Actionable pharmacogenetic markers for prediction and prognosis in breast cancer

We would like to thank Professor Christian Scerri for advice and constructive discussions.Breast cancer is a heterogeneous disease that necessitates proper patient classification to direct surgery, pharmacotherapy, and radiotherapy. Despite patients within the same subgroup receiving similar pharmacotherapy, substantial variation in clinical outcomes is observed. Pharmacogenetic variations with direct effect on pharmacokinetics and pharmacodynamics play a central role in clinical outcomes. Pharmacogenetic markers associated with clinical outcome are known as biomarkers. They are termed prognostic biomarkers when their presence is associated with a specific clinical outcome. If the presence of such biomarkers guides treatment, they are termed predictive biomarkers. A number of pharmacogenetic markers have been described in relation to breast cancer pharmacotherapy both in the adjuvant and neoadjuvant setting. CYP2D6 allelic variants produce variable rates of tamoxifen metabolism and are associated with survival outcomes. Other biomarkers have been described in relation to other forms of endocrine therapy and trastuzumab. In neoadjuvant and adjuvant breast cancer chemotherapy, specific biomarkers were correlated with clinical outcomes and risk of drug toxicity. This review highlights key biomarkers in breast cancer pharmacotherapy with the potential of translating such study outcomes into clinical practice.peer-reviewe

Design of ternary signals for MIMO identification in the presence of noise and nonlinear distortion

A new approach to designing sets of ternary periodic signals with different periods for multi-input multi-output system identification is described. The signals are pseudo-random signals with uniform nonzero harmonics, generated from Galois field GF(q), where q is a prime or a power of a prime. The signals are designed to be uncorrelated, so that effects of different inputs can be easily decoupled. However, correlated harmonics can be included if necessary, for applications in the identification of ill-conditioned processes. A design table is given for q les 31. An example is presented for the design of five uncorrelated signals with a common period N = 168 . Three of these signals are applied to identify the transfer function matrix as well as the singular values of a simulated distillation column. Results obtained are compared with those achieved using two alternative methods

Practical synthesis of ternary sequences for system identification

Several issues related to the practical synthesis of ternary sequences with specified spectra are addressed in this paper. Specifically, sequences with harmonic multiples of two and three suppressed are studied, given their relevance to system identification applications. In particular, the effect of non-uniform Digital to Analog Converter (DAC) levels on the spectral properties of the generated signal is analyzed. It is analytically shown that the DAC non-uniform levels result in degraded harmonic suppression performance. Moreover, a new approach is proposed for designing ternary sequences, which is flexible and can be adapted to suit different requirements. The resulting sequences, denoted as randomized constrained sequences, are compared to direct sequences already proposed in the literature. The approach is validated by numerical simulations and experimental results, showing the potential to achieve harmonic suppression performance of approximately 100 dB

The evaluation of brine prospects and the requirement for modifications to filing standards

The recent increase in demand for lithium has led to the development of new brine prospects, particularly in the Central Andes. The brines are hosted in closed basin aquifers of two types: mature, halite dominant, and immature, clastic dominant. The estimate of elemental resources in these salars depends on a detailed knowledge of aquifer geometry, porosity, and brine grade. The geometry of the aquifers can be evaluated by classical geophysical and drilling techniques, but because the resource is a fluid, with the attendant problems of in-aquifer mixing and reorganization, existing codes for filing resource and reserve estimates need modification. Total porosity is relatively straightforward to measure, but effective porosity and specific yield, which are required to estimate the resource, are more difficult. Recovery factors are low compared with most metalliferous and industrial mineral deposits due to reliance on pumping of the brine from wells for extraction. These and related issues lead us to believe that modifications to the existing standards for reporting mineral resources and reserves are required for these prospects

Fetal liver blood flow distribution: role in human developmental strategy to prioritize fat deposition versus brain development

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fa

Are There Oscillations in the Baryon/Meson Ratio?

All available data indicate a surplus of baryon states over meson states for energies greater than about 1.5 GeV. Since hadron-scale string theory suggests that their numbers should become equal with increasing energy, it has recently been proposed that there must exist exotic mesons with masses just above 1.7 GeV in order to fill the deficit. We demonstrate that a string-like picture is actually consistent with the present numbers of baryon and meson states, and in fact predicts regular oscillations in their ratio. This suggests a different role for new hadronic states.Comment: 14 pages (RevTeX), McGill/92-0

A coupled drug kinetics-cell cycle model to analyse the response of human cells to intervention by topotecan

A model describing the response of the growth of single human cells in the absence and presence of the anti-cancer agent topotecan (TPT) is presented. The model includes a novel coupling of both the kinetics of TPT and cell cycle responses to the agent. By linking the models in this way, rather than using separate (disjoint) approaches, it is possible to illustrate how the drug perturbs the cell cycle. The model is compared to experimental in vitro cell cycle response data (comprising single cell descriptors for molecular and behavioural events), showing good qualitative agreement for a range of TPT dose levels

Molecular classification of breast cancer patients using formalin-fixed paraffin-embedded derived RNA samples

The use of archival formalin-fixed paraffin-embedded (FFPE) material to analyse gene expression is limited by the low quality of extracted RNA. In this paper, we utilised an RNA based assay to quantify expression of luminal and basal markers, together with ERBB2 probes, in FFPE archival tissue from 2009 to 2010, all of which had clinical and therapeutic information of more than 5 years. Receptor status of the patients was characterised using the QuantiGene® Plex assay with 100% concordance to immunohistochemical (IHC) and fluorescence in situ hybridisation (FISH) results. A panel of molecular markers known to classify luminal and basal tumours were used and correlated with receptor status of the tumours. As expected, the triple negative breast cancer (TNBC) samples were classified as basal and oestrogen receptor (ER) positive cases as luminal. In summary, the QuantiGene® Plex technology provides a platform to quantitate novel panels of biomarkers on archival material. Moreover, multiplex analysis allows the use of minimal amounts of material providing an opportunity to utilise laser micro-dissected material. FFPE tissue samples are an invaluable resource for retrospective studies to interrogate current novel biomarkers, particularly to generate disease free survival and overall survival graphs to measure predictive value using well annotated retrospective samples with full clinical and pharmacological outcomes.This study was funded by the Faculty of Medicine and Surgery, University of Malta and the Italia Malta Genome Breast Cancer Cross Border Risk Surveillance (ImaGenX) project financed under Operational Program Italia Malta 2007-2013 and co-financed by the University of Malta.peer-reviewe