The evolution of complex and higher organisms

The evolution of Phanerozoic life has probably been influenced by extraterrestrial events and properties of the Earth-Moon system that have not, until now, been widely recognized. Tide range, gravitational strength, the Earth's axial tilt, and other planetary properties provide background conditions whose effects on evolution may be difficult to distinguish. Solar flares, asteroid impacts, supernovae, and passage of the solar system through galactic clouds can provide catastrophic changes on the Earth with consequent characteristic extinctions. Study of the fossil record and the evolution of complex Phanerozoic life can reveal evidence of past disturbances in space near the Earth. Conversely, better understanding of environmental influences caused by extraterrestrial factors and properties of the solar system can clarify aspects of evolution, and may aid in visualizing life on other planets with different properties

Dynamics and pattern formation in invasive tumor growth

In this work, we study the in-vitro dynamics of the most malignant form of the primary brain tumor: Glioblastoma Multiforme. Typically, the growing tumor consists of the inner dense proliferating zone and the outer less dense invasive region. Experiments with different types of cells show qualitatively different behavior. Wild-type cells invade a spherically symmetric manner, but mutant cells are organized in tenuous branches. We formulate a model for this sort of growth using two coupled reaction-diffusion equations for the cell and nutrient concentrations. When the ratio of the nutrient and cell diffusion coefficients exceeds some critical value, the plane propagating front becomes unstable with respect to transversal perturbations. The instability threshold and the full phase-plane diagram in the parameter space are determined. The results are in a good agreement with experimental findings for the two types of cells.Comment: 4 pages, 4 figure

An asymptotic theory for the propagation of a surface-catalysed flame in a tube

Experiments have shown that when a mixture of fuel and oxygen is passed through a zirconia tube whose inner surface is coated with a catalyst, and then ignited at the end of the tube, a reaction front, or flame, propagates back along the tube towards the fuel inlet. The reaction front is visible as a red hot region moving at a speed of a few millimetres per second. In this paper we study a model of the flow, which takes into account diffusion, advection and chemical reaction at the inner surface of the tube. By assuming that the flame propagates at a constant speed without change of form, we can formulate a steady problem in a frame of reference moving with the reaction front. This is solved using the method of matched asymptotic expansions, assuming that the Reynolds and Damköhler numbers are large. We present numerical and, where possible, analytical results, first when the change in fluid density is small (a simplistic but informative limit) and secondly in the variable-density case. The speed of the travelling wave decreases as the critical temperature of the surface reaction increases and as the mass flow rate of fuel increases. We also make a comparison between our results and some preliminary experiments

Biscale Chaos in Propagating Fronts

The propagating chemical fronts found in cubic autocatalytic reaction-diffusion processes are studied. Simulations of the reaction-diffusion equation near to and far from the onset of the front instability are performed and the structure and dynamics of chemical fronts are studied. Qualitatively different front dynamics are observed in these two regimes. Close to onset the front dynamics can be characterized by a single length scale and described by the Kuramoto-Sivashinsky equation. Far from onset the front dynamics exhibits two characteristic lengths and cannot be modeled by this amplitude equation. An amplitude equation is proposed for this biscale chaos. The reduction of the cubic autocatalysis reaction-diffusion equation to the Kuramoto-Sivashinsky equation is explicitly carried out. The critical diffusion ratio delta, where the planar front loses its stability to transverse perturbations, is determined and found to be delta=2.300.Comment: Typeset using RevTeX, fig.1 and fig.4 are not available, mpeg simulations are at http://www.chem.utoronto.ca/staff/REK/Videos/front/front.htm

Cassini encounters with hot flow anomaly-like phenomena at Saturn's bow shock

Crossings of Saturn´s magnetopause made by the Cassini spacecraft on 12, 13 and 17 March 2006 are analysed. During this period Cassini´s trajectory was approximately parallel to the magnetopause boundary given by a model of the surface. Magnetic field and electron data are used to identify excursions into the magnetosheath bounded by crossings of the magnetopause current layer. Minimum variance analysis of the magnetic field vector measurements is used to determine the normal to the boundary for each crossing. The normals corresponding to the crossings oscillate about an average orientation that is consistent with the unperturbed normal predicted by the surface model. This reveals the presence of regular boundary waves with a direction of propagation found to be within 24° of Saturn´s rotational equator. Two categories of boundary wave are identified: the first with a period of the order of hours, and the second with a period of 45±9 min. Based on the propagation direction and a comparison of magnetospheric and magnetosheath magnetic fields, we conclude that both types of wave were driven by the Kelvin-Helmholtz instability. The observed boundary perturbations are consistent with a superposition of different types of surface wave activity.Fil: Masters, A.. Imperial College London; Reino UnidoFil: Arridge, C. S.. University College London; Estados UnidosFil: Dougherty, M. K.. Imperial College London; Reino UnidoFil: Bertucci, Cesar. Consejo Nacional de Investigaciónes Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Astronomía y Física del Espacio. - Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Astronomía y Física del Espacio; ArgentinaFil: Billingham, L.. Imperial College London; Reino UnidoFil: Schwartz, S. J.. Imperial College London; Reino UnidoFil: Jackman, C. M.. Imperial College London; Reino UnidoFil: Bebesi, Z.. Research Institute for Particle and Nuclear Physics; HungríaFil: Coates, A. J.. University College London; Estados UnidosFil: Thomsen, M. F.. Los Alamos National Laboratory; Estados Unido

Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study

Background: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate.  Objectives: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity.  Methods: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool.  Results: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%.  Conclusions: The pCR rate was insufficient to justify phase III investigation of imiquimod vs.  Surgery: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy

The Speed of Fronts of the Reaction Diffusion Equation

We study the speed of propagation of fronts for the scalar reaction-diffusion equation $u_t = u_{xx} + f(u)$\, with $f(0) = f(1) = 0$. We give a new integral variational principle for the speed of the fronts joining the state $u=1$ to $u=0$. No assumptions are made on the reaction term $f(u)$ other than those needed to guarantee the existence of the front. Therefore our results apply to the classical case $f > 0$ in $(0,1)$, to the bistable case and to cases in which $f$ has more than one internal zero in $(0,1)$.Comment: 7 pages Revtex, 1 figure not include

Stratified medicine in European Medicines Agency licensing : a systematic review of predictive biomarkers

OBJECTIVES: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. SETTING: EMA licensing. PARTICIPANTS: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. RESULTS: 49 biomarker–indication–drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends. CONCLUSIONS: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice

ES-Cell Derived Hematopoietic Cells Induce Transplantation Tolerance

Background: Bone marrow cells induce stable mixed chimerism under appropriate conditioning of the host, mediating the induction of transplantation tolerance. However, their strong immunogenicity precludes routine use in clinical transplantation due to the need for harsh preconditioning and the requirement for toxic immunosuppression to prevent rejection and graft-versus-host disease. Alternatively, embryonic stem (ES) cells have emerged as a potential source of less immunogenic hematopoietic progenitor cells (HPCs). Up till now, however, it has been difficult to generate stable hematopoietic cells from ES cells. Methodology/Principal Findings: Here, we derived CD45 + HPCs from HOXB4-transduced ES cells and showed that they poorly express MHC antigens. This property allowed their long-term engraftment in sublethally irradiated recipients across MHC barriers without the need for immunosuppressive agents. Although donor cells declined in peripheral blood over 2 months, low level chimerism was maintained in the bone marrow of these mice over 100 days. More importantly, chimeric animals were protected from rejection of donor-type cardiac allografts. Conclusions: Our data show, for the first time, the efficacy of ES-derived CD45 + HPCs to engraft in allogenic recipient