Breast cancer genome heterogeneity: a challenge to personalised medicine?

Implementation of high-throughput genomics sequencing approaches into routine laboratory practice has raised the potential for the identification of multiple breast cancer targets suitable for future therapeutic intervention in order to improve cancer outcomes. Results from these studies have revealed bewildering breast cancer genome complexity with very few aberrations occurring in common between breast cancers. In addition, such complexity is compounded by evidence of genomic heterogeneity occurring within individual breast cancers. Such inter-tumoural and intratumoural heterogeneity is likely to present a challenge to personalised therapeutic approaches that might be circumvented through the definition of genome instability mechanisms governing such diversity and their exploitation using synthetic lethal approaches

The ethics of uncertainty for data subjects

Modern health data practices come with many practical uncertainties. In this paper, I argue that data subjects’ trust in the institutions and organizations that control their data, and their ability to know their own moral obligations in relation to their data, are undermined by significant uncertainties regarding the what, how, and who of mass data collection and analysis. I conclude by considering how proposals for managing situations of high uncertainty might be applied to this problem. These emphasize increasing organizational flexibility, knowledge, and capacity, and reducing hazard

The chemical signatures underlying host plant discrimination by aphids

The diversity of phytophagous insects is largely attributable to speciation involving shifts between host plants. These shifts are mediated by the close interaction between insects and plant metabolites. However, there has been limited progress in understanding the chemical signatures that underlie host preferences. We use the pea aphid (Acyrthosiphon pisum) to address this problem. Host-associated races of pea aphid discriminate between plant species in race-specific ways. We combined metabolomic profiling of multiple plant species with behavioural tests on two A. pisum races, to identify metabolites that explain variation in either acceptance or discrimination. Candidate compounds were identified using tandem mass spectrometry. Our results reveal a small number of compounds that explain a large proportion of variation in the differential acceptability of plants to A. pisum races. Two of these were identified as L-phenylalanine and L-tyrosine but it may be that metabolically-related compounds directly influence insect behaviour. The compounds implicated in differential acceptability were not related to the set correlated with general acceptability of plants to aphids, regardless of host race. Small changes in response to common metabolites may underlie host shifts. This study opens new opportunities for understanding the mechanistic basis of host discrimination and host shifts in insects

Prepatterning in the Stem Cell Compartment

The mechanism by which an apparently uniform population of cells can generate a heterogeneous population of differentiated derivatives is a fundamental aspect of pluripotent and multipotent stem cell behaviour. One possibility is that the environment and the differentiation cues to which the cells are exposed are not uniform. An alternative, but not mutually exclusive possibility is that the observed heterogeneity arises from the stem cells themselves through the existence of different interconvertible substates that pre-exist before the cells commit to differentiate. We have tested this hypothesis in the case of apparently homogeneous pluripotent human embryonal carcinoma (EC) stem cells, which do not follow a uniform pattern of differentiation when exposed to retinoic acid. Instead, they produce differentiated progeny that include both neuronal and non-neural phenotypes. Our results suggest that pluripotent NTERA2 stem cells oscillate between functionally distinct substates that are primed to select distinct lineages when differentiation is induced

Comparison of 1- and 2-year screening intervals for women undergoing screening mammography

We compared the long-term impact of 1- and 2-year screening mammography intervals using prognostic, screening, and outcome information for women aged 50–74 years obtained from the Screening Mammography Program of British Columbia in two time periods, prior to 1997 (policy of annual mammography) and after 1997 (biennial mammography). Survival was estimated for both periods using a prognostic model and the expected rate of interval and screen-detected cancers. The likelihood of a screen-detected cancer with annual screening was 2.32 per thousand screens and with biennial screening was 3.32 per thousand screens. The prognostic profile of screen-detected cancers was better than that of interval cancers. Among both screen-detected and interval cancers, the prognostic profiles with annual and biennial screening were similar. The estimated breast cancer-specific survival rates for women undergoing annual and biennial screening mammography were 95.2 and 94.6% at 5 years, and 90.4 and 89.2% at 10 years, respectively. Annual compared to biennial mammography was associated with a 1.2% increase in the estimated 10-year breast cancer-specific survival for women aged 50–74 years, diagnosed with invasive breast cancer after screening programme attendance

Receptor-Induced Dilatation in the Systemic and Intrarenal Adaptation to Pregnancy in Rats

Normal pregnancy is associated with systemic and intrarenal vasodilatation resulting in an increased glomerular filtration rate. This adaptive response occurs in spite of elevated circulating levels of angiotensin II (Ang II). In the present study, we evaluated the potential mechanisms responsible for this adaptation. The reactivity of the mesangial cells (MCs) cultured from 14-day-pregnant rats to Ang II was measured through changes in the intracellular calcium concentration ([Cai]). The expression levels of inducible nitric oxide synthase (iNOS), the Ang II-induced vasodilatation receptor AT2, and the relaxin (LGR7) receptor were evaluated in cultured MCs and in the aorta, renal artery and kidney cortex by real time-PCR. The intrarenal distribution of LGR7 was further analyzed by immunohistochemistry. The MCs displayed a relative insensitivity to Ang II, which was paralleled by an impressive increase in the expression level of iNOS, AT2 and LGR7. These results suggest that the MCs also adapt to the pregnancy, thereby contributing to the maintenance of the glomerular surface area even in the presence of high levels of Ang II. The mRNA expression levels of AT2 and LGR7 also increased in the aorta, renal artery and kidney of the pregnant animals, whereas the expression of the AT1 did not significantly change. This further suggests a role of these vasodilatation-induced receptors in the systemic and intrarenal adaptation during pregnancy. LGR7 was localized in the glomeruli and on the apical membrane of the tubular cells, with stronger labeling in the kidneys of pregnant rats. These results suggest a role of iNOS, AT2, and LGR7 in the systemic vasodilatation and intrarenal adaptation to pregnancy and also suggest a pivotal role for relaxin in the tubular function during gestation

Therapeutic opportunities within the DNA damage response

The DNA damage response (DDR) is essential for maintaining the genomic integrity of the cell, and its disruption is one of the hallmarks of cancer. Classically, defects in the DDR have been exploited therapeutically in the treatment of cancer with radiation therapies or genotoxic chemotherapies. More recently, protein components of the DDR systems have been identified as promising avenues for targeted cancer therapeutics. Here, we present an in-depth analysis of the function, role in cancer and therapeutic potential of 450 expert-curated human DDR genes. We discuss the DDR drugs that have been approved by the US Food and Drug Administration (FDA) or that are under clinical investigation. We examine large-scale genomic and expression data for 15 cancers to identify deregulated components of the DDR, and we apply systematic computational analysis to identify DDR proteins that are amenable to modulation by small molecules, highlighting potential novel therapeutic targets

Radionuclide imaging of bone marrow disorders

Noninvasive imaging techniques have been used in the past for visualization the functional activity of the bone marrow compartment. Imaging with radiolabelled compounds may allow different bone marrow disorders to be distinguished. These imaging techniques, almost all of which use radionuclide-labelled tracers, such as 99mTc-nanocolloid, 99mTc-sulphur colloid, 111In-chloride, and radiolabelled white blood cells, have been used in nuclear medicine for several decades. With these techniques three separate compartments can be recognized including the reticuloendothelial system, the erythroid compartment and the myeloid compartment. Recent developments in research and the clinical use of PET tracers have made possible the analysis of additional properties such as cellular metabolism and proliferative activity, using 18F-FDG and 18F-FLT. These tracers may lead to better quantification and targeting of different cell systems in the bone marrow. In this review the imaging of different bone marrow targets with radionuclides including PET tracers in various bone marrow diseases are discussed