311 research outputs found
HER2 testing in breast cancer: Opportunities and challenges
Human epidermal growth factor receptor 2 (HER2) is overexpressed in 15-25% of breast cancers, usually as a result of HER2 gene amplification. Positive HER2 status is considered to be an adverse prognostic factor. Recognition of the role of HER2 in breast cancer growth has led to the development of anti-HER2 directed therapy, with the humanized monoclonal antibody trastuzumab (Herceptin (R)) having been approved for the therapy of HER2-positive metastatic breast cancer. Clinical studies have further suggested that HER2 status can provide important information regarding success or failure of certain hormonal therapies or chemotherapies. As a result of these developments, there has been increasing demand to perform HER2 testing on current and archived breast cancer specimens. This article reviews the molecular background of HER2 function, activation and inhibition as well as current opinions concerning its role in chemosensitivity and interaction with estrogen receptor biology. The different tissue-based assays used to detect HER2 amplification and overexpression are discussed with respect to their advantages and disadvantages, when to test (at initial diagnosis or pre-treatment), where to test (locally or centralized) and the need for quality assurance to ensure accurate and valid testing results
A biophysical model of cell adhesion mediated by immunoadhesin drugs and antibodies
A promising direction in drug development is to exploit the ability of
natural killer cells to kill antibody-labeled target cells. Monoclonal
antibodies and drugs designed to elicit this effect typically bind cell-surface
epitopes that are overexpressed on target cells but also present on other
cells. Thus it is important to understand adhesion of cells by antibodies and
similar molecules. We present an equilibrium model of such adhesion,
incorporating heterogeneity in target cell epitope density and epitope
immobility. We compare with experiments on the adhesion of Jurkat T cells to
bilayers containing the relevant natural killer cell receptor, with adhesion
mediated by the drug alefacept. We show that a model in which all target cell
epitopes are mobile and available is inconsistent with the data, suggesting
that more complex mechanisms are at work. We hypothesize that the immobile
epitope fraction may change with cell adhesion, and we find that such a model
is more consistent with the data. We also quantitatively describe the parameter
space in which binding occurs. Our results point toward mechanisms relating
epitope immobility to cell adhesion and offer insight into the activity of an
important class of drugs.Comment: 13 pages, 5 figure
Sexual Size Dimorphism and Body Condition in the Australasian Gannet
Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD
3D Echo systematically underestimates right ventricular volumes compared to cardiovascular magnetic resonance in adult congenital heart disease patients with moderate or severe RV dilatation
<p>Abstract</p> <p>Background</p> <p>Three dimensional echo is a relatively new technique which may offer a rapid alternative for the examination of the right heart. However its role in patients with non-standard ventricular size or anatomy is unclear. This study compared volumetric measurements of the right ventricle in 25 patients with adult congenital heart disease using both cardiovascular magnetic resonance (CMR) and three dimensional echocardiography.</p> <p>Methods</p> <p>Patients were grouped by diagnosis into those expected to have normal or near-normal RV size (patients with repaired coarctation of the aorta) and patients expected to have moderate or worse RV enlargement (patients with repaired tetralogy of Fallot or transposition of the great arteries). Right ventricular end diastolic volume, end systolic volume and ejection fraction were compared using both methods with CMR regarded as the reference standard</p> <p>Results</p> <p>Bland-Altman analysis of the 25 patients demonstrated that for both RV EDV and RV ESV, there was a significant and systematic under-estimation of volume by 3D echo compared to CMR. This bias led to a mean underestimation of RV EDV by -34% (95%CI: -91% to + 23%). The degree of underestimation was more marked for RV ESV with a bias of -42% (95%CI: -117% to + 32%). There was also a tendency to overestimate RV EF by 3D echo with a bias of approximately 13% (95% CI -52% to +27%).</p> <p>Conclusions</p> <p>Statistically significant and clinically meaningful differences in volumetric measurements were observed between the two techniques. Three dimensional echocardiography does not appear ready for routine clinical use in RV assessment in congenital heart disease patients with more than mild RV dilatation at the current time.</p
Physics of Neutron Star Crusts
The physics of neutron star crusts is vast, involving many different research
fields, from nuclear and condensed matter physics to general relativity. This
review summarizes the progress, which has been achieved over the last few
years, in modeling neutron star crusts, both at the microscopic and macroscopic
levels. The confrontation of these theoretical models with observations is also
briefly discussed.Comment: 182 pages, published version available at
<http://www.livingreviews.org/lrr-2008-10
Chromogenic in situ hybridization (CISH): a novel alternative in screening archival breast cancer tissue samples for HER-2/neu status
BACKGROUND: Chromogenic in situ hybridization (CISH) is emerging as a practical, cost-effective, and valid alternative to fluorescent in situ hybridization in testing for gene alteration, especially in centers primarily working with immunohistochemistry (IHC). METHODS: We assessed Her-2/neu alteration using CISH on formalin-fixed paraffin-embedded primary invasive ductal carcinoma tumors in which IHC (CB11 antibody) had previously been performed, and we compared the results with IHC. The 160 selected cases were equally stratified randomly into the four IHC categories (scores of 0, 1+, 2+, and 3+). We also compared age at diagnosis and tumor histologic grade with IHC and CISH Her-2/neu. RESULTS: We were able to perform and evaluate CISH successfully on all cases. The agreement between 3+ IHC and CISH-amplified cases as well as between all IHC and CISH Her-2/neu negative cases was 100%, and the concordance on all positive cases was 72.50%, with an overall agreement of 86.25%. All the discordant cases had 2+ IHC scores. Although we noted Her-2/neu positivity more in premenopausal women, the age at diagnosis was not significantly associated with IHC or CISH results. Similarly, although the small group of well-differentiated tumors was apparently Her-2/neu negative in both tests, no significant association was noted between any tumor histologic grade and either IHC or CISH results. CONCLUSIONS: CISH is easily integrated into routine testing in our laboratory. It is a necessary adjunct in determining the subset of non-amplified IHC-positive invasive tumors that will not benefit from trastuzumab therapy. Those cases with 2+ IHC results will be triaged and subjected to CISH. Her-2/neu testing should be done on all breast cancer cases regardless of age at presentation and tumor histologic grade
The stellar halo of the Galaxy
Stellar halos may hold some of the best preserved fossils of the formation
history of galaxies. They are a natural product of the merging processes that
probably take place during the assembly of a galaxy, and hence may well be the
most ubiquitous component of galaxies, independently of their Hubble type. This
review focuses on our current understanding of the spatial structure, the
kinematics and chemistry of halo stars in the Milky Way. In recent years, we
have experienced a change in paradigm thanks to the discovery of large amounts
of substructure, especially in the outer halo. I discuss the implications of
the currently available observational constraints and fold them into several
possible formation scenarios. Unraveling the formation of the Galactic halo
will be possible in the near future through a combination of large wide field
photometric and spectroscopic surveys, and especially in the era of Gaia.Comment: 46 pages, 16 figures. References updated and some minor changes.
Full-resolution version available at
http://www.astro.rug.nl/~ahelmi/stellar-halo-review.pd
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