bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunohistochemical expression of insulin-like growth factor binding protein-3 in invasive breast cancers and ductal carcinoma in situ: implications for clinicopathology and patient outcome
Authors: Vestey Sarah B , Perks Claire M , Sen Chandan , Calder Caroline J , Holly Jeff MP , Winters Zoe E 
Published: January 2005

Abstract
Introduction
Insulin-like growth factor binding protein-3 (IGFBP-3) differentially modulates breast epithelial cell growth through insulin-like growth factor (IGF)-dependent and IGF-independent pathways and is a direct (IGF-independent) growth inhibitor as well as a mitogen that potentiates EGF (epidermal growth factor) and interacts with HER-2. Previously, high IGFBP-3 levels in breast cancers have been determined by enzyme-linked immunosorbent assay and immunoradiometric assay methods. In vitro, IGFBP-3's mechanisms of action may involve cell membrane binding and nuclear translocation. To evaluate tumour-specific IGFBP-3 expression and its subcellular localisation, this study examined immunohistochemical IGFBP-3 expression in a series of invasive ductal breast cancers (IDCs) with synchronous ductal carcinomas in situ (DCIS) in relation to clinicopathological variables and patient outcome.

Methods
Immunohistochemical expression of IGFBP-3 was evaluated with the sheep polyclonal antiserum (developed in house) with staining performed as described previously.

Results
IGFBP-3 was evaluable in 101 patients with a variable pattern of cytoplasmic expression (positivity of 1+/2+ score) in 85% of invasive and 90% of DCIS components. Strong (2+) IGFBP-3 expression was evident in 32 IDCs and 40 cases of DCIS. A minority of invasive tumours (15%) and DCIS (10%) lacked IGFBP-3 expression. Nuclear IGFBP-3 expression was not detectable in either invasive cancers or DCIS, with a consistent similarity in IGFBP-3 immunoreactivity in IDCs and DCIS. Positive IGFBP-3 expression showed a possible trend in association with increased proliferation (P = 0.096), oestrogen receptor (ER) negativity (P = 0.06) and HER-2 overexpression (P = 0.065) in invasive tumours and a strong association with ER negativity (P = 0.037) in DCIS. Although IGFBP-3 expression was not an independent prognosticator, IGFBP-3-positive breast cancers may have shorter disease-free and overall survivals, although these did not reach statistical significance.

Conclusions
Increased breast epithelial IGFBP-3 expression is a feature of tumorigenesis with cytoplasmic immunoreactivity in the absence of significant nuclear localisation in IDCs and DCIS. There are trends between high levels of IGFBP-3 and poor prognostic features, suggesting that IGFBP-3 is a potential mitogen. IGFBP-3 is not an independent prognosticator for overall survival or disease-free survival, to reflect its dual effects on breast cancer growth regulated by complex pathways in vivo that may relate to its interactions with other growth factors.
Letrozole sensitizes breast cancer cells to ionizing radiation
Authors: Azria David , Larbouret Christel , Cunat Severine , Ozsahin Mahmut , Gourgou Sophie , Martineau Pierre , Evans Dean B , Romieu Gilles , Pujol Pascal , Pèlegrin Andre 
Published: January 2005

Abstract
Introduction
Radiotherapy (RT) is considered a standard treatment option after surgery for breast cancer. Letrozole, an aromatase inhibitor, is being evaluated in the adjuvant setting. We determined the effects of the combination of RT and letrozole in the aromatase-expressing breast tumour cell line MCF-7CA, stably transfected with the CYP19 gene.

Methods
Irradiations were performed using a cobalt-60 source with doses ranging from 0 to 4 Gy. Cells were incubated with androstenedione in the presence or absence of letrozole. Effects of treatment were evaluated using clonogenic assays, tetrazolium salt colorimetric (MTT) assays, and cell number determinations. Cell-cycle analyses were conducted using flow cytometry.

Results
The survival fraction at 2 Gy was 0.66 for RT alone and was 0.44 for RT plus letrozole (P = 0.02). Growth of MCF-7CA cells as measured by the cell number 6 days after radiotherapy (2 and 4 Gy) was decreased by 76% in those cells treated additionally with letrozole (0.7 μM) compared with those receiving radiotherapy alone (P = 0.009). Growth inhibition, assessed either by cell number (P = 0.009) or by the MTT assay (P = 0.02), was increased after 12 days of the combination treatment. Compared with radiation alone, the combination of radiation and letrozole produced a significant decrease in radiation-induced G2 phase arrest and a decrease of cells in the S phase, with cell redistribution in the G1 phase.

Conclusions
These radiobiological results may form the basis for concurrent use of letrozole and radiation as postsurgical adjuvant therapy for breast cancer.
Haplotype analysis of common variants in the BRCA1 gene and risk of sporadic breast cancer
Authors: Cox David G , Kraft Peter , Hankinson Susan E , Hunter David J 
Published: January 2005

Abstract
Introduction
Truncation mutations in the BRCA1 gene cause a substantial increase in risk of breast cancer. However, these mutations are rare in the general population and account for little of the overall incidence of sporadic breast cancer.

Method
We used whole-gene resequencing data to select haplotype tagging single nucleotide polymorphisms, and examined the association between common haplotypes of BRCA1 and breast cancer in a nested case-control study in the Nurses' Health Study (1323 cases and 1910 controls).

Results
One haplotype was associated with a slight increase in risk (odds ratio 1.18, 95% confidence interval 1.02–1.37). A significant interaction (P = 0.05) was seen between this haplotype, positive family history of breast cancer, and breast cancer risk. Although not statistically significant, similar interactions were observed with age at diagnosis and with menopausal status at diagnosis; risk tended to be higher among younger, pre-menopausal women.

Conclusions
We have described a haplotype in the BRCA1 gene that was associated with an approximately 20% increase in risk of sporadic breast cancer in the general population. However, the functional variant(s) responsible for the association are unclear.
Differentiating midazolam over-sedation from neurological damage in the intensive care unit
Authors: McKenzie Catherine A , McKinnon William , Naughton Declan P , Treacher David , Davies Graham , Phillips Gary J , Hilton Philip J 
Published: January 2005

Abstract
Introduction
Midazolam is used routinely to sedate patients in the intensive care unit (ICU). We suspected that midazolam over-sedation was occurring in the ICU of the Guy's and St. Thomas' Trust and that it could be difficult to differentiate this from underlying neurological damage. A sensitive assay for detecting midazolam and 1-hydroxymidazolam glucuronide (1-OHMG) in serum was developed and applied in the clinical setting.

Methods
In the present study we evaluated a series of cases managed in a mixed medical, surgical and trauma ICU. Serum was collected from 26 patients who received midazolam, were 'slow to wake' and in whom there was suspicion of neurological damage. Patient outcome was followed in terms of mortality, neurological recovery and neurological damage on discharge.

Results
Out of 26 patients, 13 had detectable serum levels of midazolam and/or 1-OHMG after a median of 67 hours (range 36–146 hours) from midazolam cessation. Of these 13 patients in whom midazolam/1-OHMG was detectable, 10 made a full neurological recovery. Of the remaining 13 patients with no detectable midazolam/1-OHMG, three made a full neurological recovery; 10 patients were subsequently found to have suffered neurological damage (P < 0.002), eight of whom died and two were discharged from the ICU with profound neurological damage.

Conclusion
These findings confirm that prolonged sedation after midazolam therapy should be considered in the differential diagnosis of neurological damage in the ICU. This can be reliably detected by the assay method described. The effects of midazolam/1-OHMG persist days after administration of midazolam has ceased. After prolonged sedation has been excluded in this patient group, it is highly likely that neurological damage has occurred.
Increased blood flow prevents intramucosal acidosis in sheep endotoxemia: a controlled study
Authors: Dubin Arnaldo , Murias Gastón , Maskin Bernardo , Pozo Mario O , Sottile Juan P , Barán Marcelo , Edul Vanina S Kanoore , Canales Héctor S , Badie Julio C , Etcheverry Graciela , Estenssoro Elisa 
Published: January 2005

Abstract
Introduction
Increased intramucosal–arterial carbon dioxide tension (PCO2) difference (ΔPCO2) is common in experimental endotoxemia. However, its meaning remains controversial because it has been ascribed to hypoperfusion of intestinal villi or to cytopathic hypoxia. Our hypothesis was that increased blood flow could prevent the increase in ΔPCO2.

Methods
In 19 anesthetized and mechanically ventilated sheep, we measured cardiac output, superior mesenteric blood flow, lactate, gases, hemoglobin and oxygen saturations in arterial, mixed venous and mesenteric venous blood, and ileal intramucosal PCO2 by saline tonometry. Intestinal oxygen transport and consumption were calculated. After basal measurements, sheep were assigned to the following groups, for 120 min: (1) sham (n = 6), (2) normal blood flow (n = 7) and (3) increased blood flow (n = 6). Escherichia coli lipopolysaccharide (5 μg/kg) was injected in the last two groups. Saline solution was used to maintain blood flood at basal levels in the sham and normal blood flow groups, or to increase it to about 50% of basal in the increased blood flow group.

Results
In the normal blood flow group, systemic and intestinal oxygen transport and consumption were preserved, but ΔPCO2 increased (basal versus 120 min endotoxemia, 7 ± 4 versus 19 ± 4 mmHg; P < 0.001) and metabolic acidosis with a high anion gap ensued (arterial pH 7.39 versus 7.35; anion gap 15 ± 3 versus 18 ± 2 mmol/l; P < 0.001 for both). Increased blood flow prevented the elevation in ΔPCO2 (5 ± 7 versus 9 ± 6 mmHg; P = not significant). However, anion-gap metabolic acidosis was deeper (7.42 versus 7.25; 16 ± 3 versus 22 ± 3 mmol/l; P < 0.001 for both).

Conclusions
In this model of endotoxemia, intramucosal acidosis was corrected by increased blood flow and so might follow tissue hypoperfusion. In contrast, anion-gap metabolic acidosis was left uncorrected and even worsened with aggressive volume expansion. These results point to different mechanisms generating both alterations.
GOToolBox: functional analysis of gene datasets based on Gene Ontology
Authors: Martin David , Brun Christine , Remy Elisabeth , Mouren Pierre , Thieffry Denis , Jacq Bernard 
Published: January 2005

AbstractWe have developed methods and tools based on the Gene Ontology (GO) resource allowing the identification of statistically over- or under-represented terms in a gene dataset; the clustering of functionally related genes within a set; and the retrieval of genes sharing annotations with a query gene. GO annotations can also be constrained to a slim hierarchy or a given level of the ontology. The source codes are available upon request, and distributed under the GPL license.
Integrating phenotypic and expression profiles to map arsenic-response networks
Authors: Haugen Astrid C , Kelley Ryan , Collins Jennifer B , Tucker Charles J , Deng Changchun , Afshari Cynthia A , Brown J Martin , Ideker Trey , Van Houten Bennett 
Published: January 2005

Abstract
Background
Arsenic is a nonmutagenic carcinogen affecting millions of people. The cellular impact of this metalloid in Saccharomyces cerevisiae was determined by profiling global gene expression and sensitivity phenotypes. These data were then mapped to a metabolic network composed of all known biochemical reactions in yeast, as well as the yeast network of 20,985 protein-protein/protein-DNA interactions.

Results
While the expression data unveiled no significant nodes in the metabolic network, the regulatory network revealed several important nodes as centers of arsenic-induced activity. The highest-scoring proteins included Fhl1, Msn2, Msn4, Yap1, Cad1 (Yap2), Pre1, Hsf1 and Met31. Contrary to the gene-expression analyses, the phenotypic-profiling data mapped to the metabolic network. The two significant metabolic networks unveiled were shikimate, and serine, threonine and glutamate biosynthesis. We also carried out transcriptional profiling of specific deletion strains, confirming that the transcription factors Yap1, Arr1 (Yap8), and Rpn4 strongly mediate the cell's adaptation to arsenic-induced stress but that Cad1 has negligible impact.

Conclusions
By integrating phenotypic and transcriptional profiling and mapping the data onto the metabolic and regulatory networks, we have shown that arsenic is likely to channel sulfur into glutathione for detoxification, leads to indirect oxidative stress by depleting glutathione pools, and alters protein turnover via arsenation of sulfhydryl groups on proteins. Furthermore, we show that phenotypically sensitive pathways are upstream of differentially expressed ones, indicating that transcriptional and phenotypic profiling implicate distinct, but related, pathways.
Hidden localization motifs: naturally occurring peroxisomal targeting signals in non-peroxisomal proteins
Authors: Neuberger Georg , Kunze Markus , Eisenhaber Frank , Berger Johannes , Hartig Andreas , Brocard Cecile 
Published: January 2005

Abstract
Background
Can sequence segments coding for subcellular targeting or for posttranslational modifications occur in proteins that are not substrates in either of these processes? Although considerable effort has been invested in achieving low false-positive prediction rates, even accurate sequence-analysis tools for the recognition of these motifs generate a small but noticeable number of protein hits that lack the appropriate biological context but cannot be rationalized as false positives.

Results
We show that the carboxyl termini of a set of definitely non-peroxisomal proteins with predicted peroxisomal targeting signals interact with the peroxisomal matrix protein receptor peroxin 5 (PEX5) in a yeast two-hybrid test. Moreover, we show that examples of these proteins - chicken lysozyme, human tyrosinase and the yeast mitochondrial ribosomal protein L2 (encoded by MRP7) - are imported into peroxisomes in vivo if their original sorting signals are disguised. We also show that even prokaryotic proteins can contain peroxisomal targeting sequences.

Conclusions
Thus, functional localization signals can evolve in unrelated protein sequences as a result of neutral mutations, and subcellular targeting is hierarchically organized, with signal accessibility playing a decisive role. The occurrence of silent functional motifs in unrelated proteins is important for the development of sequence-based function prediction tools and the interpretation of their results. Silent functional signals have the potential to acquire importance in future evolutionary scenarios and in pathological conditions.
Reflectivity and rain rate in and below drizzling stratocumulus
Authors: Comstock Kimberly K. , Wood Robert , Yuter Sandra E. , Bretherton Christopher S. 
Published: January 2005

AbstractShip‐based radar measurements obtained during the East Pacific Investigation of Climate 2001 stratocumulus (Sc) cruise are used to derive characteristics of the rainfall from drizzling Sc. Reflectivity to rain rate (Z–R) relationships are determined from shipboard raindrop‐size distribution measurements obtained from observations using filter‐paper, and compared to Z–R relationships derived from aircraft probe data from below north‐east Atlantic drizzling Sc and stratus. A model for the evaporation and sedimentation of drizzle is combined with reflectivity profiles from a millimetre‐wavelength cloud radar to derive information on the mean raindrop radius and drizzle drop concentrations at cloud base, and to show how Z–R relationships change with height below the cloud base. The Z–R relationships are used in conjunction with shipborne C‐band radar reflectivity data to estimate areal average precipitation with uncertainties at cloud base and at the surface. In the Sc drizzle Z–R relationship, Z = aRb (where a and b are constants), the estimated exponent b = 1.1 to 1.4 is lower than commonly observed in deep convective rain (b = 1.5). Analyses indicate that variations in Sc rain rates and reflectivities are influenced both by fluctuations in drizzle drop concentration and in mean radius, but that number concentration contributes more to the modulation of rain rate in Sc. Rain rates derived using the scanning C‐band radar are found to be spatially variable, with much of the accumulation originating from a small fraction of the drizzling area. The observations also suggest that rain rate in marine Sc is strongly dependent on cloud liquid‐water path, and inversely correlated with cloud droplet concentration. Copyright © 2004 Royal Meteorological Society
Soil moisture–precipitation feedback on the North American monsoon system in the MM5‐OSU model
Authors: Xu Jianjun , James Shuttleworth W. , Gao X. , Sorooshian Soroosh , Small Eric E. 
Published: January 2005

AbstractIn this study, the Pennsylvania State University/National Center for Atmospheric Research fifth generation Mesoscale Model (MM5) linked to the Oregon State University (OSU) land‐surface scheme, is used to assess the strength of soil moisture–precipitation feedback in the region of influence of the North American monsoon (NAM). Two control simulations are made with external forcing taken from the National Centers for Environmental Prediction re‐analysis, and with a nested horizontal resolution of 30 km, for the period 1 June to 30 September in wetter than average (1999) and drier than average (2000) monsoon seasons. These two model runs are then repeated with a prescribed precipitation rate anomaly in July over the entire NAM region, and comparisons made between atmospheric and land‐surface states in the two control runs and the two runs with anomalous precipitation. The results show that size and importance of soil moisture–precipitation feedbacks in the NAM region have substantial interannual variability, and that the resulting behaviour has a strong dependency on the intensity of the prescribed precipitation anomaly. It is also shown that a marked precipitation anomaly in the NAM region results in modified soil moisture, rainfall, and surface temperature, which persist for about one month, and that a precipitation anomaly within the NAM region not only has an impact on soil moisture locally, but also causes a remote, downwind soil moisture anomaly one month later. Analysis of the modelled response to the soil moisture anomaly indicates that not only land–atmosphere interactions, but also the large‐scale atmospheric circulation act together to determine the modified precipitation and soil moisture fields in the NAM system. Copyright © 2004 Royal Meteorological Society
Investigating atmospheric predictability on Mars using breeding vectors in a general‐circulation model
Authors: Newman C. E. , Read P. L. , Lewis S. R. 
Published: January 2005

AbstractA breeding vectors approach is used to investigate the hypothesis that the Martian atmosphere is predictable at certain times of year, by identifying the fastest‐growing modes of instability at different times in a Mars general‐circulation model. Results indicate that the period from northern mid‐spring until mid‐autumn is remarkably predictable, with negative global growth rates for a range of conditions, in contrast to the situation on the earth.From northern late autumn to early spring growing modes do occur, peaking in northern high latitudes and near winter solstice. Reducing the size of the initial perturbations increases global growth rates in most cases, supporting the idea that instabilities which saturate nonlinearly at lower amplitudes have generally faster growth rates. In late autumn/early winter the fastest‐growing modes (‘bred vectors’) are around the north pole, increase with dust loading, and probably grow via barotropic as well as baroclinic energy conversion. In northern late winter/early spring the bred vectors are around the north pole and are strongly baroclinic in nature. As dust loading (and with it the global circulation strength) is increased their growth rates first decrease, as the baroclinic mode is suppressed, then increase again as the fastest‐growing instabilities switch to being those which dominated earlier in the year. If dust levels are very low during late northern autumn (late southern spring) then baroclinic modes are also found around the spring pole in the south, though for a slight increase in dust loading the dominant modes shift back to northern high latitudes.The bred vectors are also used as perturbations to the initial conditions for ensemble simulations. One possible application within the Mars model is as a means of identifying regions and times when dust‐lifting activity (related to surface wind stress) might show significant interannual variability for a given model configuration, without the need to perform long, computationally expensive multi‐year model runs with each new set‐up. This is tested for a time of year when previous multi‐year experiments showed significant variability in dust storm onset in the region north of Chryse. Despite the model having no feedbacks between dust lifting and atmospheric state (unlike the original multi‐year run), the ensemble members still show maximum divergence in this region in terms of near‐surface wind stress, suggesting both that this application deserves further testing, and that the intrinsic atmospheric variability alone may be important in producing interannual variability in this storm type. Copyright © 2004 Royal Meteorological Society
Kelvin–Helmholtz billow evolution from a localized source
Authors: Smyth W. D. 
Published: January 2005

AbstractThe envelope function for Kelvin–Helmholtz billows growing from a point disturbance is derived on the basis of linear perturbation theory. The result describes an elliptical patch of billows that expands linearly in time as the billows grow. An analytical model of the dispersion relation is used to derive quantitative expressions for the spreading rate and ellipticity of the patch as functions of the bulk Richardson number. The theoretical results are verified using a combination of two‐ and three‐dimensional nonlinear simulations, and are compared with visual observations of billow patches in the atmosphere. Copyright © 2004 Royal Meteorological Society