A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy

BACKGROUND: The efficacy of chemotherapy regimens in breast cancer patients is variable and unpredictable. Whether individual patients either achieve long-term remission or suffer recurrence after therapy may be dictated by intrinsic properties of their breast tumors including genetic lesions and consequent aberrant transcriptional programs. Global gene expression profiling provides a powerful tool to identify such tumor-intrinsic transcriptional programs, whose analyses provide insight into the underlying biology of individual patient tumors. For example, multi-gene expression signatures have been identified that can predict the likelihood of disease reccurrence, and thus guide patient prognosis. Whereas such prognostic signatures are being introduced in the clinical setting, similar signatures that predict sensitivity or resistance to chemotherapy are not currently clinically available. METHODS: We used gene expression profiling to identify genes that were co-expressed with genes whose transcripts encode the protein targets of commonly used chemotherapeutic agents. RESULTS: Here, we present target based expression indices that predict breast tumor response to anthracycline and taxane based chemotherapy. Indeed, these signatures were independently predictive of chemotherapy response after adjusting for standard clinic-pathological variables such as age, grade, and estrogen receptor status in a cohort of 488 breast cancer patients treated with adriamycin and taxotere/taxol. CONCLUSIONS: Importantly, our findings suggest the practicality of developing target based indices that predict response to therapeutics, as well as highlight the possibility of using gene signatures to guide the use of chemotherapy during treatment of breast cancer patients

PCR for the detection of pathogens in neonatal early onset sepsis.

BACKGROUND: A large proportion of neonates are treated for presumed bacterial sepsis with broad spectrum antibiotics even though their blood cultures subsequently show no growth. This study aimed to investigate PCR-based methods to identify pathogens not detected by conventional culture. METHODS: Whole blood samples of 208 neonates with suspected early onset sepsis were tested using a panel of multiplexed bacterial PCRs targeting Streptococcus pneumoniae, Streptococcus agalactiae (GBS), Staphylococcus aureus, Streptococcus pyogenes (GAS), Enterobacteriaceae, Enterococcus faecalis, Enterococcus faecium, Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis and Mycoplasma genitalium, a 16S rRNA gene broad-range PCR and a multiplexed PCR for Candida spp. RESULTS: Two-hundred and eight samples were processed. In five of those samples, organisms were detected by conventional culture; all of those were also identified by PCR. PCR detected bacteria in 91 (45%) of the 203 samples that did not show bacterial growth in culture. S. aureus, Enterobacteriaceae and S. pneumoniae were the most frequently detected pathogens. A higher bacterial load detected by PCR was correlated positively with the number of clinical signs at presentation. CONCLUSION: Real-time PCR has the potential to be a valuable additional tool for the diagnosis of neonatal sepsis

Irreducible Representations of Diperiodic Groups

The irreducible representations of all of the 80 diperiodic groups, being the symmetries of the systems translationally periodical in two directions, are calculated. To this end, each of these groups is factorized as the product of a generalized translational group and an axial point group. The results are presented in the form of the tables, containing the matrices of the irreducible representations of the generators of the groups. General properties and some physical applications (degeneracy and topology of the energy bands, selection rules, etc.) are discussed.Comment: 30 pages, 5 figures, 28 tables, 18 refs, LaTex2.0

Student perceptions of quality in higher education : effect of year of study, gender and ethnicity

Student expectations with regard to what comprises quality in higher education can impact upon their learning, engagement and overall satisfaction. Perceptions of quality are not always clearly articulated and may vary by gender, ethnicity and year of study. In this study, undergraduate students completed a questionnaire indicating whether they agreed, disagreed or were unsure about 15 statements related to quality in higher education. A total of 340 students across four year groups participated (Levels 3-6), with more female than male participants and a range of ethnicities represented. There was broad unanimity in the recognition of the importance of both teaching and learning and relationships with academic staff in defining quality. Overall, there were low levels of satisfaction with the amount of contact with academic staff and uncertainty about whether students thought they were getting a high quality education. Some differences in relation to support services were seen in different ethnic groups, and more males than females were satisfied with support services although this varied by year group, and student numbers were small. These results suggest the importance of clearly articulating what is available in terms of support (academic, pastoral, study and health) to all students. The teaching and learning experience, and relationships with academic staff are clearly important and given the uncertainty about overall perceptions of quality, these aspects need to be highlighted to students so that they understand the value of what they are receiving

The limited utility of electrocardiography variables used to predict arrhythmia in psychotropic drug overdose

OBJECTIVE: The aim of the present study was to examine the relationship between serious arrhythmias in patients with psychotropic drug overdose and electrocardiography (ECG) findings that have been suggested previously to predict this complication. METHODS: Thirty-nine patients with serious arrhythmias (ventricular tachycardia, supraventricular tachycardia or cardiac arrest) after tricyclic antidepressant overdose or thioridazine overdose were compared with 117 controls with clinically significant overdose matched to each case for the drug ingested. These patients with psychotropic drug overdose had presented for treatment to the Department of Clinical Toxicology, Newcastle and to the Princess Alexandra Hospital, Brisbane. The heart rate, the QRS width, the QTc and QT intervals, the QT dispersion, and the R wave and R/S ratios in aVR on the initial ECGs were compared in cases and controls. RESULTS: The cases had taken dothiepin (16 patients), doxepin (six patients), thioridazine (five patients), amitriptyline (five patients), nortriptyline (three patients), imipramine (one patient) and a combination of dothiepin and thioridazine (three patients). In 20 of the 39 patients with arrhythmias, the arrhythmia had been a presumed ventricular tachycardia. Of the other 19 patients, 15 patients had a supraventricular tachycardia, two patients had cardiac arrests (one asystole, one without ECG monitoring) and two patients had insufficient data recorded to make classification of the arrhythmias possible. The QRS was ≥ 100 ms in 82% of cases but also in 76% of controls. QRS ≥ 160 ms had a sensitivity of only 13% and occurred in 2% of controls. QRS > 120 ms, QTc > 500 and the R/S ratio in aVR appeared to have a stronger association with the occurrence of arrhythmia: QRS > 120 ms (odds ratio [OR], 3.56; 95% confidence interval [CI], 1.46–8.68), QTc > 500 (OR, 3.07; 95% CI, 1.33–7.07), and R/S ratio in aVR > 0.7 (OR, 16; 95% CI, 3.47–74). Excluding thioridazine overdoses and performing the analysis for tricyclic antidepressant overdoses alone gave increased odds ratios for QRS > 120 ms (OR, 4.83; 95% CI, 1.73–13.5) and QTc > 500 (OR, 4.5; 95% CI, 1.56–13) but had little effect on that for the R/S ratio in aVR > 0.7 (OR, 14.5; 95% CI, 3.10–68). CONCLUSION: ECG measurements were generally weakly related to the occurrence of arrhythmia and should not be used as the sole criteria for risk assessment in tricyclic antidepressant overdose. The frequently recommended practice of using either QRS ≥ 100 ms or QRS ≥ 160 ms to predict arrhythmias is not supported by our study. R/S ratio in aVR > 0.7 was most strongly related to arrhythmia but had estimated positive and negative predictive values of only 41% and 95%, respectively. The use of these specific predictors in other drug overdoses is not recommended without specific studies

CodonTest: Modeling Amino Acid Substitution Preferences in Coding Sequences

Codon models of evolution have facilitated the interpretation of selective forces operating on genomes. These models, however, assume a single rate of non-synonymous substitution irrespective of the nature of amino acids being exchanged. Recent developments have shown that models which allow for amino acid pairs to have independent rates of substitution offer improved fit over single rate models. However, these approaches have been limited by the necessity for large alignments in their estimation. An alternative approach is to assume that substitution rates between amino acid pairs can be subdivided into rate classes, dependent on the information content of the alignment. However, given the combinatorially large number of such models, an efficient model search strategy is needed. Here we develop a Genetic Algorithm (GA) method for the estimation of such models. A GA is used to assign amino acid substitution pairs to a series of rate classes, where is estimated from the alignment. Other parameters of the phylogenetic Markov model, including substitution rates, character frequencies and branch lengths are estimated using standard maximum likelihood optimization procedures. We apply the GA to empirical alignments and show improved model fit over existing models of codon evolution. Our results suggest that current models are poor approximations of protein evolution and thus gene and organism specific multi-rate models that incorporate amino acid substitution biases are preferred. We further anticipate that the clustering of amino acid substitution rates into classes will be biologically informative, such that genes with similar functions exhibit similar clustering, and hence this clustering will be useful for the evolutionary fingerprinting of genes

Recent changes in summer distribution and numbers of migratory caribou on the southern Hudson Bay coast

The status of migratory woodland caribou inhabiting the coastal region in southern Hudson Bay is dynamic. The Pen Islands Herd within that region was defined in the 1990s, but opportunistic observations between 1999 and 2007 suggested that its status had significantly changed since the late 1980s and early 1990s. We undertook systematic surveys from the Hayes River, MB, to the Lakitusaki River, ON, in 2008 and 2009 to determine current distribution and minimum numbers of woodland caribou on the southern Hudson Bay coast from the Hayes River, Manitoba, to the Lakitusaki River, Ontario. We documented a significant change in summer distribution during the historical peak aggregation period (7-15 July) compared to the 1990s. In 2008 and 2009, respectively, we tallied 3529 and 3304 animals; however, fewer than 180 caribou were observed each year in the Pen Islands Herd’s former summer range where over 10 798 caribou were observed during a systematic survey in 1994. Over 80% of caribou were in the Cape Henrietta Maria area of Ontario. Calf proportions in herds varied from 8% of animals in the west to 20% in the east. Our 2008 and 2009 systematic surveys were focused on the immediate coast, but one exploratory flight inland suggested that more caribou may be inland than had been observed in the 1980s-1990s. The causes of change in the numbers and distribution in the coastal Hudson Bay Lowlands and the association of current caribou with the formerly large Pen Islands Herd may be difficult to determine because of gaps in monitoring, but satellite telemetry, genetic sampling, remote sensing, habitat analysis, and aboriginal knowledge are all being used to pursue answers

Probing a Complex of Cytochromecand Cardiolipin by Magnetic Circular Dichroism Spectroscopy: Implications for the Initial Events in Apoptosis

Oxidation of cardiolipin (CL) by its complex with cytochrome c (cyt c) plays a crucial role in triggering apoptosis. Through a combination of magnetic circular dichroism spectroscopy and potentiometric titrations, we show that both the ferric and ferrous forms of the heme group of a CL:cyt c complex exist as multiple conformers at a physiologically relevant pH of 7.4. For the ferric state, these conformers are His/Lys- and His/OH–-ligated. The ferrous state is predominantly high-spin and, most likely, His/–. Interconversion of the ferric and ferrous conformers is described by a single midpoint potential of -80 ± 9 mV vs SHE. These results suggest that CL oxidation in mitochondria could occur by the reaction of molecular oxygen with the ferrous CL:cyt c complex in addition to the well-described reaction of peroxides with the ferric form