The promise of microarrays in the management and treatment of breast cancer

Breast cancer is the most common malignancy afflicting women from Western cultures. Developments in breast cancer molecular and cellular biology research have brought us closer to understanding the genetic basis of this disease. Recent advances in microarray technology hold the promise of further increasing our understanding of the complexity and heterogeneity of this disease, and providing new avenues for the prognostication and prediction of breast cancer outcomes. These new technologies have some limitations and have yet to be incorporated into clinical use, for both the diagnosis and treatment of women with breast cancer. The most recent application of microarray genomic technologies to studying breast cancer is the focus of this review

Flavour Physics in the Soft Wall Model

We extend the description of flavour that exists in the Randall-Sundrum (RS) model to the soft wall (SW) model in which the IR brane is removed and the Higgs is free to propagate in the bulk. It is demonstrated that, like the RS model, one can generate the hierarchy of fermion masses by localising the fermions at different locations throughout the space. However, there are two significant differences. Firstly the possible fermion masses scale down, from the electroweak scale, less steeply than in the RS model and secondly there now exists a minimum fermion mass for fermions sitting towards the UV brane. With a quadratic Higgs VEV, this minimum mass is about fifteen orders of magnitude lower than the electroweak scale. We derive the gauge propagator and despite the KK masses scaling as $m_n^2\sim n$, it is demonstrated that the coefficients of four fermion operators are not divergent at tree level. FCNC's amongst kaons and leptons are considered and compared to calculations in the RS model, with a brane localised Higgs and equivalent levels of tuning. It is found that since the gauge fermion couplings are slightly more universal and the SM fermions typically sit slightly further towards the UV brane, the contributions to observables such as $\epsilon_K$ and $\Delta m_K$, from the exchange of KK gauge fields, are significantly reduced.Comment: 33 pages, 15 figures, 5 tables; v2: references added; v3: modifications to figures 4,5 and 6. version to appear in JHE

Global Development and Climate Change: A Game Theory Approach

The increasing concern with climate change is one of the main issues of our time, and thus we aim to theoretically and mathematically analyse its causes. However our approach follows a different stream of thought, presenting the reasoning and decision-making processes between technical and moral solutions. We have resorted to game theory models in order to demonstrate cooperative and non-cooperative scenarios, ranging from the traditional to the evolutionary within game theory. In doing so we are able to glimpse the development of modern society and a paradigm shift regarding human control over nature and to what extent it is harmful to the sustainability of our environment and the survival of future generations. Merging different fields of knowledge, we present a theoretical-philosophical approach, combined with empirical-mathematical solutions taking into account the agent-based behaviour guided blindly by instrumental rationality

Genomic approaches in the management and treatment of breast cancer

Breast cancer is the most common malignancy afflicting women from Western cultures. It has been estimated that approximately 211 000 women will be diagnosed with breast cancer in 2003 in the United States alone, and each year over 40 000 women will die of this disease. Developments in breast cancer molecular and cellular biology research have brought us closer to understanding the genetic basis of this disease. Unfortunately, this information has not yet been incorporated into the routine diagnosis and treatment of breast cancer in the clinic. Recent advancements in microarray technology hold the promise of further increasing our understanding of the complexity and heterogeneity of this disease, and providing new avenues for the prognostication and prediction of breast cancer outcomes. The most recent application of microarray genomic technologies to studying breast cancer will be the focus of this review

Polycystic ovary syndrome: a complex condition with psychological, reproductive and metabolic manifestations that impacts on health across the lifespan

Polycystic ovary syndrome (PCOS) is of clinical and public health importance as it is very common, affecting up to one in five women of reproductive age. It has significant and diverse clinical implications including reproductive (infertility, hyperandrogenism, hirsutism), metabolic (insulin resistance, impaired glucose tolerance, type 2 diabetes mellitus, adverse cardiovascular risk profiles) and psychological features (increased anxiety, depression and worsened quality of life). Polycystic ovary syndrome is a heterogeneous condition and, as such, clinical and research agendas are broad and involve many disciplines. The phenotype varies widely depending on life stage, genotype, ethnicity and environmental factors including lifestyle and bodyweight. Importantly, PCOS has unique interactions with the ever increasing obesity prevalence worldwide as obesity-induced insulin resistance significantly exacerbates all the features of PCOS. Furthermore, it has clinical implications across the lifespan and is relevant to related family members with an increased risk for metabolic conditions reported in first-degree relatives. Therapy should focus on both the short and long-term reproductive, metabolic and psychological features. Given the aetiological role of insulin resistance and the impact of obesity on both hyperinsulinaemia and hyperandrogenism, multidisciplinary lifestyle improvement aimed at normalising insulin resistance, improving androgen status and aiding weight management is recognised as a crucial initial treatment strategy. Modest weight loss of 5% to 10% of initial body weight has been demonstrated to improve many of the features of PCOS. Management should focus on support, education, addressing psychological factors and strongly emphasising healthy lifestyle with targeted medical therapy as required. Monitoring and management of long-term metabolic complications is also an important part of routine clinical care. Comprehensive evidence-based guidelines are needed to aid early diagnosis, appropriate investigation, regular screening and treatment of this common condition. Whilst reproductive features of PCOS are well recognised and are covered here, this review focuses primarily on the less appreciated cardiometabolic and psychological features of PCOS

Search for New Physics in e mu X Data at D0 Using Sleuth: A Quasi-Model-Independent Search Strategy for New Physics

We present a quasi-model-independent search for the physics responsible for electroweak symmetry breaking. We define final states to be studied, and construct a rule that identifies a set of relevant variables for any particular final state. A new algorithm ("Sleuth") searches for regions of excess in those variables and quantifies the significance of any detected excess. After demonstrating the sensitivity of the method, we apply it to the semi-inclusive channel e mu X collected in 108 pb^-1 of ppbar collisions at sqrt(s) = 1.8 TeV at the D0 experiment during 1992-1996 at the Fermilab Tevatron. We find no evidence of new high p_T physics in this sample.Comment: 23 pages, 12 figures. Submitted to Physical Review

Ratio of the Isolated Photon Cross Sections at \sqrt{s} = 630 and 1800 GeV

The inclusive cross section for production of isolated photons has been measured in \pbarp collisions at $\sqrt{s} = 630$ GeV with the \D0 detector at the Fermilab Tevatron Collider. The photons span a transverse energy ($E_T$) range from 7-49 GeV and have pseudorapidity $|\eta| < 2.5$. This measurement is combined with to previous \D0 result at $\sqrt{s} = 1800$ GeV to form a ratio of the cross sections. Comparison of next-to-leading order QCD with the measured cross section at 630 GeV and ratio of cross sections show satisfactory agreement in most of the $E_T$ range.Comment: 7 pages. Published in Phys. Rev. Lett. 87, 251805, (2001

Primary chemotherapy with gemcitabine, epirubicin and taxol (GET) in operable breast cancer: a phase II study

This trial was conducted to assess the activity and tolerability of the gemcitabine, epirubicin, taxol triplet combination in patients with operable breast cancer. After core biopsy, 43 women with stage II–IIIA breast cancer were treated with gemcitabine 1000 mg m−2 over 30 min on days 1 and 4, epirubicin 90 mg m−2 as an intravenous bolus on day 1, and taxol 175 mg m−2 as a 3-h infusion on day 1, every 21 days for four cycles. The primary end point was the percentage of pathological complete responses (pCR) in the breast; secondary end points were tolerability, clinical response rates, overall and progression-free survival, tumour biomarkers before and after primary chemotherapy (PCT). All patients were included in safety and survival analyses; 41 eligible patients were evaluated for response. The overall clinical response rate was 87.8% (95% CI 77.8–97.8), with 26.8% complete responses (95% CI 13.3–40.3). A pCR in the breast was observed in six patients (14.6%; 95% CI 3.8–25.4); 15 patients (36.6%; 95% CI 21.9–51.3) had negative axillary lymph nodes. Grade 4 neutropenia was observed in 67.4% of the patients; febrile neutropenia occurred in 1.9% of cycles (granulocyte colony-stimulating factor was used in 3.2% of the cycles to shorten the duration of neutropenia). A statistically significant difference between Mib-1 at baseline (⩾20% in 71.4% of the patients) and at definitive surgery (28.6%, P<0.05) was observed. The gemcitabine, epirubicin, taxol regimen is active and well tolerated as PCT for operable breast cancer. This combination allows the administration of full doses of active agents with a low incidence of febrile neutropenia

Characterization of Xenopus Tissue Inhibitor of Metalloproteinases-2: A Role in Regulating Matrix Metalloproteinase Activity during Development

Frog metamorphosis is totally dependent on thyroid hormone (T3) and mimics the postembryonic period around birth in mammals. It is an excellent model to study the molecular basis of postembryonic development in vertebrate. We and others have shown that many, if not all, matrix metalloproteinases (MMPs), which cleave proteins of the extracellular matrix as well as other substrates, are induced by T3 and important for metamorphosis. MMP activity can be inhibited by tissue inhibitors of metalloproteinase (TIMPs). There are 4 TIMPs in vertebrates and their roles in postembryonic development are poorly studied.We analyzed the TIMP2 genes in Xenopus laevis and the highly related species Xenopus tropicalis and discovered that TIMP2 is a single copy gene in Xenopus tropicalis as in mammals but is duplicated in Xenopus laevis. Furthermore, the TIMP2 locus in Xenopus tropicalis genome is different from that in human, suggesting an evolutionary reorganization of the locus. More importantly, we found that the duplicated TIMP2 genes were similarly regulated in the developing limb, remodeling intestine, resorbing tail during metamorphosis. Unexpectedly, like its MMP target genes, the TIMP2 genes were upregulated by T3 during both natural and T3-induced metamorphosis.Our results indicate that TIMP2 is highly conserved among vertebrates and that the TIMP2 locus underwent a chromosomal reorganization during evolution. Furthermore, the unexpected upregulation of TIMP2 genes during metamorphosis suggests that proper balance of MMP activity is important for metamorphosis