Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations.

Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations

Low-energy quasiparticle excitations in dirty d-wave superconductors and the Bogoliubov-de Gennes kicked rotator

We investigate the quasiparticle density of states in disordered d-wave superconductors. By constructing a quantum map describing the quasiparticle dynamics in such a medium, we explore deviations of the density of states from its universal form ($\propto E$), and show that additional low-energy quasiparticle states exist provided (i) the range of the impurity potential is much larger than the Fermi wavelength [allowing to use recently developed semiclassical methods]; (ii) classical trajectories exist along which the pair-potential changes sign; and (iii) the diffractive scattering length is longer than the superconducting coherence length. In the classically chaotic regime, universal random matrix theory behavior is restored by quantum dynamical diffraction which shifts the low energy states away from zero energy, and the quasiparticle density of states exhibits a linear pseudogap below an energy threshold $E^* \ll \Delta_0$.Comment: 4 pages, 3 figures, RevTe

Asymptotic Scaling and Infrared Behavior of the Gluon Propagator

The Landau gauge gluon propagator for the pure gauge theory is evaluated on a 32^3x64 lattice with a physical volume of (3.35^3x6.7)fm^4. Comparison with two smaller lattices at different lattice spacings allows an assessment of finite volume and finite lattice spacing errors. Cuts on the data are imposed to minimize these errors. Scaling of the gluon propagator is verified between beta=6.0 and beta=6.2. The tensor structure is evaluated and found to be in good agreement with the Landau gauge form, except at very small momentum values, where some small finite volume errors persist. A number of functional forms for the momentum dependence of the propagator are investigated. The form D(q^2)=D_ir+D_uv, where D_ir(q^2) ~ (q^2+M^2)^-\eta and D_uv is an infrared regulated one-loop asymptotic form, is found to provide an adequate description of the data over the entire momentum region studied - thereby bridging the gap between the infrared confinement region and the ultraviolet asymptotic region. The best estimate for the exponent \eta is 3.2(+0.1/-0.2)(+0.2/-0.3), where the first set of errors represents the uncertainty associated with varying the fitting range, while the second set of errors reflects the variation arising from different choices of infrared regulator in D_uv. Fixing the form of D_uv, we find that the mass parameter M is (1020+/-100)MeV.Comment: 37 pages, RevTeX, 16 postscript figures, 7 gif figures. Revised version accepted for publication in Phys. Rev. D. Model functions and discussion of asymptotic behaviour modified; all model fits have been redone. This paper, including postscript version of all figures, can be found at http://www.physics.adelaide.edu.au/~jskuller/papers

Headache during airplane travel (“airplane headache”): first case in Greece

Headache related to airplane flights is rare. We describe a 37-year-old female patient with multiple intense, jabbing headache episodes over the last 3 years that occur exclusively during airplane flights. The pain manifests during take-off and landing, and is located always in the left retro-orbital and frontotemporal area. It is occasionally accompanied by dizziness, but no additional symptoms occur. Pain intensity diminishes and disappears after 15–20 min. Apart from occasional dizziness, no other symptoms occur. The patient has a history of tension-type headache and polycystic ovaries. Blood tests and imaging revealed no abnormalities. Here, we present the first case in Greece. We review the current literature on this rare syndrome and discuss on possible pathophysiology and the investigation of possible co-factors such as anxiety and depression

Effects of growth rate, size, and light availability on tree survival across life stages: a demographic analysis accounting for missing values and small sample sizes.

The data set supporting the results of this article is available in the Dryad repository, http://dx.doi.org/10.5061/dryad.6f4qs. Moustakas, A. and Evans, M. R. (2015) Effects of growth rate, size, and light availability on tree survival across life stages: a demographic analysis accounting for missing values.Plant survival is a key factor in forest dynamics and survival probabilities often vary across life stages. Studies specifically aimed at assessing tree survival are unusual and so data initially designed for other purposes often need to be used; such data are more likely to contain errors than data collected for this specific purpose

How paradata can illuminate technical, social and professional role changes between the Poverty in the UK (1967/1968) and Poverty and Social Exclusion in the UK (2012) surveys

© 2016, The Author(s). This article brings together analyses of the micro paradata ‘by-products’ from the 1967/1968 Poverty in the United Kingdom (PinUK) and 2012 Poverty and Social Exclusion in the UK (PSE) surveys to explore changes in the conditions of production over this 45year period. We highlight technical, social and professional role continuities and changes, shaped by the institutionalisation of survey researchers, the professionalization of the field interviewer, and economisation. While there are similarities between the surveys in that field interviewers were and are at the bottom of the research hierarchy, we demonstrate an increasing segregation between the core research team and field interviewers. In PinUK the field interviewers are visible in the paper survey booklets; through their handwritten notes on codes and in written marginalia they can ‘talk’ to the central research team. In PSE they are absent from the computer mediated data, and from communication with the central team. We argue that, while there have been other benefits to field interviewers, their relational labour has become less visible in a shift from the exercise of observational judgement to an emphasis on standardisation. Yet, analyses of what field interviewers actually do show that they still need to deploy the same interpersonal skills and resourcefulness to secure and maintain interviews as they did 45years previously

Breast cancer risk factors and a novel measure of volumetric breast density: cross-sectional study

We conducted a cross-sectional study nested within a prospective cohort of breast cancer risk factors and two novel measures of breast density volume among 590 women who had attended Glasgow University (1948–1968), replied to a postal questionnaire (2001) and attended breast screening in Scotland (1989–2002). Volumetric breast density was estimated using a fully automated computer programme applied to digitised film-screen mammograms, from medio-lateral oblique mammograms at the first-screening visit. This measured the proportion of the breast volume composed of dense (non-fatty) tissue (Standard Mammogram Form (SMF)%) and the absolute volume of this tissue (SMF volume, cm3). Median age at first screening was 54.1 years (range: 40.0–71.5), median SMF volume 70.25 cm3 (interquartile range: 51.0–103.0) and mean SMF% 26.3%, s.d.=8.0% (range: 12.7–58.8%). Age-adjusted logistic regression models showed a positive relationship between age at last menstrual period and SMF%, odds ratio (OR) per year later: 1.05 (95% confidence interval: 1.01–1.08, P=0.004). Number of pregnancies was inversely related to SMF volume, OR per extra pregnancy: 0.78 (0.70–0.86, P<0.001). There was a suggestion of a quadratic relationship between birthweight and SMF%, with lowest risks in women born under 2.5 and over 4 kg. Body mass index (BMI) at university (median age 19) and in 2001 (median age 62) were positively related to SMF volume, OR per extra kg m−2 1.21 (1.15–1.28) and 1.17 (1.09–1.26), respectively, and inversely related to SMF%, OR per extra kg m−2 0.83 (0.79–0.88) and 0.82 (0.76–0.88), respectively, P<0.001. Standard Mammogram Form% and absolute SMF volume are related to several, but not all, breast cancer risk factors. In particular, the positive relationship between BMI and SMF volume suggests that volume of dense breast tissue will be a useful marker in breast cancer studies

Determinants of parents' reticence toward vaccination in urban areas in Benin (West Africa)

Analysis of the data reveals those who are vaccination-reticent say it goes against the will of God, that it is a poison from the “white witch doctor,” and a sin. Members of the control group argued against this, but without conviction. They adhere to the principle of obedience to authority, a biblical precept invoked when the vaccinators oblige them to vaccinate their children. To limit the spread of this phenomenon among the religious population of the cities like Parakou and Cotonou in Benin, more detailed information and negotiation between health authorities and pastors of the churches are essential