Gene products of chromosome 11q and their association with CCND1 gene amplification and tamoxifen resistance in premenopausal breast cancer

Introduction: The amplification event occurring at chromosome locus 11q13, reported in several different cancers, includes a number of potential oncogenes. We have previously reported amplification of one such oncogene, namely CCND1, to be correlated with an adverse effect of tamoxifen in premenopausal breast cancer patients. Over-expression of cyclin D-1 protein, however, confers tamoxifen resistance but not a tamoxifen-induced adverse effect. Potentially, co-amplification of an additional 11q13 gene, with a resulting protein over-expression, is required to cause an agonistic effect. Moreover, during 11q13 amplification a deletion of the distal 11q region has been described. In order to assess the potential impact of the deletion we examined a selected marker for this event. Method: Array comparative genomic hybridization analysis was employed to identify and confirm changes in the gene expression of a number of different genes mapping to the 11q chromosomal region, associated with CCND1 amplification. The subsequent protein expression of these candidate genes was then examined in a clinical material of 500 primary breast cancers from premenopausal patients who were randomly assigned to either tamoxifen or no adjuvant treatment. The protein expression was also compared with gene expression data in a subset of 56 breast cancer samples. Results: Cortactin and FADD (Fas-associated death domain) over-expression was linked to CCND1 amplification, determined by fluorescence in situ hybridization, but was not associated with a diminished effect of tamoxifen. However, deletion of distal chromosome 11q, defined as downregulation of the marker Chk1 (checkpoint kinase 1), was associated with an impaired tamoxifen response, and interestingly with low proliferative breast cancer of low grade. For Pak1 (p21-activated kinase 1) and cyclin D-1 the protein expression corresponded to the gene expression data. Conclusions: The results indicate that many 11q13 associated gene products are over-expressed in conjunction with cyclin D-1 but not linked to an agonistic effect of tamoxifen. Finally, the deletion of distal 11q, linked to 11q13 amplification, might be an important event affecting breast cancer outcome and tamoxifen response

Sonographic assessment of abdominal fat distribution in infancy

There is growing evidence that not only the total amount of fat, but also the distribution of body fat determines risks for metabolic and cardiovascular disease. Developmental studies on factors influencing body fat distribution have been hampered by a lack of appropriate techniques for measuring intraabdominal fat in early life. Sonography, which is an established method for assessing abdominal fat distribution in adults, has not yet been evaluated in infants. To adapt the sonographic measurement of abdominal fat distribution to infants and study its reliability. The Generation R study, a population-based prospective cohort study. We included 212 one- and 227 two-year old Dutch infants in the present analysis. Sixty-two infants underwent replicate measurements to assess reproducibility. We developed a standardized protocol to measure the thickness of (1) subcutaneous and (2) preperitoneal fat in the upper abdomen of infants. To this end we defined infancy specific measurement areas to quantify fat thickness. Reproducibility of fat measurements was good to excellent with intraclass correlation coefficients of 0.93–0.97 for intra-observer agreement and of 0.89–0.95 for inter-observer agreement. We observed a pronounced increase in preperitoneal fat thickness in the second year of life while subcutaneous fat thickness increased only slightly, resulting in an altered body fat distribution. Gender did not significantly influence fat distribution in the first two years of life. Our age specific protocol for the sonographic measurement of central subcutaneous and preperitoneal fat is a reproducible method that can be instrumental for investigating fat distribution in early life

Advances in estrogen receptor biology: prospects for improvements in targeted breast cancer therapy

Estrogen receptor (ER) has a crucial role in normal breast development and is expressed in the most common breast cancer subtypes. Importantly, its expression is very highly predictive for response to endocrine therapy. Current endocrine therapies for ER-positive breast cancers target ER function at multiple levels. These include targeting the level of estrogen, blocking estrogen action at the ER, and decreasing ER levels. However, the ultimate effectiveness of therapy is limited by either intrinsic or acquired resistance. Identifying the factors and pathways responsible for sensitivity and resistance remains a challenge in improving the treatment of breast cancer. With a better understanding of coordinated action of ER, its coregulatory factors, and the influence of other intracellular signaling cascades, improvements in breast cancer therapy are emerging

Molecular evolution of cyclin proteins in animals and fungi

<p>Abstract</p> <p>Background</p> <p>The passage through the cell cycle is controlled by complexes of cyclins, the regulatory units, with cyclin-dependent kinases, the catalytic units. It is also known that cyclins form several families, which differ considerably in primary structure from one eukaryotic organism to another. Despite these lines of evidence, the relationship between the evolution of cyclins and their function is an open issue. Here we present the results of our study on the molecular evolution of A-, B-, D-, E-type cyclin proteins in animals and fungi.</p> <p>Results</p> <p>We constructed phylogenetic trees for these proteins, their ancestral sequences and analyzed patterns of amino acid replacements. The analysis of infrequently fixed atypical amino acid replacements in cyclins evidenced that accelerated evolution proceeded predominantly during paralog duplication or after it in animals and fungi and that it was related to aromorphic changes in animals. It was shown also that evolutionary flexibility of cyclin function may be provided by consequential reorganization of regions on protein surface remote from CDK binding sites in animal and fungal cyclins and by functional differentiation of paralogous cyclins formed in animal evolution.</p> <p>Conclusions</p> <p>The results suggested that changes in the number and/or nature of cyclin-binding proteins may underlie the evolutionary role of the alterations in the molecular structure of cyclins and their involvement in diverse molecular-genetic events.</p

Privacy by Design Principles in Design of New Generation Cognitive Assistive Technologies

Today, simple analogue assistive technologies are transformed into complex and sophisticated sensor networks. This raises many new privacy issues that need to be considered. In this paper, we investigate how this new generation of assistive technology incorporates Privacy by Design (PbD) principles. The research is conducted as a case study where we use PbD principles as an analytical lens to investigate the design of the new generation of digitalized assistive technology as well as the users’ privacy preferences that arise in use of this technology in real homes. Based on the findings from the case study, we present guidelines for building in privacy in new generations of assistive technologies and in this way protect the privacy of the people using these technologies.</p

Lean thinking in dementia care through smart assistive technology: an evaluation

This chapter provides an analysis and evaluation of a community based project trialling the use of Smart Assistive Technologies (AT) for people with dementia and their families. The 12 month project was funded by Home and Community Care (HACC) Queensland and conducted by Alzheimer's Queensland and the University of Southern Queensland in the North Brisbane and Toowoomba areas