The fibre of a pinch map in a model category

In the category of pointed topological spaces, let F be the homotopy fibre of the pinching map X ∪ CA → X ∪ CA/ X from the mapping cone on a cofibration A → X onto the suspension of A. Gray (Proc Lond Math Soc (3) 26:497–520, 1973) proved that F is weakly homotopy equivalent to the reduced product (X, A)∞. In this paper we prove an analogue of this phenomenon in a model category, under suitable conditions including a cube axiom.Web of Scienc

An international randomised controlled trial to compare targeted intra-operative radiotherapy (TARGIT) with conventional post-operative radiotherapy after conservative breast surgery for women with early stage breast cancer (The TARGIT-A trial)

BACKGROUND: Based on our laboratory work and clinical trials we hypothesised that radiotherapy after lumpectomy for breast cancer could be restricted to the tumour bed. In collaboration with the industry we developed a new radiotherapy device and a new surgical operation for delivering single-dose radiation to the tumour bed - the tissues at highest risk of local recurrence. We named it TARGeted Intraoperative radioTherapy (TARGIT). From 1998 we confirmed its feasibility and safety in pilot studies. OBJECTIVE: To compare TARGIT within a risk-adapted approach with whole breast external beam radiotherapy over several weeks (EBRT). DESIGN AND SETTING: The TARGIT-A trial was a pragmatic, prospective, international, multicenter, non-inferiority, non-blinded, randomised (1:1 ratio), clinical trial from 33 centres in 11 countries. Originally, randomisation occurred before initial lumpectomy (prepathology) and if allocated TARGIT, the patient received it during the lumpectomy. Subsequently, the postpathology stratum was added, in which randomisation occurred after initial lumpectomy, allowing potentially easier logistics and a more stringent case selection, but needed a reoperation to reopen the wound to give TARGIT as delayed procedure. Risk-adapted approach meant that in the experimental arm, if pre-specified unsuspected adverse factors were found postoperatively after receiving TARGIT, then EBRT was recommended. Pragmatically, this reflected how TARGIT would be practiced in the real world. PARTICIPANTS: Women who were >=45 years of age with unifocal invasive ductal carcinoma preferably <= 3.5cm in size; 3451 patients were recruited between March 2000 and June 2012. OUTCOMES: Primary: absolute difference in local recurrence, with a non-inferiority margin of 2.5%. Secondary: included toxicity, breast cancer specific and non-breast-cancer mortality. RESULTS: Values below are 5-year Kaplan-Meier rates for TARGIT vs. EBRT. There was no statistically significant difference in local recurrence between TARGIT and EBRT. TARGIT was non-inferior to EBRT overall (3·3%(2·1–5·1) vs. 1·3%(0·7–2·5),p=0.04,Pnoninferiority =0.00000012) and in the prepathology stratum(n=2298) when TARGIT was given concurrently with lumpectomy(2·1%(1·1–4·2) vs. 1·1%(0·5–2·5),p=0.31,Pnoninferiority =0.0000000013). With delayed TARGIT postpathology,(n=1153) the between-group difference was larger than 2·5% and non-inferiority was not established for this stratum((5·4%(3·0–9·7) vs. 1·7%(0·6–4·9),p=0.069,Pnoninferiority= 0.06640). The local-recurrence-free survival when TARGIT was given with lumpectomy was 93.9%(95%CI 90.9 – 95.9) vs. EBRT: 92.5%(95%CI 89.7 – 94.6),p=0.35. In a planned subgroup analysis, progesterone (PgR) receptor status was found to be the only predictor of outcome - hormone responsive patients (PgRpositive) had similar 5-year local recurrence with TARGIT during lumpectomy 1.4%(0.5-3.9) vs. EBRT 1.2%(0.5-2.9),p=0.77. Grade 3 or 4 radiotherapy toxicity was significantly reduced with TARGIT. Overall, breast cancer mortality was much the same between groups (2·6%[1·5–4·3] vs. 1·9%[1·1–3·2];p=0·56) but there were significantly fewer non-breast-cancer deaths with TARGIT (1·4% [0·8–2·5] vs 3·5%[2·3–5·2];p=0·0086), attributable to fewer deaths from cardiovascular causes and other cancers, leading to a trend in reduced overall mortality in the TARGIT arm 37 deaths, 3·9%(2·7–5·8) vs. 51 deaths, 5·3%(3·9–7·3),p=0.099). Health economic analyses suggest that TARGIT was statistically significantly less costly than EBRT, produced similar QALYs, had a positive incremental Net Monetary Benefit that was borderline statistically significant from zero, and had a probability of over 90% of being cost-effective. There appears to be little uncertainty in the point estimates, based on deterministic and probabilistic sensitivity analyses. If TARGIT were given instead of EBRT in suitable patients, it might potentially reduce costs to the health care providers by £8 million to £9.1 million each year. This does not include environmental, patient and societal costs. LIMITATIONS: The number of local recurrences is small however, the number of events for local-recurrence-free survival is not small (59 vs. 61); Occurrence of only a few events implies that the treatments are effective and any difference is unlikely to be large. The follow up not all 3451 patients is 5 years, although the number required to answer the main trial question (n=585) have more than 5 years follow up. FUTURE WORK: We shall repeat the analyses with longer follow up. Although this may not change the primary result, the larger number of events may confirm the effect on mortality and allow more detailed subgroup analyses. The TARGIT-B trial is testing whether TARGIT-Boost is superior to EBRT boost. CONCLUSION: For patients with breast cancer (women who are 45 years of age and older with hormone sensitive invasive ductal carcinoma that is up to 3.5cm in size), TARGIT concurrent with lumpectomy within a risk-adapted approach is as effective, safer and less expensive alternative to postoperative EBRT. TRIAL REGISTRATION: ISRCTN34086741, ClinicalTrials.gov NCT00983684

Salience-based selection: attentional capture by distractors less salient than the target

Current accounts of attentional capture predict the most salient stimulus to be invariably selected first. However, existing salience and visual search models assume noise in the map computation or selection process. Consequently, they predict the first selection to be stochastically dependent on salience, implying that attention could even be captured first by the second most salient (instead of the most salient) stimulus in the field. Yet, capture by less salient distractors has not been reported and salience-based selection accounts claim that the distractor has to be more salient in order to capture attention. We tested this prediction using an empirical and modeling approach of the visual search distractor paradigm. For the empirical part, we manipulated salience of target and distractor parametrically and measured reaction time interference when a distractor was present compared to absent. Reaction time interference was strongly correlated with distractor salience relative to the target. Moreover, even distractors less salient than the target captured attention, as measured by reaction time interference and oculomotor capture. In the modeling part, we simulated first selection in the distractor paradigm using behavioral measures of salience and considering the time course of selection including noise. We were able to replicate the result pattern we obtained in the empirical part. We conclude that each salience value follows a specific selection time distribution and attentional capture occurs when the selection time distributions of target and distractor overlap. Hence, selection is stochastic in nature and attentional capture occurs with a certain probability depending on relative salience

Activation of Human Stearoyl-Coenzyme A Desaturase 1 Contributes to the Lipogenic Effect of PXR in HepG2 Cells

The pregnane X receptor (PXR) was previously known as a xenobiotic receptor. Several recent studies suggested that PXR also played an important role in lipid homeostasis but the underlying mechanism remains to be clearly defined. In this study, we found that rifampicin, an agonist of human PXR, induced lipid accumulation in HepG2 cells. Lipid analysis showed the total cholesterol level increased. However, the free cholesterol and triglyceride levels were not changed. Treatment of HepG2 cells with rifampicin induced the expression of the free fatty acid transporter CD36 and ABCG1, as well as several lipogenic enzymes, including stearoyl-CoA desaturase-1 (SCD1), long chain free fatty acid elongase (FAE), and lecithin-cholesterol acyltransferase (LCAT), while the expression of acyl:cholesterol acetyltransferase(ACAT1) was not affected. Moreover, in PXR over-expressing HepG2 cells (HepG2-PXR), the SCD1 expression was significantly higher than in HepG2-Vector cells, even in the absence of rifampicin. Down-regulation of PXR by shRNA abolished the rifampicin-induced SCD1 gene expression in HepG2 cells. Promoter analysis showed that the human SCD1 gene promoter is activated by PXR and a novel DR-7 type PXR response element (PXRE) response element was located at -338 bp of the SCD1 gene promoter. Taken together, these results indicated that PXR activation promoted lipid synthesis in HepG2 cells and SCD1 is a novel PXR target gene. © 2013 Zhang et al

Happiness matters : exploring the linkages between personality, personal happiness, and work-related psychological health among priests and sisters in Italy

This study responds to the challenge posed by Rossetti’s work to explore the antecedents and consequences of individual differences in happiness among priests and religious sisters. The Oxford Happiness Questionnaire was completed together with measures of personality and work-related psychological health by 95 priests and 61 religious sisters. Overall the data demonstrated high levels of personal happiness among priests and religious sisters, but also significant signs of vulnerability. Personality provided significant prediction of individual differences in both personal happiness and work-related psychological health. However, personal happiness provided additional protection against work-related emotional exhaustion and additional enhancement of work-related satisfaction. These findings suggest that acknowledging and affirming personal happiness may enhance the work-related psychological health of Catholic priests and religious sisters

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

The Effect of Epstein-Barr Virus Latent Membrane Protein 2 Expression on the Kinetics of Early B Cell Infection

Infection of human B cells with wild-type Epstein-Barr virus (EBV) in vitro leads to activation and proliferation that result in efficient production of lymphoblastoid cell lines (LCLs). Latent Membrane Protein 2 (LMP2) is expressed early after infection and previous research has suggested a possible role in this process. Therefore, we generated recombinant EBV with knockouts of either or both protein isoforms, LMP2A and LMP2B (Δ2A, Δ2B, Δ2A/Δ2B) to study the effect of LMP2 in early B cell infection. Infection of B cells with Δ2A and Δ2A/Δ2B viruses led to a marked decrease in activation and proliferation relative to wild-type (wt) viruses, and resulted in higher percentages of apoptotic B cells. Δ2B virus infection showed activation levels comparable to wt, but fewer numbers of proliferating B cells. Early B cell infection with wt, Δ2A and Δ2B viruses did not result in changes in latent gene expression, with the exception of elevated LMP2B transcript in Δ2A virus infection. Infection with Δ2A and Δ2B viruses did not affect viral latency, determined by changes in LMP1/Zebra expression following BCR stimulation. However, BCR stimulation of Δ2A/Δ2B cells resulted in decreased LMP1 expression, which suggests loss of stability in viral latency. Long-term outgrowth assays revealed that LMP2A, but not LMP2B, is critical for efficient long-term growth of B cells in vitro. The lowest levels of activation, proliferation, and LCL formation were observed when both isoforms were deleted. These results suggest that LMP2A appears to be critical for efficient activation, proliferation and survival of EBV-infected B cells at early times after infection, which impacts the efficient long-term growth of B cells in culture. In contrast, LMP2B did not appear to play a significant role in these processes, and long-term growth of infected B cells was not affected by the absence of this protein. © 2013 Wasil et al

Serum microrna biomarkers for detection of non-small cell lung cancer

Non small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality world-wide and the majority of cases are diagnosed at late stages of disease. There is currently no cost-effective screening test for NSCLC, and the development of such a test is a public health imperative. Recent studies have suggested that chest computed tomography screening of patients at high risk of lung cancer can increase survival from disease, however, the cost effectiveness of such screening has not been established. In this Phase I/II biomarker study we examined the feasibility of using serum miRNA as biomarkers of NSCLC using RT-qPCR to examine the expression of 180 miRNAs in sera from 30 treatment naive NSCLC patients and 20 healthy controls. Receiver operating characteristic curves (ROC) and area under the curve were used to identify differentially expressed miRNA pairs that could distinguish NSCLC from healthy controls. Selected miRNA candidates were further validated in sera from an additional 55 NSCLC patients and 75 healthy controls. Examination of miRNA expression levels in serum from a multi-institutional cohort of 50 subjects (30 NSCLC patients and 20 healthy controls) identified differentially expressed miRNAs. A combination of two differentially expressed miRNAs miR-15b and miR-27b, was able to discriminate NSCLC from healthy controls with sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 100% in the training set. Upon further testing on additional 130 subjects (55 NSCLC and 75 healthy controls), this miRNA pair predicted NSCLC with a specificity of 84% (95% CI 0.73-0.91), sensitivity of 100% (95% CI; 0.93-1.0), NPV of 100%, and PPV of 82%. These data provide evidence that serum miRNAs have the potential to be sensitive, cost-effective biomarkers for the early detection of NSCLC. Further testing in a Phase III biomarker study in is necessary for validation of these results. © 2012 Hennessey et al

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions

The perceptions of social responsibility for community resilience to flooding: the impact of past experience, age, gender and ethnicity

Community resilience to flooding depends, to a large extent, on the participation of community members to take more responsibility for enhancing their own resilience. The perception of social responsibility (SR) which is argued to be one of the antecedents influencing individual’s willingness to undertake resilient behaviours can significantly contribute to community resilience through individual and collective actions. Understanding of factors influencing the perceptions of SR of individuals within community might help with developing strategies to increase the perceptions of SR. This research explores perceptions of SR in relation to flooding for householders and local businesses and establishes their relationships with experience of flooding and demographic factors of age, gender and ethnicity. The data were obtained via a questionnaire survey of three communities in Birmingham and one community in South East London, UK, three with experience of flooding and one without. A total of 414 responses were received and used in the multiple regression analysis. The analysis identified ‘experience of flooding’, ‘age’ and ‘South Asian’ ethnic group as significant variables, suggesting that older individuals from South Asian ethnic groups with previous experience of flooding are likely to be more socially responsible than others without these attributes