Rapid modification of the bone microenvironment following short-term treatment with Cabozantinib in vivo

Introduction: Bone metastasis remains incurable with treatment restricted to palliative care. Cabozantinib (CBZ) is targeted against multiple receptor tyrosine kinases involved in tumour pathobiology, including hepatocyte growth factor receptor (MET) and vascular endothelial growth factor receptor 2 (VEGFR-2). CBZ has demonstrated clinical activity in advanced prostate cancer with resolution of lesions visible on bone scans, implicating a potential role of the bone microenvironment as a mediator of CBZ effects. We characterised the effects of short-term administration of CBZ on bone in a range of in vivo models to determine how CBZ affects bone in the absence of tumour. Methods: Studies were performed in a variety of in vivo models including male and female BALB/c nude mice (age 6– 17-weeks). Animals received CBZ (30 mg/kg, 5× weekly) or sterile H2O control for 5 or 10 days. Effects on bone integrity (μCT), bone cell activity (PINP, TRAP ELISA), osteoblast and osteoclast number/mm trabecular bone surface, area of epiphyseal growth plate cartilage, megakaryocyte numbers and bone marrow composition were assessed. Effects of longer-term treatment (15-day & 6-week administration) were assessed in male NOD/SCID and beige SCID mice. Results: CBZ treatment had significant effects on the bone microenvironment, including reduced osteoclast and increased osteoblast numbers compared to control. Trabecular bone structure was altered after 8 administrations. A significant elongation of the epiphyseal growth plate, in particular the hypertrophic chondrocyte zone, was observed in all CBZ treated animals irrespective of administration schedule. Both male and female BALB/c nude mice had increased megakaryocyte numbers/mm2 tissue after 10-day CBZ treatment, in addition to vascular ectasia, reduced bone marrow cellularity and extravasation of red blood cells into the extra-vascular bone marrow. All CBZinduced effects were transient and rapidly lost following cessation of treatment. Conclusion: Short-term administration of CBZ induces rapid, reversible effects on the bone microenvironmentin vivo highlighting a potential role in mediating treatment responses

Modifying the osteoblastic niche with zoledronic acid in vivo - potential implications for breast cancer bone metastasis

INTRODUCTION: Bone metastasis is the most common complication of advanced breast cancer. The associated cancer-induced bone disease is treated with bone-sparing agents like zoledronic acid. Clinical trials have shown that zoledronic acid also reduces breast cancer recurrence in bone; potentially by modifying the bone microenvironment surrounding disseminated tumour cells. We have characterised the early effects of zoledronic acid on key cell types of the metastatic niche in vivo, and investigated how these modify the location of breast tumour cells homing to bone. METHODS: Female mice were treated with a single, clinically achievable dose of zoledronic acid (100μg/kg) or PBS. Bone integrity, osteoclast and osteoblast activity and number/mm trabecular bone on 1, 3, 5 and 10days after treatment were assessed using μCT, ELISA (TRAP, PINP) and bone histomorphometry, respectively. The effect of zoledronic acid on osteoblasts was validated in genetically engineered mice with GFP-positive osteoblastic cells. The effects on growth plate cartilage were visualised by toluidine blue staining. For tumour studies, mice were injected i.c. with DID-labelled MDA-MB-231-NW1-luc2 breast cancer cells 5days after zoledronic acid treatment, followed by assessment of tumour cell homing to bone and soft tissues by multiphoton microscopy, flow cytometry and ex vivo cultures. RESULTS: As early as 3days after treatment, animals receiving zoledronic acid had significantly increased trabecular bone volume vs. control. This rapid bone effect was reflected in a significant reduction in osteoclast and osteoblast number/mm trabecular bone and reduced bone marker serum levels (day 3-5). These results were confirmed in mice expressing GFP in osteoblastic linage cells. Pre-treatment with zoledronic acid caused accumulation of an extra-cellular matrix in the growth plate associated with a trend towards preferential [1] homing of tumour cells to osteoblast-rich areas of bone, but without affecting the total number of tumour cells. The number of circulating tumour cells was reduced in ZOL treated animals. CONCLUSION: A single dose of zoledronic acid caused significant changes in the bone area suggested to contain the metastatic niche. Tumour cells arriving in this modified bone microenvironment appeared to preferentially locate to osteoblast-rich areas, supporting that osteoblasts may be key components of the bone metastasis niche and therefore a potential therapeutic target in breast cancer.Marie-Therese Haider, Ingunn Holen, T. Neil Dear, Keith Hunter, Hannah K. Brow

Remarks on Conserved Quantities and Entropy of BTZ Black Hole Solutions. Part I: the General Setting

The BTZ stationary black hole solution is considered and its mass and angular momentum are calculated by means of Noether theorem. In particular, relative conserved quantities with respect to a suitably fixed background are discussed. Entropy is then computed in a geometric and macroscopic framework, so that it satisfies the first principle of thermodynamics. In order to compare this more general framework to the prescription by Wald et al. we construct the maximal extension of the BTZ horizon by means of Kruskal-like coordinates. A discussion about the different features of the two methods for computing entropy is finally developed.Comment: PlainTEX, 16 pages. Revised version 1.

SOPHIE+: First results of an octagonal-section fiber for high-precision radial velocity measurements

High-precision spectrographs play a key role in exoplanet searches and Doppler asteroseismology using the radial velocity technique. The 1 m/s level of precision requires very high stability and uniformity of the illumination of the spectrograph. In fiber-fed spectrographs such as SOPHIE, the fiber-link scrambling properties are one of the main conditions for high precision. To significantly improve the radial velocity precision of the SOPHIE spectrograph, which was limited to 5-6 m/s, we implemented a piece of octagonal-section fiber in the fiber link. We present here the scientific validation of the upgrade of this instrument, demonstrating a real improvement. The upgraded instrument, renamed SOPHIE+, reaches radial velocity precision in the range of 1-2 m/s. It is now fully efficient for the detection of low-mass exoplanets down to 5-10 Earth mass and for the identification of acoustic modes down to a few tens of cm/s.Comment: 12 pages, 11 figures, accepted in Astronomy and Astrophysic

Boundary Conditions, Energies and Gravitational Heat in General Relativity (a Classical Analysis)

The variation of the energy for a gravitational system is directly defined from the Hamiltonian field equations of General Relativity. When the variation of the energy is written in a covariant form it splits into two (covariant) contributions: one of them is the Komar energy, while the other is the so-called covariant ADM correction term. When specific boundary conditions are analyzed one sees that the Komar energy is related to the gravitational heat while the ADM correction term plays the role of the Helmholtz free energy. These properties allow to establish, inside a classical geometric framework, a formal analogy between gravitation and the laws governing the evolution of a thermodynamic system. The analogy applies to stationary spacetimes admitting multiple causal horizons as well as to AdS Taub-bolt solutions.Comment: Latex file, 31 pages; one reference and two comments added, misprints correcte

Quasilocal Thermodynamics of Kerr de Sitter Spacetimes and the dS/CFT Correspondence

We consider the quasilocal thermodynamics of rotating black holes in asymptotic de Sitter spacetimes. Using the minimal number of intrinsic boundary counterterms, we carry out an analysis of the quasilocal thermodynamics of Kerr-de Sitter black holes for virtually all possible values of the mass, rotation parameter and cosmological constant that leave the quasilocal boundary inside the cosmological event horizon. Specifically, we compute the quasilocal energy, the conserved charges, the temperature and the heat capacity for the $(3+1)$-dimensional Kerr-dS black holes. We perform a quasilocal stability analysis and find phase behavior that is commensurate with previous analysis carried out through the use of Arnowitt-Deser-Misner (ADM) parameters. Finally, we investigate the non-rotating case analytically.Comment: RevTeX4, 19 pages, 11 figures, a few typos fixed, the version to be published in Phys. Rev. D6

A luminosity constraint on the origin of unidentified high energy sources

The identification of point sources poses a great challenge for the high energy community. We present a new approach to evaluate the likelihood of a set of sources being a Galactic population based on the simple assumption that galaxies similar to the Milky Way host comparable populations of gamma-ray emitters. We propose a luminosity constraint on Galactic source populations which complements existing approaches by constraining the abundance and spatial distribution of any objects of Galactic origin, rather than focusing on the properties of a specific candidate emitter. We use M31 as a proxy for the Milky Way, and demonstrate this technique by applying it to the unidentified EGRET sources. We find that it is highly improbable that the majority of the unidentified EGRET sources are members of a Galactic halo population (e.g., dark matter subhalos), but that current observations do not provide any constraints on all of these sources being Galactic objects if they reside entirely in the disk and bulge. Applying this method to upcoming observations by the Fermi Gamma-ray Space Telescope has the potential to exclude association of an even larger number of unidentified sources with any Galactic source class.Comment: 18 pages, 4 figures, to appear in JPhys

Directly e-mailing authors of newly published papers encourages community curation

Much of the data within Model Organism Databases (MODs) comes from manual curation of the primary research literature. Given limited funding and an increasing density of published material, a significant challenge facing all MODs is how to efficiently and effectively prioritize the most relevant research papers for detailed curation. Here, we report recent improvements to the triaging process used by FlyBase. We describe an automated method to directly e-mail corresponding authors of new papers, requesting that they list the genes studied and indicate (‘flag’) the types of data described in the paper using an online tool. Based on the author-assigned flags, papers are then prioritized for detailed curation and channelled to appropriate curator teams for full data extraction. The overall response rate has been 44% and the flagging of data types by authors is sufficiently accurate for effective prioritization of papers. In summary, we have established a sustainable community curation program, with the result that FlyBase curators now spend less time triaging and can devote more effort to the specialized task of detailed data extraction

Hospitalists in Teaching Hospitals: Opportunities but Not Without Danger

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73210/1/j.1525-1497.2004.42002.x.pd

Treatment of chronic or relapsing COVID-19 in immunodeficiency

BACKGROUND: Patients with some types of immunodeficiency can suffer chronic or relapsing infection with SARS-CoV-2. This leads to morbidity and mortality, infection control challenges and the risk of evolution of novel viral variants. Optimal treatment for chronic COVID-19 is unknown. OBJECTIVE: To characterise a cohort of patients with chronic or relapsing COVID-19 disease and to record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features and treatment response of immune deficient patients with chronic (at least 21 days) or relapsing (at least two episodes) of COVID-19. RESULTS: We identified 31 cases with a median age of 49 years. Underlying immune deficiency was characterised by antibody deficiency with absent or profoundly reduced peripheral B cells; prior anti-CD20 therapy and X-linked agammaglobulinemia were most common. Clinical features of COVID-19 were similar to the general population, but the median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to five episodes of illness. Remdesivir monotherapy (including when given for prolonged courses up to 20 days) was associated with sustained viral clearance in 7/23 (30.4%) clinical episodes whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 monoclonal antibodies resulted in viral clearance in 13/14 (92.8%) episodes. Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise