NOD/SCID-GAMMA Mice Are an Ideal Strain to Assess the Efficacy of Therapeutic Agents Used in the Treatment of Myeloma Bone Disease

Animal models of multiple myeloma vary in terms of consistency of onset, degree of tumour burden and degree of myeloma bone disease. Here we describe five pre-clinical models of myeloma in NOD/SCID-GAMMA mice to specifically study the effects of therapeutic agents on myeloma bone disease. Groups of 7–8 week old female irradiated NOD/SCID-GAMMA mice were injected intravenously via the tail vein with either 1x106 JJN3, U266, XG-1 or OPM-2 human myeloma cell lines or patient-derived myeloma cells. At the first signs of morbidity in each tumour group all animals were sacrificed. Tumour load was measured by histological analysis, and bone disease was assessed by micro-CT and standard histomorphometric methods. Mice injected with JJN3, U266 or OPM-2 cells showed high tumour bone marrow infiltration of the long bones with low variability, resulting in osteolytic lesions. In contrast, mice injected with XG-1 or patient-derived myeloma cells showed lower tumour bone marrow infiltration and less bone disease with high variability. Injection of JJN3 cells into NOD/SCID-GAMMA mice resulted in an aggressive, short-term model of myeloma with mice exhibiting signs of morbidity 3 weeks later. Treating these mice with zoledronic acid at the time of tumour cell injection or once tumour was established prevented JJN3-induced bone disease but did not reduce tumour burden, whereas, carfilzomib treatment given once tumour was established significantly reduced tumour burden. Injection of U266, XG-1, OPM-2 and patient-derived myeloma cells resulted in less aggressive longer-term models of myeloma with mice exhibiting signs of morbidity 8 weeks later. Treating U266-induced disease with zoledronic acid prevented the formation of osteolytic lesions and trabecular bone loss as well as reducing tumour burden whereas, carfilzomib treatment only reduced tumour burden. In summary, JJN3, U266 or OPM-2 cells injected into NOD/SCID-GAMMA mice provide robust models to study anti-myeloma therapies, particularly those targeting myeloma bone disease

Improving the sensitivity of future GW observatories in the 1-10 Hz band: Newtonian and seismic noise

The next generation gravitational wave interferometric detectors will likely be underground detectors to extend the GW detection frequency band to frequencies below the Newtonian noise limit. Newtonian noise originates from the continuous motion of the Earth’s crust driven by human activity, tidal stresses and seismic motion, and from mass density fluctuations in the atmosphere. It is calculated that on Earth’s surface, on a typical day, it will exceed the expected GW signals at frequencies below 10 Hz. The noise will decrease underground by an unknown amount. It is important to investigate and to quantify this expected reduction and its effect on the sensitivity of future detectors, to plan for further improvement strategies. We report about some of these aspects. Analytical models can be used in the simplest scenarios to get a better qualitative and semi-quantitative understanding. As more complete modeling can be done numerically, we will discuss also some results obtained with a finite-element-based modeling tool. The method is verified by comparing its results with the results of analytic calculations for surface detectors. A key point about noise models is their initial parameters and conditions, which require detailed information about seismic motion in a real scenario. We will describe an effort to characterize the seismic activity at the Homestake mine which is currently in progress. This activity is specifically aimed to provide informations and to explore the site as a possible candidate for an underground observatory. Although the only compelling reason to put the interferometer underground is to reduce the Newtonian noise, we expect that the more stable underground environment will have a more general positive impact on the sensitivity.We will end this report with some considerations about seismic and suspension noise

Preventing and repairing myeloma bone disease by combining conventional antiresorptive treatment with a bone anabolic agent in murine models

Multiple myeloma is a plasma cell malignancy, which develops in the bone marrow and frequently leads to severe bone destruction. Current antiresorptive therapies to treat the bone disease do little to repair damaged bone; therefore, new treatment strategies incorporating bone anabolic therapies are urgently required. We hypothesized that combination therapy using the standard of care antiresorptive zoledronic acid (Zol) with a bone anabolic (anti-TGFβ/1D11) would be more effective at treating myeloma-induced bone disease than Zol therapy alone. JJN3 myeloma-bearing mice (n = 8/group) treated with combined Zol and 1D11 resulted in a 48% increase (p≤0.001) in BV/TV compared to Zol alone and a 65% increase (p≤0.0001) compared to 1D11 alone. Our most significant finding was the substantial repair of U266-induced osteolytic bone lesions with combination therapy (n = 8/group), which resulted in a significant reduction in lesion area compared to vehicle (p≤0.01) or Zol alone (p≤0.01). These results demonstrate that combined antiresorptive and bone anabolic therapy is significantly more effective at preventing myeloma-induced bone disease than Zol alone. Furthermore, we demonstrate that combined therapy is able to repair established myelomatous bone lesions. This is a highly translational strategy which could significantly improve bone outcomes and quality of life for patients with myeloma

Post-Newtonian SPH calculations of binary neutron star coalescence. II. Binary mass ratio, equation of state, and spin dependence

Using our new Post-Newtonian SPH (smoothed particle hydrodynamics) code, we study the final coalescence and merging of neutron star (NS) binaries. We vary the stiffness of the equation of state (EOS) as well as the initial binary mass ratio and stellar spins. Results are compared to those of Newtonian calculations, with and without the inclusion of the gravitational radiation reaction. We find a much steeper decrease in the gravity wave peak strain and luminosity with decreasing mass ratio than would be predicted by simple point-mass formulae. For NS with softer EOS (which we model as simple $\Gamma=2$ polytropes) we find a stronger gravity wave emission, with a different morphology than for stiffer EOS (modeled as $\Gamma=3$ polytropes as in our previous work). We also calculate the coalescence of NS binaries with an irrotational initial condition, and find that the gravity wave signal is relatively suppressed compared to the synchronized case, but shows a very significant second peak of emission. Mass shedding is also greatly reduced, and occurs via a different mechanism than in the synchronized case. We discuss the implications of our results for gravity wave astronomy with laser interferometers such as LIGO, and for theoretical models of gamma-ray bursts (GRBs) based on NS mergers.Comment: RevTeX, 38 pages, 24 figures, Minor Corrections, to appear in Phys. Rev.

Onshore carboniferous basins : third review report

focussed on achieving a better understanding of the Bowland Shale in northern England. The broad aim is to understand the geological variability of the formation from a basin- through to microscale, and assess the impact of variability on hydrocarbon generation, storage and production (for example, the co-incidence or otherwise of factors including organic content and kerogen type; mineralogy; and engineering behaviour). This report is the third summary report describing activities of the consortium, covering the period October 2015 – June 2016. A series of 3 inter-related work packages are designed to improve understanding of the Bowland Shale of northern England. The original numbering of these is retained to allow continuity between previous progress reports. Specifically, these work packages address: 1. Work Package 1,2: Basin analysis of the Pennine Basin; Characterization of shale facies; 2. Work Package 3: Development of chemical stratigraphies through prospective parts of the stratigraphic column; 3. Work Package 4: Hydromechanical behaviour of shales. Two work packages outside the consortium are also considered, namely 4. Retrieval of new materials to test 5. Reprocessing of 3D seismic data to assess rock properties Descriptions of previous activities have been released, covering the period July 2014 to March 2015 (Hough et al., 2015a), and the period April 2015 to September 2015 (Hough et al., 2015b). The consortium currently has 4 sponsors who each contribute £25 000 per year; BGS contributes around £200 000 annually, which results in an annual budget of approximately £300 000. The consortium is planned to last 3 years initially, and started in July 2014 with a scheduled end date of June 2017

Detector Description and Performance for the First Coincidence Observations between LIGO and GEO

For 17 days in August and September 2002, the LIGO and GEO interferometer gravitational wave detectors were operated in coincidence to produce their first data for scientific analysis. Although the detectors were still far from their design sensitivity levels, the data can be used to place better upper limits on the flux of gravitational waves incident on the earth than previous direct measurements. This paper describes the instruments and the data in some detail, as a companion to analysis papers based on the first data.Comment: 41 pages, 9 figures 17 Sept 03: author list amended, minor editorial change

A First Search for coincident Gravitational Waves and High Energy Neutrinos using LIGO, Virgo and ANTARES data from 2007

We present the results of the first search for gravitational wave bursts associated with high energy neutrinos. Together, these messengers could reveal new, hidden sources that are not observed by conventional photon astronomy, particularly at high energy. Our search uses neutrinos detected by the underwater neutrino telescope ANTARES in its 5 line configuration during the period January - September 2007, which coincided with the fifth and first science runs of LIGO and Virgo, respectively. The LIGO-Virgo data were analysed for candidate gravitational-wave signals coincident in time and direction with the neutrino events. No significant coincident events were observed. We place limits on the density of joint high energy neutrino - gravitational wave emission events in the local universe, and compare them with densities of merger and core-collapse events.Comment: 19 pages, 8 figures, science summary page at http://www.ligo.org/science/Publication-S5LV_ANTARES/index.php. Public access area to figures, tables at https://dcc.ligo.org/cgi-bin/DocDB/ShowDocument?docid=p120000

Models of peer support to remediate post-intensive care syndrome: A report developed by the SCCM Thrive International Peer Support Collaborative

Objective: Patients and caregivers can experience a range of physical, psychological, and cognitive problems following critical care discharge. The use of peer support has been proposed as an innovative support mechanism. Design: We sought to identify technical, safety and procedural aspects of existing operational models of peer support, among the Society of Critical Care Medicine Thrive Peer Support Collaborative. We also sought to categorize key distinctions between these models and elucidate barriers and facilitators to implementation. Subjects: 17 Thrive sites from the USA, UK, and Australia were represented by a range of healthcare professionals. Interventions: Via an iterative process of in-person and email/conference calls, members of the Collaborative, defined the key areas on which peer support models could be defined and compared; collected detailed self-reports from all sites; reviewed the information and identified clusters of models. Barriers and challenges to implementation of peer support models were also documented. Results: Within the Thrive Collaborative, six general models of peer support were identified: Community based, Psychologist-led outpatient, Models based within ICU follow-up clinics, Online, Groups based within ICU and Peer mentor models. The most common barriers to implementation were: recruitment to groups, personnel input and training: sustainability and funding, risk management and measuring success. Conclusion: A number of different models of peer support are currently being developed to help patients and families recover and grow in the post-critical care setting

Dimensions of invasiveness: Links between local abundance, geographic range size, and habitat breadth in Europe's alien and native floras

Understanding drivers of success for alien species can inform on potential future invasions. Recent conceptual advances highlight that species may achieve invasiveness via performance along at least three distinct dimensions: 1) local abundance, 2) geographic range size, and 3) habitat breadth in naturalized distributions. Associations among these dimensions and the factors that determine success in each have yet to be assessed at large geographic scales. Here, we combine data from over one million vegetation plots covering the extent of Europe and its habitat diversity with databases on species' distributions, traits, and historical origins to provide a comprehensive assessment of invasiveness dimensions for the European alien seed plant flora. Invasiveness dimensions are linked in alien distributions, leading to a continuum from overall poor invaders to super invaders - abundant, widespread aliens that invade diverse habitats. This pattern echoes relationships among analogous dimensions measured for native European species. Success along invasiveness dimensions was associated with details of alien species' introduction histories: earlier introduction dates were positively associated with all three dimensions, and consistent with theory-based expectations, species originating from other continents, particularly acquisitive growth strategists, were among the most successful invaders in Europe. Despite general correlations among invasiveness dimensions, we identified habitats and traits associated with atypical patterns of success in only one or two dimensions - for example, the role of disturbed habitats in facilitating widespread specialists. We conclude that considering invasiveness within a multidimensional framework can provide insights into invasion processes while also informing general understanding of the dynamics of species distributions.Deutsche Forschungsgemeinschaft (264740629) Grantová Agentura České Republiky (19-28491X) Grantová Agentura České Republiky (19-28807X) Grantová Agentura České Republiky (RVO 67985939) Austrian Science Fund (I 2086 - B29) Bundesministerium für Bildung und Forschung (01LC1807A) Eusko Jaurlaritza (IT299-10) National Research Foundation of Korea (2018R1C1B6005351) University of Latvia (AAp2016/B041//Zd2016/AZ03) Villum Fonden (16549