Predicting the Effect of Indirect Cell Kill in the Treatment of Multiple Brain Metastases via Single-Isocenter/Multitarget Volumetric Modulated Arc Therapy Stereotactic Radiosurgery

PURPOSE: Due to spatial uncertainty, patient setup errors are of major concern for radiosurgery of multiple brain metastases (m-bm) when using single-isocenter/multitarget (SIMT) volumetric modulated arc therapy (VMAT) techniques. However, recent clinical outcome studies show high rates of tumor local control for SIMT-VMAT. In addition to direct cell kill (DCK), another possible explanation includes the effects of indirect cell kill (ICK) via devascularization for a single dose of 15 Gy or more and by inducing a radiation immune intratumor response. This study quantifies the role of indirect cell death in dosimetric errors as a function of spatial patient setup uncertainty for stereotactic treatments of multiple lesions. MATERIAL AND METHODS: Nine complex patients with 61 total tumors (2-16 tumors/patient) were planned using SIMT-VMAT with geometry similar to HyperArc with a 10MV-FFF beam (2400 MU/min). Isocenter was placed at the geometric center of all tumors. Average gross tumor volume (GTV) and planning target volume (PTV) were 1.1 cc (0.02–11.5) and 1.9 cc (0.11–18.8) with an average distance to isocenter of 5.4 cm (2.2–8.9). The prescription was 20 Gy to each PTV. Plans were recalculated with induced clinically observable patient setup errors [±2 mm, ±2o] in all six directions. Boolean structures were generated to calculate the effect of DCK via 20 Gy isodose volume (IDV) and ICK via 15 Gy IDV minus the 20 Gy IDV. Contributions of each IDV to the PTV coverage were analyzed along with normal brain toxicity due to the patient setup uncertainty. Induced uncertainty and minimum dose covering the entire PTV were analyzed to determine the maximum tolerable patient setup errors to utilize the ICK effect for radiosurgery of m-bm via SIMT-VMAT. RESULTS: Patient setup errors of 1.3 mm /1.3° in all six directions must be maintained to achieve PTV coverage of the 15 Gy IDV for ICK. Setup errors of ±2 mm/2° showed clinically unacceptable loss of PTV coverage of 29.4 ± 14.6% even accounting the ICK effect. However, no clinically significant effect on normal brain dosimetry was observed. CONCLUSIONS: Radiosurgery of m-bm using SIMT-VMAT treatments have shown positive clinical outcomes even with small residual patient setup errors. These clinical outcomes, while largely due to DCK, may also potentially be due to the ICK. Potential mechanisms, such as devascularization and/or radiation-induced intratumor immune enhancement, should be explored to provide a better understanding of the radiobiological response of stereotactic radiosurgery of m-bm using a SIMT-VMAT plan

Gravity and active acceleration limit the ability of killer flies (Coenosia attenuata) to steer towards prey when attacking from above.

Insects that predate aerially usually contrast prey against the sky and attack upwards. However, killer flies (Coenosia attenuata) can attack prey flying below them, performing what we term 'aerial dives'. During these dives, killer flies accelerate up to 36 m s-2. Although the trajectories of the killer fly's dives appear highly variable, proportional navigation explains them, as long as the model has the lateral acceleration limit of a real killer fly. The trajectory's steepness is explained by the initial geometry of engagement; steep attacks result from the killer fly taking off when the target is approaching the predator. Under such circumstances, the killer fly dives almost vertically towards the target, and gravity significantly increases its acceleration. Although killer flies usually time their take-off to minimize flight duration, during aerial dives killer flies cannot reach the lateral accelerations necessary to match the increase in speed caused by gravity. Since a close miss still leads the predator closer to the target, and might even slow the prey down, there may not be a selective pressure for killer flies to account for gravity during aerial dives

A Novel Interception Strategy in a Miniature Robber Fly with Extreme Visual Acuity

Our visual system allows us to rapidly identify and intercept a moving object. When this object is far away, we base the trajectory on the target's location relative to an external frame of reference [1]. This process forms the basis for the constant bearing angle (CBA) model, a reactive strategy that ensures interception since the bearing angle, formed between the line joining pursuer and target (called the range vector) and an external reference line, is held constant [2-4]. The CBA model may be a fundamental and widespread strategy, as it is also known to explain the interception trajectories of bats and fish [5, 6]. Here, we show that the aerial attack of the tiny robber fly Holcocephala fusca is consistent with the CBA model. In addition, Holcocephala fusca displays a novel proactive strategy, termed "lock-on" phase, embedded with the later part of the flight. We found the object detection threshold for this species to be 0.13°, enabled by an extremely specialized, forward pointing fovea (∼5 ommatidia wide, interommatidial angle Δφ = 0.28°, photoreceptor acceptance angle Δρ = 0.27°). This study furthers our understanding of the accurate performance that a miniature brain can achieve in highly demanding sensorimotor tasks and suggests the presence of equivalent mechanisms for target interception across a wide range of taxa.This work was funded by the Air Force Office of Scientific Research (FA9550-15-1-0188 to P.T.G.-B. and K.N. and FA9550-15-1-0068 to D.G.S.), an Isaac Newton Trust/Wellcome Trust ISSF/University of Cambridge Joint Research Grant (097814/Z/11/Z) to P.T.G.-B., a Biotechnology and Biological Sciences Research Council David Phillips Fellowship (BBSRC, BB/L024667/1) to T.J.W., a Royal Society International Exchange Scheme grant to P.T.G.-B. (75166), a Swedish Research Council grant (2012-4740) to K.N., and a Shared Equipment Grant from the School of Biological Sciences (University of Cambridge, RG70368)

miR-132/212 knockout mice reveal roles for these miRNAs in regulating cortical synaptic transmission and plasticity

miR-132 and miR-212 are two closely related miRNAs encoded in the same intron of a small non-coding gene, which have been suggested to play roles in both immune and neuronal function. We describe here the generation and initial characterisation of a miR-132/212 double knockout mouse. These mice were viable and fertile with no overt adverse phenotype. Analysis of innate immune responses, including TLR-induced cytokine production and IFNβ induction in response to viral infection of primary fibroblasts did not reveal any phenotype in the knockouts. In contrast, the loss of miR-132 and miR-212, while not overtly affecting neuronal morphology, did affect synaptic function. In both hippocampal and neocortical slices miR-132/212 knockout reduced basal synaptic transmission, without affecting paired-pulse facilitation. Hippocampal long-term potentiation (LTP) induced by tetanic stimulation was not affected by miR-132/212 deletion, whilst theta burst LTP was enhanced. In contrast, neocortical theta burst-induced LTP was inhibited by loss of miR-132/212. Together these results indicate that miR-132 and/or miR-212 play a significant role in synaptic function, possibly by regulating the number of postsynaptic AMPA receptors under basal conditions and during activity-dependent synaptic plasticity

Discovery of high-amplitude X-ray variability in the Seyfert-LINER transition galaxy NGC7589

We present the first result of a programme to search for large flux variations in the X-ray sources of the XMM Serendipitous Survey compared to previous ROSAT observations. An increase in X-ray flux by a factor >10 was discovered from the nucleus of the galaxy NGC7589 on a timescale of less than 5 years. The 0.4-10keV XMM spectrum can be approximated by a power-law with photon index of 1.7-1.8, though it seems to flatten above 5keV, suggesting a possible complex model, such as partial covering or disc reflection. A classification based on an analysis of its optical spectrum places NGC7589 in the Seyfert region, but close to the Seyfert-LINER border-line on the AGN diagnostic diagrams. We classify NGC7589 as either Seyfert1.9 or LINERI, in the light of the detection of a broad H_alpha line, which makes NGC7589 an AGN in the low-luminosity regime. We interpret the observed variability in terms of either changes in covering factor of absorbing gas in the AGN, or variability in the intrinsic X-ray luminosity. Should the latter be the case, the inferred Eddington accretion rate increased from the radiatively inefficient accretion dominated regime to a value close to the putative critical value, at which a transition of the accretion mode is supposed to take place. This possibility presents a new prospect of studying accretion physics in the central black holes of external galaxies by direct observing changes of `spectral state', as is common in stellar black hole binary systems.Comment: 6 pages, 4 figures, accepted for publication in MNRAS Lette

Clusters of galaxies : observational properties of the diffuse radio emission

Clusters of galaxies, as the largest virialized systems in the Universe, are ideal laboratories to study the formation and evolution of cosmic structures...(abridged)... Most of the detailed knowledge of galaxy clusters has been obtained in recent years from the study of ICM through X-ray Astronomy. At the same time, radio observations have proved that the ICM is mixed with non-thermal components, i.e. highly relativistic particles and large-scale magnetic fields, detected through their synchrotron emission. The knowledge of the properties of these non-thermal ICM components has increased significantly, owing to sensitive radio images and to the development of theoretical models. Diffuse synchrotron radio emission in the central and peripheral cluster regions has been found in many clusters. Moreover large-scale magnetic fields appear to be present in all galaxy clusters, as derived from Rotation Measure (RM) studies. Non-thermal components are linked to the cluster X-ray properties, and to the cluster evolutionary stage, and are crucial for a comprehensive physical description of the intracluster medium. They play an important role in the cluster formation and evolution. We review here the observational properties of diffuse non-thermal sources detected in galaxy clusters: halos, relics and mini-halos. We discuss their classification and properties. We report published results up to date and obtain and discuss statistical properties. We present the properties of large-scale magnetic fields in clusters and in even larger structures: filaments connecting galaxy clusters. We summarize the current models of the origin of these cluster components, and outline the improvements that are expected in this area from future developments thanks to the new generation of radio telescopes.Comment: Accepted for the publication in The Astronomy and Astrophysics Review. 58 pages, 26 figure

The effects of breastfeeding on retinoblastoma development: Results from an international multicenter retinoblastoma survey

The protective effects of breastfeeding on various childhood malignancies have been established but an association has not yet been determined for retinoblastoma (RB). We aimed to further investigate the role of breastfeeding in the severity of nonhereditary RB development, assessing relationship to (1) age at diagnosis, (2) ocular prognosis, measured by International Intraocular RB Classification (IIRC) or Intraocular Classification of RB (ICRB) group and success of eye salvage, and (3) extraocular involvement. Analyses were performed on a global dataset subgroup of 344 RB patients whose legal guardian(s) consented to answer a neonatal questionnaire. Patients with undetermined or mixed feeding history, family history of RB, or sporadic bilateral RB were excluded. There was no statistically significant difference between breastfed and formula-fed groups in (1) age at diagnosis (p = 0.20), (2) ocular prognosis measures of IIRC/ICRB group (p = 0.62) and success of eye salvage (p = 0.16), or (3) extraocular involvement shown by International Retinoblastoma Staging System (IRSS) at presentation (p = 0.74), lymph node involvement (p = 0.20), and distant metastases (p = 0.37). This study suggests that breastfeeding neither impacts the sporadic development nor is associated with a decrease in the severity of nonhereditary RB as measured by age at diagnosis, stage of disease, ocular prognosis, and extraocular spread. A further exploration into the impact of diet on children who develop RB is warranted

Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS.

Many mutations confer one or more toxic function(s) on copper/zinc superoxide dismutase 1 (SOD1) that impair motor neuron viability and cause familial amyotrophic lateral sclerosis (FALS). Using a conformation-specific antibody that detects misfolded SOD1 (C4F6), we found that oxidized wild-type SOD1 and mutant SOD1 share a conformational epitope that is not present in normal wild-type SOD1. In a subset of human sporadic ALS (SALS) cases, motor neurons in the lumbosacral spinal cord were markedly C4F6 immunoreactive, indicating that an aberrant wild-type SOD1 species was present. Recombinant, oxidized wild-type SOD1 and wild-type SOD1 immunopurified from SALS tissues inhibited kinesin-based fast axonal transport in a manner similar to that of FALS-linked mutant SOD1. Our findings suggest that wild-type SOD1 can be pathogenic in SALS and identify an SOD1-dependent pathogenic mechanism common to FALS and SALS

Aldose reductase deficiency in mice protects from ragweed pollen extract (RWE)-induced allergic asthma

<p>Abstract</p> <p>Background</p> <p>Childhood hospitalization related to asthma remains at historically high levels, and its incidence is on the rise world-wide. Previously, we have demonstrated that aldose reductase (AR), a regulatory enzyme of polyol pathway, is a major mediator of allergen-induced asthma pathogenesis in mouse models. Here, using AR null (AR^-/-) mice we have investigated the effect of AR deficiency on the pathogenesis of ragweed pollen extract (RWE)-induced allergic asthma in mice and also examined the efficacy of enteral administration of highly specific AR inhibitor, fidarestat.</p> <p>Methods</p> <p>The wild type (WT) and AR^-/-mice were sensitized and challenged with RWE to induce allergic asthma. AR inhibitor, fidarestat was administered orally. Airway hyper-responsiveness was measured in unrestrained animals using whole body plethysmography. Mucin levels and Th2 cytokine in broncho-alveolar lavage (BAL) were determined using mouse anti-Muc5A/C ELISA kit and multiplex cytokine array, respectively. Eosinophils infiltration and goblet cells were assessed by H&E and periodic acid Schiff (PAS)-staining of formalin-fixed, paraffin-embedded lung sections. T regulatory cells were assessed in spleen derived CD4⁺CD25⁺T cells population.</p> <p>Results</p> <p>Deficiency of AR in mice led to significantly decreased PENH, a marker of airway hyper-responsiveness, metaplasia of airway epithelial cells and mucus hyper-secretion following RWE-challenge. This was accompanied by a dramatic decrease in infiltration of eosinophils into sub-epithelium of lung as well as in BAL and release of Th2 cytokines in response to RWE-challenge of AR^-/-mice. Further, enteral administration of fidarestat significantly prevented eosinophils infiltration, airway hyper-responsiveness and also markedly increased population of T regulatory (CD4⁺CD25⁺FoxP3⁺) cells as compared to RWE-sensitized and challenged mice not treated with fidarestat.</p> <p>Conclusion</p> <p>Our results using AR^-/-mice strongly suggest the role of AR in allergic asthma pathogenesis and effectiveness of oral administration of AR inhibitor in RWE-induced asthma in mice supports the use of AR inhibitors in the treatment of allergic asthma.</p