bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Resolution Array-Based Comparative Genomic Hybridization of Bladder Cancers IdentifiesMouse Double Minute 4(MDM4) as an Amplification Target Exclusive ofMDM2andTP53
Authors: Veerakumarasivam Abhi , Scott Helen E. , Chin Suet-Feung , Warren Anne , Wallard Matthew J. , Grimmer Donna , Ichimura Koichi , Caldas Carlos , Collins V. Peter , Neal David E. , Kelly John D. 
Published: May 2008

AbstractPurpose: Loss of p53 function in urothelial cell carcinoma (UCC) by mutation or inactivation disrupts normal cell cycle checkpoints, generating a favorable milieu for genomic instability, a hallmark of UCC. The aim of this study was to characterize novel DNA copy number changes to identify putative therapeutic targets.Experimental Design: We report our findings using array comparative genomic hybridization on a whole-genome BAC/PAC/cosmid array with a median clone interval of 0.97 Mb to study a series of UCC cases. TP53 status was determined by direct sequencing, and an in-house tissue microarray was constructed to identify protein expression of target genes.Results: Array comparative genomic hybridization allowed identification of novel regions of copy number changes in addition to those already known from previous studies. A novel amplification previously unreported in UCC was identified at 1q32. A chromosome 1 tile path array was used to analyze tumors that showed gains and amplification; the mouse double minute 4 (MDM4) homologue was identified as the amplified gene. MDM4 mRNA expression correlated with copy number and tumor grade. Copy number changes of MDM4 and MDM2 occurred exclusively in tumors with wild-type p53. Overexpression of MDM4 corresponded to disruption of p53 transcriptional activity. Immunohistochemistry on an independent series by tissue microarray identified an inverse relationship between Mdm4 and Mdm2, with Mdm4 expression highest in invasive UCC.Conclusion: The data indicate that gain/amplification and overexpression of MDM4 is a novel molecular mechanism by which a subset of UCC escapes p53-dependent growth control, thus providing new avenues for therapeutic intervention.
The Effect of Ketoconazole on the Pharmacokinetics and Pharmacodynamics of Ixabepilone: A First in Class Epothilone B Analogue in Late-Phase Clinical Development
Authors: Goel Sanjay , Cohen Marvin , Çömezoglu S. Nilgün , Perrin Lionel , André François , Jayabalan David , Iacono Lisa , Comprelli Adriana , Ly Van T. , Zhang Donglu , Xu Carrie , Humphreys W. Griffith , McDaid Hayley , Goldberg Gary , Horwitz Susan B. , Mani Sridhar 
Published: May 2008

Abstract
Purpose: To determine if ixabepilone is a substrate for cytochrome P450 3A4 (CYP3A4) and if its metabolism by this cytochrome is clinically important, we did a clinical drug interaction study in humans using ketoconazole as an inhibitor of CYP3A4.
Experimental Design: Human microsomes were used to determine the cytochrome P450 enzyme(s) involved in the metabolism of ixabepilone. Computational docking (CYP3A4) studies were done for epothilone B and ixabepilone. A follow-up clinical study was done in patients with cancer to determine if 400 mg/d ketoconazole (inhibitor of CYP3A4) altered the pharmacokinetics, drug-target interactions, and pharmacodynamics of ixabepilone.
Results: Molecular modeling and human microsomal studies predicted ixabepilone to be a good substrate for CYP3A4. In patients, ketoconazole coadministration resulted in a maximum ixabepilone dose administration to 25 mg/m2 when compared with single-agent therapy of 40 mg/m2. Coadministration of ketoconazole with ixabepilone resulted in a 79% increase in AUC0-∞. The relationship of microtubule bundle formation in peripheral blood mononuclear cells to plasma ixabepilone concentration was well described by the Hill equation. Microtubule bundle formation in peripheral blood mononuclear cells correlated with neutropenia.
Conclusions: Ixabepilone is a good CYP3A4 substrate in vitro; however, in humans, it is likely to be cleared by multiple mechanisms. Furthermore, our results provide evidence that there is a direct relationship between ixabepilone pharmacokinetics, neutrophil counts, and microtubule bundle formation in PBMCs. Strong inhibitors of CYP3A4 should be used cautiously in the context of ixabepilone dosing.
The Average Cumulative Risks of Breast and Ovarian Cancer for Carriers of Mutations in BRCA1 and BRCA2 Attending Genetic Counseling Units in Spain
Authors: Milne Roger L. , Osorio Ana , Cajal Teresa Ramón y , Vega Ana , Llort Gemma , de la Hoya Miguel , Díez Orland , Alonso M. Carmen , Lazaro Conxi , Blanco Ignacio , Sánchez-de-Abajo Ana , Caldés Trinidad , Blanco Ana , Graña Begoña , Durán Mercedes , Velasco Eladio , Chirivella Isabel , Cardeñosa Eva Esteban , Tejada María-Isabel , Beristain Elena , Miramar María-Dolores , Calvo María-Teresa , Martínez Eduardo , Guillén Carmen , Salazar Raquel , San Román Carlos , Antoniou Antonis C. , Urioste Miguel , Benítez Javier 
Published: May 2008

Abstract
Purpose: It is not clear that the published estimates of the breast and ovarian cancer penetrances of mutations in BRCA1 and BRCA2 can be used in genetic counseling in countries such as Spain, where the incidence of breast cancer in the general population is considerably lower, the prevalence of BRCA2 mutations seems to be higher, and a distinct spectrum of recurrent mutations exists for both genes. We aimed to estimate these penetrances for women attending genetic counseling units in Spain.
Experimental Design: We collected phenotype and genotype data on 155 BRCA1 and 164 BRCA2 mutation carrier families from 12 centers across the country. Average age-specific cumulative risks of breast cancer and ovarian cancer were estimated using a modified segregation analysis method.
Results: The estimated average cumulative risk of breast cancer to age 70 years was estimated to be 52% [95% confidence interval (95% CI), 26-69%] for BRCA1 mutation carriers and 47% (95% CI, 29-60%) for BRCA2 mutation carriers. The corresponding estimates for ovarian cancer were 22% (95% CI, 0-40%) and 18% (95% CI, 0-35%), respectively. There was some evidence (two-sided P = 0.09) that 330A&gt;G (R71G) in BRCA1 may have lower breast cancer penetrance.
Conclusions: These results are consistent with those from a recent meta-analysis of practically all previous penetrance studies, suggesting that women with BRCA1 and BRCA2 mutations attending genetic counseling services in Spain have similar risks of breast and ovarian cancer to those published for other Caucasian populations. Carriers should be fully informed of their mutation- and age-specific risks to make appropriate decisions regarding prophylactic interventions such as oophorectomy.
Cardiac Toxicity and Efficacy of Trastuzumab Combined with Pertuzumab in Patients with Trastuzumab-Insensitive Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer
Authors: Portera Chia C. , Walshe Janice M. , Rosing Douglas R. , Denduluri Neelima , Berman Arlene W. , Vatas Ujala , Velarde Margarita , Chow Catherine K. , Steinberg Seth M. , Nguyen Diana , Yang Sherry X. , Swain Sandra M. 
Published: May 2008

Abstract
Purpose: To evaluate safety and efficacy of trastuzumab with pertuzumab in patients with human epidermal growth factor receptor 2 (HER2)–positive metastatic breast cancer who had progressive disease on trastuzumab-based therapy.
Experimental Design: Patients with measurable HER2+ metastatic breast cancer, ≤3 trastuzumab-based regimens, and left ventricular ejection fraction (LVEF) ≥55% received 8 or 6 mg/kg trastuzumab and 840 mg pertuzumab i.v. followed by 6 mg/kg trastuzumab and 420 mg pertuzumab every 3 weeks. Cardiac evaluation and tumor response were assessed every 3 and 6 weeks, respectively.
Results: Eleven patients received 64 cycles of trastuzumab plus pertuzumab. A total of 92 echocardiograms and 8 cardiac magnetic resonance imaging studies were done. With the lower limit of normal LVEF 55%, left ventricular systolic dysfunction was observed in six patients, three grade 1, two grade 2, and one grade 3 according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The objective response rate was 18%. Two patients had partial responses, three had stable disease, and six had progressive disease. The median time to progression was 6 weeks. In baseline tumors from formalin-fixed paraffin-embedded primary and/or metastatic tumor biopsies, pHER2-Y1248 trended toward an increase in patients with partial response compared with those with stable disease/progressive disease (P = 0.095).
Conclusion: Trastuzumab plus pertuzumab may have clinical benefit in selected patients who have previously been treated with trastuzumab. Cardiac toxicity, although asymptomatic in most cases, was associated with this treatment. Further evaluation of efficacy of this combination is required to define the overall risks and benefits.
The Morphology of Northern Hemisphere Blocking
Authors: Tyrlis E. , Hoskins B. J. 
Published: May 2008

Abstract
The morphology of regional blocking in the Northern Hemisphere is discussed using the 40-yr ECMWF Re-Analysis (ERA-40) dataset and a measure of blocking based on the reversal at storm-track latitudes of meridional θ contrasts on a potential vorticity (PV) surface representative of the tropopause. The focus is on cyclonic and anticyclonic Rossby wave breaking that is inherent to the blocking development, and the extent to which this is determined by the climatological jet position and the ambient shears. More generally, the importance of the climatological planetary scale is discussed. The approach is mainly through composite behavior, but informed by consideration of many individual events. A diversity of behavior is found with longitude in both winter and summer, and there is a striking reversal of the sense of the wave breaking between the two seasons that is generally consistent with the difference in the jet locations. Preferred behaviors are found in various regions and seasons, and retrogression of blocking is discussed.
High-Resolution Observations with MU Radar of a KH Instability Triggered by an Inertia–Gravity Wave in the Upper Part of a Jet Stream
Authors: Luce H. , Hassenpflug G. , Yamamoto M. , Fukao S. , Sato K. 
Published: May 2008

Abstract
Kelvin–Helmholtz (KH) instability is likely one of the most important sources of clear-air turbulence in the lower atmosphere. It produces billows, which mix and transport heat and materials vertically in the stably stratified atmosphere. Billows can also dissipate energy; therefore they can affect the larger-scale dynamics. While only a few direct observations have been reported in the tropopause region, in this work the authors report very detailed observations of billow structures around 16-km altitude, in the upper part of the jet stream. Observations were made with very high frequency (VHF)-band mid- and upper-atmosphere (MU) radar (Shigaraki, Japan; 34.85°N, 136.10°E) whose height resolution was improved with a range-imaging technique. KH billow structures were observed for at least 2 h and were found to have horizontal wavelengths of about 5.3 km and vertical extents between 0.5 and 1.0 km. Analysis of wind and temperature profiles measured by radiosondes launched from nearby meteorological stations indicated the presence of nearly monochromatic disturbances, likely due to a dominant inertia–gravity wave (IGW) superimposed on the background wind field. The presence of the IGW was also confirmed by analysis of wind profiles measured by the MU radar just before the KH billows were detected by the observations in range-imaging mode. The IGW, with vertical and horizontal wavelengths of about 3.5 and 600 km, respectively, may have been a direct radiation from the jet stream, as suggested by recent works, and likely played a major role in the onset of the observed KH instability.
Predictable Components and Singular Vectors
Authors: DelSole Timothy , Tippett Michael K. 
Published: May 2008

Abstract
This paper shows that if a measure of predictability is invariant to affine transformations and monotonically related to forecast uncertainty, then the component that maximizes this measure for normally distributed variables is independent of the detailed form of the measure. This result explains why different measures of predictability such as anomaly correlation, signal-to-noise ratio, predictive information, and the Mahalanobis error are each maximized by the same components. These components can be determined by applying principal component analysis to a transformed forecast ensemble, a procedure called predictable component analysis (PrCA). The resulting vectors define a complete set of components that can be ordered such that the first maximizes predictability, the second maximizes predictability subject to being uncorrelated of the first, and so on. The transformation in question, called the whitening transformation, can be interpreted as changing the norm in principal component analysis. The resulting norm renders noise variance analysis equivalent to signal variance analysis, whereas these two analyses lead to inconsistent results if other norms are chosen to define variance. Predictable components also can be determined by applying singular value decomposition to a whitened propagator in linear models. The whitening transformation is tantamount to changing the initial and final norms in the singular vector calculation. The norm for measuring forecast uncertainty has not appeared in prior predictability studies. Nevertheless, the norms that emerge from this framework have several attractive properties that make their use compelling. This framework generalizes singular vector methods to models with both stochastic forcing and initial condition error. These and other components of interest to predictability are illustrated with an empirical model for sea surface temperature.
Numerical Simulation of Mammatus
Authors: Kanak Katharine M. , Straka Jerry M. , Schultz David M. 
Published: May 2008

AbstractMammatus are hanging lobes on the underside of clouds. Although many different mechanisms have been proposed for their formation, none have been rigorously tested. In this study, three-dimensional numerical simulations of mammatus on a portion of a cumulonimbus cirruslike anvil are performed to explore some of the dynamic and microphysical factors that affect mammatus formation and evolution. Initial conditions for the simulations are derived from observed thermodynamic soundings. Five observed soundings are chosen—four were associated with visually observed mammatus and one was not. Initial microphysical conditions in the simulations are consistent with in situ observations of cumulonimbus anvil and mammatus. Mammatus form in the four model simulations initialized with the soundings for which mammatus were observed, whereas mammatus do not form in the model simulation initialized with the no-mammatus sounding. Characteristics of the modeled mammatus compare favorably to previously published mammatus observations.Three hypothesized formation mechanisms for mammatus are tested: cloud-base detrainment instability, fallout of hydrometeors from cloud base, and sublimation of ice hydrometeors below cloud base. For the parameters considered, cloud-base detrainment instability is a necessary, but not sufficient, condition for mammatus formation. Mammatus can form without fallout, but not without sublimation. All the observed soundings for which mammatus were observed feature a dry-adiabatic subcloud layer of varying depth with low relative humidity, which supports the importance of sublimation to mammatus formation.
Structure and Formation of an Annular Hurricane Simulated in a Fully Compressible, Nonhydrostatic Model—TCM4*
Authors: Wang Yuqing 
Published: May 2008

Abstract
The structure and formation of an annular hurricane simulated in a fully compressible, nonhydrostatic tropical cyclone model—TCM4—are analyzed. The model is initialized with an axisymmetric vortex on an f plane in a quiescent environment, and thus the transition from the nonannular hurricane to the annular hurricane is attributed to the internal dynamics. The simulated annular hurricane has all characteristics of those recently documented by Knaff et al. from satellite observations: quasi-axisymmetric structure, large eye and wide eyewall, high intensity, and suppressed major spiral rainbands. A striking feature of the simulated annular hurricane is its large outward tilt of the wide eyewall, which is critical to the quasi-steady high intensity and is responsible for the maintenance of the large size of the eye and eyewall of the storm. Although the annular hurricane has a quasi-axisymmetric structure, marked low-wavenumber asymmetries exist in the eyewall region.
The formation of the simulated annular hurricane is found to be closely related to the interaction between the inner spiral rainbands and the eyewall convection. As the inner rainbands spiral cyclonically inward, they experience axisymmetrization due to strong shear deformation and filamentation outside the eyewall and evolve into a quasi-symmetric convective ring, which intensifies as it contracts while the eyewall breaks down and weakens. Eventually, the convective ring replaces the original eyewall. The new eyewall formed in such a way is wider and tilts more outward with height than the original eyewall. Several such eyewall cycles in our simulation produce an annular hurricane with large eyewall slope, large eye, and wide eyewall. The response of low-level winds to the tilted convective heating in the eyewall is an increase outside and a decrease inside the radius of maximum wind, prohibiting further contraction of the new eyewall. Strong convective mass flux in the eyewall updraft corresponds to strong convective overturning subsidence outside the eyewall, greatly suppressing the development of any major rainbands outside the eyewall. Although the eyewall cycle documented in this study contributes to the formation of annular hurricanes, it could be a general process causing the increase in eye size of real tropical cyclones as well.
Total and caspase-cleaved cytokeratin 18 in chronic cholecystitis: A prospective study
Authors: Simopoulos Constantinos , Tsaroucha Alexandra K , Asimakopoulos Byron , Giatromanolaki Alexandra , Gavriilidis Paschalis , Polychronidis Alexandros , Karayiannakis Anastasios 
Published: May 2008

Abstract

Background
Cell death mode has been studied in cancer, autoimmune, and neurodegenerative diseases. In this study, apoptosis and necrosis are investigated for the first time in patients with chronic calculous cholecystitis.

Methods and materials
Thirty five (35) patients (27 women and 8 men, aged 55.65 ± 13.48 years) with symptomatic chronic calculous cholecystitis underwent laparoscopic cholecystectomy. The early specific apoptotic tendency (caspase-cleaved cytokeratin 18) was studied in these patients with M30 Apoptosense ELISA and the total cytokerarin 18 (both derived from apoptosis and necrosis) with M65 ELISA. The ratio M30/M65 (caspase-cleaved to total cytokeratin 18) was also computed. According to the histopathological examination, the patients were divided in two groups: group A included patients with chronic inactive cholecystitis (n = 10), and group B those with chronic active cholecystitis (n = 25).

Results
The concentrations of caspase-cleaved cytokerarin 18 (CK18), and especially those of total CK18, were higher in bile samples than in serum samples. In group B, there were significant differences between serum and bile samples regarding both caspase-cleaved CK18 and total CK18. Cells staining positive for caspase-cleaved CK18 were present in the epithelial cells of the mucosa of the gallbladder.

Conclusion
CK18 is expressed in the gallbladder epithelial cells. The concentrations of both caspase-cleaved CK18 and total CK18 were higher in bile samples than in serum samples. The levels of total CK18, as well as caspase-cleaved CK18, do not seem to differ between active and inactive chronic cholecystitis.
Development and validation of psychosocial determinants measures of physical activity among Iranian adolescent girls
Authors: Pirasteh Ashraf , Hidarnia Alireza , Asghari Ali , Faghihzadeh Soghrate , Ghofranipour Fazlollah 
Published: May 2008

Abstract

Background
The present study aimed at assessing the psychometric properties of psychosocial determinants of physical activity-related measures in Iranian adolescent girls.

Methods
Several measures of psychosocial determinants of physical activity were translated from English into Persian using the back-translation technique. These translated measures were administered to 512 ninth and tenth-grade Iranian high school students.

Results
The results of a series of factor analysis showed that the self-efficacy scale contained a single factor, the social support scale contained two factors: family support and friend support, the physical activity 'pros & cons' scale contained two factors: physical activity pros scale and physical activity cons scale, the change strategies scale contained a single factor, the environment scale also contained a single factor. Chronbach's alphas, mean inter-item correlations and test-retest coefficients showed that these solutions were reliable.

Conclusions
These preliminary results provide support for using the mentioned scales to measure psychosocial determinants of physical activity in Iranian adolescent girls.
Police and public health partnerships: Evidence from the evaluation of Vancouver's supervised injection facility
Authors: DeBeck Kora , Wood Evan , Zhang Ruth , Tyndall Mark , Montaner Julio , Kerr Thomas 
Published: May 2008

Abstract
In various settings, drug market policing strategies have been found to have unintended negative effects on health service use among injection drug users (IDU). This has prompted calls for more effective coordination of policing and public health efforts. In Vancouver, Canada, a supervised injection facility (SIF) was established in 2003. We sought to determine if local police impacted utilization of the SIF. We used generalized estimating equations (GEE) to prospectively identify the prevalence and correlates of being referred by local police to Vancouver's SIF among IDU participating in the Scientific Evaluation of Supervised Injecting (SEOSI) cohort during the period of December 2003 to November 2005. Among 1090 SIF clients enrolled in SEOSI, 182 (16.7%) individuals reported having ever been referred to the SIF by local police. At baseline, 22 (2.0%) participants reported that they first learned of the SIF via police. In multivariate analyses, factors positively associated with being referred to the SIF by local police when injecting in public include: sex work (Adjusted Odds Ratio [AOR] = 1.80, 95%CI 1.28 – 2.53); daily cocaine injection (AOR = 1.54, 95%CI 1.14 – 2.08); and unsafe syringe disposal (AOR = 1.46, 95%CI 1.00 – 2.11). These findings indicate that local police are facilitating use of the SIF by IDU at high risk for various adverse health outcomes. We further found that police may be helping to address public order concerns by referring IDU who are more likely to discard used syringes in public spaces. Our study suggests that the SIF provides an opportunity to coordinate policing and public health efforts and thereby resolve some of the existing tensions between public order and health initiatives.