Biplots of compositional data

The singular value decomposition and its interpretation as a linear biplot has proved to be a powerful tool for analysing many forms of multivariate data. Here we adapt biplot methodology to the speciffic case of compositional data consisting of positive vectors each of which is constrained to have unit sum. These relative variation biplots have properties relating to special features of compositional data: the study of ratios, subcompositions and models of compositional relationships. The methodology is demonstrated on a data set consisting of six-part colour compositions in 22 abstract paintings, showing how the singular value decomposition can achieve an accurate biplot of the colour ratios and how possible models interrelating the colours can be diagnosed.Logratio transformation, principal component analysis, relative variation biplot, singular value decomposition, subcomposition

Nuclear expression of Lyn, a Src family kinase member, is associated with poor prognosis in renal cancer patients

Background: 8000 cases of renal cancer are diagnosed each year in the UK, with a five-year survival rate of 50 %. Treatment options are limited; a potential therapeutic target is the Src family kinases (SFKs). SFKs have roles in multiple oncogenic processes and promote metastases in solid tumours. The aim of this study was to investigate SFKs as potential therapeutic targets for clear cell renal cell carcinoma (ccRCC). Methods: SFKs expression was assessed in a tissue microarray consisting of 192 ccRCC patients with full clinical follow-up. SFK inhibitors, dasatinib and saracatinib, were assessed in early ccRCC cell lines, 786-O and 769-P and a metastatic ccRCC cell line, ACHN (± Src) for effects on protein expression, apoptosis, proliferation and wound healing. Results: High nuclear expression of Lyn and the downstream marker of activation, paxillin, were associated with decreased patient survival. Conversely, high cytoplasmic expression of other SFK members and downstream marker of activation, focal adhesion kinase (FAK) were associated with increased patient survival. Treatment of non-metastatic 786-O and 769-P cells with dasatinib, dose dependently reduced SFK activation, shown via SFK (Y419) and FAK (Y861) phosphorylation, with no effect in metastatic ACHN cells. Dasatinib also increased apoptosis, while decreasing proliferation and migration in 786-O and 769-P cell lines, both in the presence and absence of Src protein. Conclusions: Our data suggests that nuclear Lyn is a potential therapeutic target for ccRCC and dasatinib affects cellular functions associated with cancer progression via a Src kinase independent mechanism

Metallochaperones regulate intracellular copper levels.

Copper (Cu) is an important enzyme co-factor that is also extremely toxic at high intracellular concentrations, making active efflux mechanisms essential for preventing Cu accumulation. Here, we have investigated the mechanistic role of metallochaperones in regulating Cu efflux. We have constructed a computational model of Cu trafficking and efflux based on systems analysis of the Cu stress response of Halobacterium salinarum. We have validated several model predictions via assays of transcriptional dynamics and intracellular Cu levels, discovering a completely novel function for metallochaperones. We demonstrate that in addition to trafficking Cu ions, metallochaperones also function as buffers to modulate the transcriptional responsiveness and efficacy of Cu efflux. This buffering function of metallochaperones ultimately sets the upper limit for intracellular Cu levels and provides a mechanistic explanation for previously observed Cu metallochaperone mutation phenotypes

Intestinal Metaplasia and Gastric Carcinoma

Previous studies have suggested that gastric carcinogenesis is a multistage process involving first gastritis, then intestinal metaplasia, dysplasia of increasing severity and finally carcinoma. The exact role of intestinal metaplasia in the histogenesis of gastric carcinoma has been the subject of much debate. Recent work has identified an intestinal metaplasia variant (Type IIb) which appears to be significantly associated with a particular histological type of gastric carcinoma. The aim of the studies carried out in the preparation of this thesis was to investigate the histogenesis of gastric carcinoma with particular reference to the role of intestinal metaplasia in this process. The material studied was a series of gastrectomy specimens resected for both benign and malignant disease. In addition fetal stomachs, endoscopic biopsy material from a group of patients who had undergone gastric surgery for peptic ulcer disease, and an animal experimental model of gastric carcinogensis were studied to examine specific aspects of the carcinogenetic sequence. The methods utilised in the studies involved histological assessment, mucin and immunocytochemical techniques and cell kinetic analysis. The results of the histological investigation indicate that the presence and amount of intestinal metaplasia in the gastrectomy material is related to variables such as age and inflammatory change rather than the presence of a tumour. The results also demonstrate that the presence of the type lIb variant is related to age, inflammation and ulceration within the gastrectomy rather than the presence of any particular tumour sub-type. The results of the mucin and immunocytochemical studies identified a series of phenotypic changes in the stages of gastric carcinogenesis which did not lend support to the role of intestinal metaplasia in the histogenesis of gastric carcinoma. The cell kinetic study documented the changes in cellular proliferation that occur in the stages of gastric carcinogenesis. A series of cell kinetic abnormalities in the gastric mucosa of patients who had undergone gastric surgery for benign disease were identified. These abnormalities were shown to be related to alkaline reflux gastritis. It is suggested that intestinal metaplasia and its variants do not represent a premalignant stage in the histogenesis of gastric carcinoma

Reclassification of the Fuhrman grading system in renal cell carcinoma-does it make a difference?

PURPOSE: The aim of this study was to determine whether reclassifying the Fuhrman grading system provides further prognostic information. MATERIALS AND METHODS: We studied the pathological features and cancer specific survival of 237 patients with clear cell cancer undergoing surgery between 1997–2007 in a single centre. The original Fuhrman grading system was investigated as well as various simplified models utilising the original Fuhrman grade. RESULTS: The median follow up was 69 months. On univariate analysis, the conventional Fuhrman grading system as well various simplified models were predicative of cancer specific survival. On multivariate analysis, only the three tiered modified model in which grades 1 and 2 were combined whilst grades 3 and 4 were kept separate was an independent predictor of cancer specific survival (p=0.001, HR 2.17, 95% CI 1.37-3.43). Furthermore this simplified model demonstrated a stronger relationship to recurrence than the conventional 4 tiered Fuhrman grading system. CONCLUSIONS: A modified, three-tiered Fuhrman grading system has been demonstrated to be an independent predictor of cancer specific survival

A functional variant in the serotonin receptor 7 gene (HTR7), rs7905446, is associated with good response to SSRIs in bipolar and unipolar depression.

Predicting antidepressant response has been a clinical challenge for mood disorder. Although several genome-wide association studies have suggested a number of genetic variants to be associated with antidepressant response, the sample sizes are small and the results are difficult to replicate. Previous animal studies have shown that knockout of the serotonin receptor 7 gene (HTR7) resulted in an antidepressant-like phenotype, suggesting it was important to antidepressant action. In this report, in the first stage, we used a cost-effective pooled-sequencing strategy to sequence the entire HTR7 gene and its regulatory regions to investigate the association of common variants in HTR7 and clinical response to four selective serotonin reuptake inhibitors (SSRIs: citalopram, paroxetine, fluoxetine and sertraline) in a retrospective cohort mainly consisting of subjects with bipolar disorder (n = 359). We found 80 single-nucleotide polymorphisms (SNPs) with false discovery rate < 0.05 associated with response to paroxetine. Among the significant SNPs, rs7905446 (T/G), which is located at the promoter region, also showed nominal significance (P < 0.05) in fluoxetine group. GG/TG genotypes for rs7905446 and female gender were associated with better response to two SSRIs (paroxetine and fluoxetine). In the second stage, we replicated this association in two independent prospective samples of SSRI-treated patients with major depressive disorder: the MARS (n = 253, P = 0.0169) and GENDEP studies (n = 432, P = 0.008). The GG/TG genotypes were consistently associated with response in all three samples. Functional study of rs7905446 showed greater activity of the G allele in regulating expression of HTR7. The G allele displayed higher luciferase activity in two neuronal-related cell lines, and estrogen treatment decreased the activity of only the G allele. Electrophoretic mobility shift assay suggested that the G allele interacted with CCAAT/enhancer-binding protein beta transcription factor (TF), while the T allele did not show any interaction with any TFs. Our results provided novel pharmacogenomic evidence to support the role of HTR7 in association with antidepressant response

Temporal Deconvolution study of Long and Short Gamma-Ray Burst Light curves

The light curves of Gamma-Ray Bursts (GRBs) are believed to result from internal shocks reflecting the activity of the GRB central engine. Their temporal deconvolution can reveal potential differences in the properties of the central engines in the two populations of GRBs which are believed to originate from the deaths of massive stars (long) and from mergers of compact objects (short). We present here the results of the temporal analysis of 42 GRBs detected with the Gamma-ray Burst Monitor onboard the Fermi Gamma-ray Space Telescope. We deconvolved the profiles into pulses, which we fit with lognormal functions. The distributions of the pulse shape parameters and intervals between neighboring pulses are distinct for both burst types and also fit with lognormal functions. We have studied the evolution of these parameters in different energy bands and found that they differ between long and short bursts. We discuss the implications of the differences in the temporal properties of long and short bursts within the framework of the internal shock model for GRB prompt emission.Comment: 38 pages, 11 figure

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

<p>Background: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.</p> <p>Case presentation: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.</p> <p>Conclusion: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.</p&gt

Measuring the Higgs Sector

If we find a light Higgs boson at the LHC, there should be many observable channels which we can exploit to measure the relevant parameters in the Higgs sector. We use the SFitter framework to map these measurements on the parameter space of a general weak-scale effective theory with a light Higgs state of mass 120 GeV. Our analysis benefits from the parameter determination tools and the error treatment used in new--physics searches, to study individual parameters and their error bars as well as parameter correlations.Comment: 45 pages, Journal version with comments from refere

Dimensional Crossover and Effective Exponents

We investigate the critical behavior of the lambda phi^4 theory defined on S^1 x R^d having two finite length scales beta, the circumference of S^1, and k^{-1}, the blocking scale introduced by the renormalization group transformation. By numerically solving the coupled differential RG equations for the finite-temperature blocked potential U_{beta,k}(Phi) and the wavefunction renormalization constant Z_{beta,k}(Phi), we demonstrate how the finite-size scaling variable betabar = beta k determines whether the phase transition is (d+1)- or d-dimensional in the limits betabar >> 1 and betabar << 1, respectively. For the intermediate values of betabar, finite-size effects play an important role. We also discuss the failure of the polynomial expansion of the effective potential near criticality.Comment: 24 pages, TeX, 8 figures in separate file, Updated version to appear in Nucl. Phys.