure-based strategy to design a new class of potent small-molecule inhibitor acting on Bcl-2. One such lead compound is the benzenesulfonyl derivative TW-37, which was designed to target the BH3-binding groove in Bcl-2 where proapoptotic Bcl-2 proteins, such as Bak, Bax, Bid, and Bim bind.

Results: In our fluorescence polarization–based binding assays using recombinant Bcl-2, Bcl-XL, and Mcl-1 proteins, TW-37 binds to Bcl-2, Bcl-XL, and Mcl-1 with Ki values of 290, 1,110 and 260 nmol/L, respectively. Hence, TW-37 is a potent inhibitor of Bcl-2 and has >3-fold selectivity over Bcl-XL. In vitro, TW-37 showed significant antiproliferative effect in a de novo chemoresistant WSU-DLCL2 lymphoma cell line and primary cells obtained from a lymphoma patient with no effect on normal peripheral blood lymphocytes. Coimmunoprecipitation experiments showed that TW-37 disrupted heterodimer formation between Bax or truncated-Bid and antiapoptotic proteins in the order Mcl-1 > Bcl-2 >> Bcl-XL. As expected, TW-37 caused apoptotic death. Pre-exposure of lymphoma cells to TW-37 significantly enhanced the killing effect of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP) regimen. The maximum tolerated dose of TW-37 in severe combined immunodeficient (SCID) mice was 40 mg/kg for three i.v. injections when given alone and 20 mg/kg, ×3 when given in combination with CHOP. Using WSU-DLCL2-SCID mouse xenograft model, the addition of TW-37 to CHOP resulted in more complete tumor inhibition compared with either CHOP or TW-37 alone.

Conclusions: We conclude that the administration of TW-37, as a potent Bcl-2 and Mcl-1 inhibitor, to standard chemotherapy may prove an effective strategy in the treatment of B-cell lymphoma.
Effects of the Administration of High-Dose Interleukin-2 on Immunoregulatory Cell Subsets in Patients with Advanced Melanoma and Renal Cell Cancer
Authors: van derVliet Hans J.J. , Koon Henry B. , Yue Simon C. , Uzunparmak Burak , Seery Virginia , Gavin Marc A. , Rudensky Alexander Y. , Atkins Michael B. , Balk Steven P. , Exley Mark A.
Published: April 2007

Purpose: High-dose recombinant human interleukin-2 (IL-2) therapy is of clinical benefit in a subset of patients with advanced melanoma and renal cell cancer. Although IL-2 is well known as a T-cell growth factor, its potential in vivo effects on human immunoregulatory cell subsets are largely unexplored.

Experimental Design: Here, we studied the effects of high-dose IL-2 therapy on circulating dendritic cell subsets (DC), CD1d-reactive invariant natural killer T cells (iNKT), and CD4+CD25+ regulatory-type T cells.

Results: The frequency of both circulating myeloid DC1 and plasmacytoid DC decreased during high-dose IL-2 treatment. Of these, only a significant fraction of myeloid DC expressed CD1d. Although the proportion of Th1-type CD4− iNKT increased, similarly to DC subsets, the total frequency of iNKT decreased during high-dose IL-2 treatment. In contrast, the frequency of CD4+CD25+ T cells, including CD4+Foxp3+ T cells, which have been reported to suppress antitumor immune responses, increased during high-dose IL-2 therapy. However, there was little, if any, change of expression of GITR, CD30, or CTLA-4 on CD4+CD25+ T cells in response to IL-2. Functionally, patient CD25+ T cells at their peak level (immediately after the first cycle of high-dose IL-2) were less suppressive than healthy donor CD25+ T cells and mostly failed to Th2 polarize iNKT.

Conclusions: Our data show that there are reciprocal quantitative and qualitative alterations of immunoregulatory cell subsets with opposing functions during treatment with high-dose IL-2, some of which may compromise the establishment of effective antitumor immune responses.
Systemic CTLA-4 Blockade Ameliorates Glioma-Induced Changes to the CD4+ T Cell Compartment without Affecting Regulatory T-Cell Function
Authors: Fecci Peter E. , Ochiai Hidenobu , Mitchell Duane A. , Grossi Peter M. , Sweeney Alison E. , Archer Gary E. , Cummings Thomas , Allison James P. , Bigner Darell D. , Sampson John H.
Published: April 2007

Purpose: Patients with malignant glioma suffer global compromise of their cellular immunity, characterized by dramatic reductions in CD4+ T cell numbers and function. We have previously shown that increased regulatory T cell (Treg) fractions in these patients explain T-cell functional deficits. Our murine glioma model recapitulates these findings. Here, we investigate the effects of systemic CTLA-4 blockade in this model.

Experimental Design: A monoclonal antibody (9H10) to CTLA-4 was employed against well-established glioma. Survival and risks for experimental allergic encephalomyelitis were assessed, as were CD4+ T cell numbers and function in the peripheral blood, spleen, and cervical lymph nodes. The specific capacities for anti-CTLA-4 to modify the functions of regulatory versus CD4+CD25− responder T cells were evaluated.

Results: CTLA-4 blockade confers long-term survival in 80% of treated mice, without eliciting experimental allergic encephalomyelitis. Changes to the CD4 compartment were reversed, as anti-CTLA-4 reestablishes normal CD4 counts and abrogates increases in CD4+CD25+Foxp3+GITR+ regulatory T cell fraction observed in tumor-bearing mice. CD4+ T-cell proliferative capacity is restored and the cervical lymph node antitumor response is enhanced. Treatment benefits are bestowed exclusively on the CD4+CD25− T cell population and not Tregs, as CD4+CD25− T cells from treated mice show improved proliferative responses and resistance to Treg-mediated suppression, whereas Tregs from the same mice remain anergic and exhibit no restriction of their suppressive capacity.

Conclusions: CTLA-4 blockade is a rational means of reversing glioma-induced changes to the CD4 compartment and enhancing antitumor immunity. These benefits were attained through the conferment of resistance to Treg-mediated suppression, and not through direct effects on Tregs.
Microtubule-Associated Protein-tau is a Bifunctional Predictor of Endocrine Sensitivity and Chemotherapy Resistance in Estrogen Receptor–Positive Breast Cancer
Authors: Andre Fabrice , Hatzis Christos , Anderson Keith , Sotiriou Christos , Mazouni Chafika , Mejia Jaime , Wang Bailiang , Hortobagyi Gabriel N. , Symmans W. Fraser , Pusztai Lajos
Published: April 2007

Purpose: The clinical outcome for patients with breast cancer is influenced by the metastatic competence of the cancer and its sensitivity to endocrine therapy and chemotherapy. A molecular marker may be prognostic of outcome or predictive of response to therapy, or a combination of both.

Experimental Design: We examined separately the prognostic and predictive values of tau mRNA expression in estrogen receptor (ER)–positive primary breast cancers in three patient cohorts. We used gene expression data from 209 untreated patients to assess the pure prognostic value of tau, data from 267 patients treated with adjuvant tamoxifen to assess predictive value for endocrine therapy, and data from 82 patients treated with preoperative paclitaxel followed by 5-fluorouracil, doxorubicin, and cyclophosphamide (paclitaxel/FAC) to assess predictive value for chemotherapy response. Wilcoxon rank sum test was used to compare tau expression between different outcome groups.

Results: Higher tau mRNA expression showed borderline nonsignificant association with better prognosis in the absence of systemic adjuvant therapy. Higher tau mRNA expression was significantly associated with no recurrence (at 5 and 10 years, P = 0.005 and P = 0.05, respectively) in patients treated with tamoxifen, indicating a predictive value for endocrine therapy. Tau expression was significantly lower in patients who achieved pathologic complete response to paclitaxel/FAC chemotherapy (P < 0.001).

Conclusion: This study suggests that high tau mRNA expression in ER-positive breast cancer indicates an endocrine-sensitive but chemotherapy-resistant disease. In contrast, low tau expression identifies a subset of ER-positive cancers that have poor prognosis with tamoxifen alone and may benefit from taxane-containing chemotherapy.
The Potential of Antiangiogenic Therapy in Non–Small Cell Lung Cancer
Authors: Giaccone Giuseppe
Published: April 2007

The long-term prognosis for patients with advanced non–small cell lung cancer (NSCLC) remains poor despite the availability of several cytotoxic chemotherapy regimens. The use of targeted therapies, particularly those against the key mediator of angiogenesis vascular endothelial growth factor (VEGF), has the potential to improve outcomes for NSCLC patients. Bevacizumab, a recombinant humanized monoclonal anti-VEGF antibody, is the most clinically advanced antiangiogenic agent in NSCLC. In a phase III study, bevacizumab showed significantly improved overall and progression-free survival when used in combination with standard first-line chemotherapy in patients with advanced NSCLC. Bevacizumab was generally well tolerated in patients with NSCLC; however, tumor-related bleeding adverse events have been noted in some patients, predominantly those with squamous cell histology or centrally located tumors. Several small-molecule VEGF receptor tyrosine kinase inhibitors have also shown promise in phase I and II trials in NSCLC. This review summarizes the most important findings of angiogenesis inhibitors in NSCLC and discusses the potential for the use of these novel agents in different settings of NSCLC.
Population-Based Molecular Prognosis of Breast Cancer by Transcriptional Profiling
Authors: Ma Yan , Qian Yong , Wei Liang , Abraham Jame , Shi Xianglin , Castranova Vincent , Harner E. James , Flynn Daniel C. , Guo Lan
Published: April 2007

Purpose: The purpose of this study is to predict breast cancer recurrence and metastases and to identify gene signatures indicative of clinicopathologic characteristics using gene expression patterns derived from cDNA microarray.

Experimental Design: Expression profiles of 7,650 genes were investigated on an unselected group of 99 node-negative and node-positive breast cancer patients to identify prognostic gene signature of recurrence and metastases. The identified gene signature was validated on independent 78 patients with primary invasive carcinoma (T1/T2 and N0) and on 58 patients with locally advanced breast cancer (T3/T4 and/or N2). The gene predictors were identified using a combination of random forests and linear discriminant analysis function.

Results: This study identified a new 28-gene signature that achieved highly accurate disease-free survival and overall survival (both at P < 0.001, time-dependent receiver operating characteristic analysis) in individual breast cancer patients. Patients categorized into high-risk, intermediate-risk, and low-risk groups had distinct disease-free survival (P < 0.005, Kaplan-Meier analysis, log-rank test) in three patient cohorts. A strong association (P < 0.05) was identified between risk groups and tumor size, tumor grade, estrogen receptor and progesterone receptor status, and HER2/neu overexpression in the studied cohorts. We also identified 14-gene predictors of nodal status and 9-gene predictors of tumor grade.

Conclusions: This study has established a population-based approach to predicting breast cancer outcomes at the individual level exclusively based on gene expression patterns. The 28-gene recurrence signature has been validated as quantifying the probability of recurrence and metastases in patients with heterogeneous histology and disease stage.
Evaluation of Plasma Insulin-like Growth Factor Binding Protein 2 and Her-2 Extracellular Domain as Biomarkers for 17-Allylamino-17-Demethoxygeldanamycin Treatment of Adult Patients with Advanced Solid Tumors
Authors: Eiseman Julie L. , Guo Jianxia , Ramanathan Ramesh K. , Belani Chandra P. , Solit David B. , Scher Howard I. , Ivy S. Percy , Zuhowski Eleanor G. , Egorin Merrill J.
Published: April 2007

Purpose: Interaction of 17-allylamino-17-demethoxygeldanamycin (17-AAG) with heat shock protein 90 results in proteasomal degradation of many proteins, including Her-2-neu, with subsequent decreased expression of insulin-like growth factor binding protein-2 (IGFBP-2). Concentrations of both IGFBP-2 and Her-2 extracellular domain (Her-2 ECD) in sera of mice bearing BT474 human breast cancer xenografts decrease after 17-AAG treatment. We investigated whether this phenomenon occurred in patients.

Materials and Methods: Eight to 15 plasma samples were obtained between 0 and 72 h from 27 patients treated with single-agent 17-AAG at doses between 10 and 307 mg/m2 and 18 patients treated with 17-AAG at doses between 220 and 450 mg/m2 combined with 70 to 75 mg/m2 of docetaxel. Pretreatment plasma samples were also obtained from 12 healthy volunteers. Plasma IGFBP-2 and Her-2 ECD concentrations were quantitated by ELISA.

Results: Pretreatment plasma IGFBP-2 concentrations in patients (171 ± 116 ng/mL) were 2-fold higher than those in healthy volunteers (85 ± 44 ng/mL; P < 0.05). Following 17-AAG treatment, there were no consistent dose-dependent or time-dependent changes in plasma IGFBP-2 and Her-2 ECD concentrations. IGFBP-2 concentrations decreased by ≥40% in 8 patients, increased 2- to 5-fold in 8 patients, and remained essentially unchanged in 29 patients. Her-2 ECD concentrations decreased by ≥40% in 10 patients, increased 1.5- to 5-fold in 2 patients, and remained essentially unchanged in 25 patients.

Conclusions: As previously reported, IGFBP-2 concentrations in plasma of cancer patients are significantly higher than those in healthy volunteers. In contrast to a mouse model, 17-AAG treatment was not consistently associated with decreases in IGFBP-2 or Her-2 ECD concentrations in patient plasma.
Adrenal Androgen Levels as Predictors of Outcome in Prostate Cancer Patients Treated with Ketoconazole Plus Antiandrogen Withdrawal: Results from a Cancer and Leukemia Group B Study
Authors: Ryan Charles J. , Halabi Susan , Ou San-San , Vogelzang Nicholas J. , Kantoff Philip , Small Eric J. ,   for the Cancer and Leukemia Group B
Published: April 2007

Purpose: Adrenal androgens activate the androgen receptor and stimulate prostate cancer growth. Ketoconazole is used as an inhibitor of adrenal androgen synthesis in men with androgen-independent prostate cancer. This study analyzes the relationship between pretreatment androgen levels and outcome following ketoconazole treatment.

Experimental Design: Baseline levels of three adrenal androgens (androstenedione, dehydroepiandrostenedione, and dehydroepiandrostenedione-sulfate) and testosterone were measured. Regression models (logistic and proportional hazard) were used to assess the prognostic significance of these levels in predicting overall survival and prostate-specific antigen (PSA) response defined by Consensus Criteria.

Results: In 103 patients with available levels, PSA response rate was 28% and median response duration was 4.8 months. The median baseline androstenedione level was 0.64 ng/mL and was 0.88 ng/mL versus 0.53 ng/mL for those with and without a PSA response, respectively (P = 0.034). In univariate analysis, elevation of baseline androstenedione levels was predictive of PSA response [odds ratio, 2.26; 95% confidence interval (95% CI), 1.03-4.96; P = 0.043]. In multivariate analysis, both the uppermost and the middle tertile of baseline androstenedione level were associated with an improved overall survival compared with those in the lower tertile (hazard ratio, 0.59; 95% CI, 0.36-0.98; P = 0.40; hazard ratio, 0.53; 95% CI, 0.32-0.90; P = 0.018, respectively). A linear correlation was observed among all androgen levels.

Conclusions: Higher androstenedione levels predict likelihood of response to ketoconazole and improved survival compared with patients with lower levels. These data suggest that therapy with ketoconazole is less effective in patients with low levels of androgen at baseline.
Promoter Hypermethylation Identifies Progression Risk in Bladder Cancer
Authors: Yates David R. , Rehman Ishtiaq , Abbod Maysam F. , Meuth Mark , Cross Simon S. , Linkens Derek A. , Hamdy Freddie C. , Catto James W.F.
Published: April 2007

Purpose: New methods to accurately predict an individual tumor behavior are urgently required to improve the treatment of cancer. We previously found that promoter hypermethylation can be an accurate predictor of bladder cancer progression, but it is not cancer specific. Here, we investigate a panel of methylated loci in a prospectively collected cohort of bladder tumors to determine whether hypermethylation has a useful role in the management of patients with bladder cancer.

Experimental Design: Quantitative methylation-specific PCR was done at 17 gene promoters, suspected to be associated with tumor progression, in 96 malignant and 30 normal urothelial samples. Statistical analysis and artificial intelligence techniques were used to interrogate the results.

Results: Using log-rank analysis, five loci were associated with progression to more advanced disease (RASSF1a, E-cadherin, TNFSR25, EDNRB, and APC; P < 0.05). Multivariate analysis revealed that the overall degree of methylation was more significantly associated with subsequent progression and death (Cox, P = 0.002) than tumor stage (Cox, P = 0.008). Neuro-fuzzy modeling confirmed that these five loci were those most associated with tumor progression. Epigenetic predictive models developed using artificial intelligence techniques identified the presence and timing of tumor progression with 97% specificity and 75% sensitivity.

Conclusion: Promoter hypermethylation seems a reliable predictor of tumor progression in bladder cancer. It is associated with aggressive tumors and could be used to identify patients with either superficial disease requiring radical treatment or a low progression risk suitable for less intensive surveillance. Multicenter studies are warranted to validate this marker.
Angiopoietin 2 Is a Potential Mediator of High-Dose Interleukin 2–Induced Vascular Leak
Authors: Gallagher Diana C. , Bhatt Rupal S. , Parikh Samir M. , Patel Parin , Seery Virginia , McDermott David F. , Atkins Michael B. , Sukhatme Vikas P.
Published: April 2007

Purpose: High-dose interleukin 2 (HDIL2) produces durable tumor regressions in 10% of patients with metastatic renal cell carcinoma and melanoma. However, a major toxicity is vascular leak syndrome (VLS). We previously reported elevated serum angiopoietin 2 (Ang2) in septic patients with vascular leak and hypothesized that Ang2 might also contribute to HDIL2 VLS.

Experimental Design: Blood was collected from 14 patients receiving HDIL2 and from 4 patients receiving HDIL2 and bevacizumab, an antibody against vascular endothelial growth factor (VEGF). The effect of Ang2 was studied in vitro by incubating high Ang2 patient serum with cultured endothelial cells.

Results: Pretreatment Ang2 levels were in the reference range (median, 3.3 ng/mL) and rose with each day of IL-2 therapy (median peak, 29.7 ng/mL). No trend was seen in free VEGF levels during therapy. Patients treated with HDIL2 and bevacizumab all developed VLS and elevated Ang2. High Ang2 patient sera induced propermeability structural changes in endothelial cells, an effect reversed by blockade with the competitive ligand angiopoietin 1 (Ang1).

Conclusions: Ang2 may be a mediator of HDIL2 VLS as evidenced by (a) an increase in Ang2 in all patients on HDIL2; (b) the effect of high Ang2 patient serum on cultured endothelial cells; (c) rescue of those structural changes by Ang1. The lack of correlation between VLS and serum VEGF levels in patients treated with HDIL2 alone or in combination with bevacizumab suggests that VEGF is not a major contributor to VLS or Ang2 release. These data suggest that the inhibition of Ang2 may mitigate VLS in patients receiving HDIL2.
Identification of Molecular Predictors of Response in a Study of Tipifarnib Treatment in Relapsed and Refractory Acute Myelogenous Leukemia
Authors: Raponi Mitch , Harousseau Jean-Luc , Lancet Jeffrey E. , Löwenberg Bob , Stone Richard , Zhang Yi , Rackoff Wayne , Wang Yixin , Atkins David
Published: April 2007

Purpose: Microarray technology was used to identify gene expression markers that predict response to the orally available farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777) in acute myelogenous leukemia (AML).

Experimental Design: Gene expression profiles from 58 bone marrow samples from a cohort of relapsed and refractory AML patients were analyzed on the Affymetrix U133A gene chip that contains ∼22,000 genes.

Results: Supervised statistical analysis identified eight gene expression markers that could predict patient response to tipifarnib. The most robust gene was the lymphoid blast crisis oncogene (AKAP13), which predicted response with an overall accuracy of 63%. This gene provided a negative predictive value of 93% and a positive predictive value of 31% (increased from 18%). AKAP13 was overexpressed in patients who were resistant to tipifarnib. When overexpressed in the HL60 and THP1 cell lines, AKAP13 increased the resistance to tipifarnib by approximately 5- to 7-fold.

Conclusion: Diagnostic gene expression signatures may be used to select a group of AML patients that might respond to tipifarnib.
Causes des variations phénotypiques de la mucoviscidose
Authors: Cutting Garry R.
Published: April 2007

La mucoviscidose est due à une anomalie fonctionnelle du gène régulateur de la conductance transmembranaire de la mucoviscidose (CFTR). L’évolution de la mucoviscidose est très variables, certains sujets décédant de cette maladie au cours de leur première décennie tandis que d’autres atteignent leurs quatrième et cinquième décennies. Les atteintes viscérales et les complications diffèrent également entre les patients. Certaine des variations phénotypiques de la mucoviscidose peuvent être attribuées à la nature de l’anomalie du gène du CFTR. Le génotype CFTR détermine principalement le degré de dysfonction pancréatique exocrine et est corrélé au degré d’anomalie de la concentration du chlorure dans la sueur et de malformation de l’appareil génital masculin. Des facteurs indépendants du CFTR sont cependant responsable de variations de l’atteinte respiratoire, principale cause de morbidité et de mortalité dans la mucoviscidose. Ces dernières années, des gènes modificateurs influençant la sévérité de l’atteinte respiratoire ont été identifiés chez des patients atteints de mucoviscidose. Des facteurs non génétiques tels que le statut socio-économique et le tabagisme passif influencent également l’évolution respiratoire. Des connaissances plus complètes des causes des variations entre les patients atteints de mucoviscidose sont en cours d’acquisition, facilitant le développement de nouvelles mesures pronostiques et de traitements innovants.
Soins des patients atteints d’une mucoviscidose
Authors: Strandvik Birgitta
Published: April 2007

La mucoviscidose, la maladie pédiatrique autosomique héréditaire la plus fréquente, n’atteint plus uniquement des enfants, car son traitement moderne a permis aux patients de vivre plus longtemps avec une meilleure qualité de vie. Voici plus de 16 ans, l’identification du gène responsable et de la mutation la plus fréquente, ΔF508, a suscité l’espoir général d’une guérison rapide de cette maladie. Ces découvertes ont motivé une forte intensification des recherches sur la physiopathologie, mais, à ce jour, les améliorations de la prise en charge clinique ont été totalement dues au développement des traitements traditionnels. L’amélioration de la situation des patients est liée à une meilleure supplémentation en enzymes pancréatiques et à un traitement nutritionnel plus intensif, en prêtant une attention particulière aux anomalies du métabolisme des lipides. Le traitement respiratoire a permis de mieux préserver la fonction respiratoire des patients adultes, grâce à l’accès à un ensemble d’antibiotiques efficaces et au développement de nouvelles strategies, à des mucolytiques ainsi que des incitations à l’activité physique dès le plus jeune âge en association à des modifications de la kinésithérapie et à l’amélioration des résultats de la transplantation pulmonaire en tant que traitement de dernier recours. Une atteinte hépatique est plus souvent reconnue et plus fréquemment traitée à long terme par l’acide ursodésoxycholique, bien que l’effet préventif de ce produit vis-à-vis de la progression de l’hépatopathie n’ait pas été totalement évalué. Le dépistage néonatal est de plus en plus fréquent, ce qui suscite de nouveaux problèmes à court terme, tels ceux de nature psychologique liés à la détection de porteurs ou de sujets atteints d’une forme très peu sévère, et tels que l’évaluation des résultats à long terme afin de démontrer que le statut clinique s’améliore et que la survie augmente encore. Les limitations de survie encore observées semblent principalement dues au mystère sous-tendant la colonisation chronique des voies aériennes par des micro-organismes.
Stem Cells in the Postnatal Pituitary?
Authors: Vankelecom Hugo
Published: April 2007

Tissue-specific stem cells are uncovered in a growing number of organs by their molecular expression profile and their potential for self-renewal, multipotent differentiation and tissue regeneration. Whether the pituitary gland also contains a pool of versatile ’master’ cells that drive homeostatic, plastic and regenerative cell ontogenesis is at present unknown. Here, I will give an overview of data that may lend support to the existence of stem cells in the postnatal pituitary. During the many decades of pituitary research, various approaches have been used to hunt for the pituitary stem cells. Transplantation and regeneration studies advanced chromophobes as possible source of new hormonal cells. Clonogenicity approaches identified pituitary cells that clonally expand to floating spheres, or to colonies in adherent cell cultures. Behavioural characteristics and changes of marginal, follicular and folliculostellate cells during defined developmental and (patho-)physiological conditions have been interpreted as indicative of a stem cell role. Expression of potential stem cell markers like nestin, as well as topographical localization in the marginal zone around the cleft has also been considered to designate pituitary stem cells. Finally, a ‘side population’ was recently identified in the postnatal pituitary which in many other tissues represents a stem cell-enriched fraction. Taken together, in the course of the long-standing study of the pituitary, several arguments have been presented to support the existence of stem cells, and multiple cell types have been placed in the spotlight as possible candidates. However, none of these cells has until now unequivocally been shown to meet all quintessential characteristics of stem cells.