Background
The establishment and progression of metastases remains the life‐limiting factor for dogs diagnosed with osteosarcoma (OS). The pattern of metastases is likely regulated through ...interactions between chemokine receptors and chemokines, and perturbations in these signaling cascades responsible for cytoskeletal organization and directional migration have the potential to alter metastatic cell trafficking behaviors.
Hypothesis
Zoledronate will impair directional migration of OS cells through downregulation of chemokine (C‐X‐C motif) receptor 4 (CXCR4) expression and functionality.
Samples
Nineteen archived tumor specimens and plasma from 20 dogs with OS.
Methods
Prospectively, the expressions of CXCR4 were studied in OS cell lines and spontaneous tumor samples. The effect of zoledronate on CXCR4 expression and functionality was investigated by characterizing responses in 3 OS cell lines. In 19 OS specimens and 20 dogs with OS, changes in CXCR4 expression and circulating CXCR4 concentrations were characterized in response to zoledronate therapy respectively.
Results
All canine OS cells express CXCR4, and zoledronate reduces CXCR4 expression and functionality by 27.7% (P < .0001), through augmented proteasome degradation and reduced prenylation of heterotrimeric G‐proteins in 33% of tumor cell lines evaluated. In OS‐bearing dogs, zoledronate reduces CXCR4 expressions by 40% within the primary tumor compared to untreated controls (P = .03) and also decreases the circulating concentrations of CXCR4 in 18 of 20 dogs with OS.
Conclusions and clinical importance
Zoledronate can alter CXCR4 expression and functionality in OS cells, and consequent perturbations in CXCR4 intracellular signaling cascades might influence patterns of metastases.
Aim To identify adult patients with single-ventricle congenital heart disease and Fontan procedure palliation who have been misdiagnosed with or incompletely evaluated for pulmonary embolism. ...Additionally, this study was designed to demonstrate that simultaneous, dual-injection of contrast medium into an upper and lower extremity vein is superior to single-injection protocols for CT angiography (CTA) of the chest in this population. Materials and methods Patients included in the study were retrospectively selected from the Adult Congenital Heart Disease (ACHD) database. Search criteria included history of Fontan palliation and available chest CT examination. Patients were evaluated for (1) type of congenital heart disease and prior operations;(2) indication for initial CT evaluation;(3) route of contrast medium administration for the initial CT examination and resulting diagnosis;(4) whether or not anticoagulation therapy was initiated; and (5) final diagnosis and treatment plan. Results The query of the ACHD database resulted in 28 individuals or patients with Fontan palliation (superior and inferior venae cavae anastomosed to the pulmonary arteries). Of these, 19 patients with Fontan physiology underwent CTA of the pulmonary circulation, and 17 had suboptimal imaging studies. Unfortunately, seven of these 17 patients (41%) were started on anticoagulation therapy due to a diagnosis of pulmonary embolism that was later excluded. Conclusion Patients with single-ventricle/Fontan physiology are at risk of thromboembolic disease. Therefore, studies evaluating their complex anatomy must be performed with the optimal imaging protocol to ensure diagnostic accuracy, which is best achieved with dual-injection of an upper and lower extremity central vein.
BACKGROUND: Transforming growth factor beta 1 (TGFβ1) is a pleiotropic cytokine that contributes to reparative skeletal remodeling by inducing osteoblast proliferation, migration, and angiogenesis. ...Organic bone matrix is the largest bodily reservoir for latent TGFβ1, and active osteoblasts express cognate receptors for TGFβ1 (TGFβRI and TGFβRII). During malignant osteolysis, TGFβ1 is liberated from eroded bone matrix and promotes local progression of osteotropic solid tumors by its mitogenic and prosurvival activities. HYPOTHESIS: Canine osteosarcoma (OS) cells will possess TGFβ1 signaling machinery. Blockade of TGFβ1 signaling will attenuate pro‐tumorigenic activities in OS cells. Naturally occurring primary OS samples will express cognate TGFβ1 receptors; and in dogs with OS, focal malignant osteolysis will contribute to circulating TGFβ1 concentrations. ANIMALS: Thirty‐three dogs with appendicular OS. METHODS: Expression of TGFβ1 and its cognate receptors, as well as the biologic effects of TGFβ1 blockade, was characterized in OS cells. Ten spontaneous OS samples were characterized for TGFβRI/II expressions by immunohistochemistry. In 33 dogs with OS, plasma TGFβ1 concentrations were quantified and correlated with bone resorption. RESULTS: Canine OS cells secrete TGFβ1, express cognate receptors, and TGFβ1 signaling blockade decreases proliferation, migration, and vascular endothelial growth factor secretion. Naturally occurring OS samples abundantly and uniformly express TGFβRI/II, and in OS‐bearing dogs, circulating TGFβ1 concentrations correlate with urine N‐telopeptide excretion. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine OS cells possess TGFβ1 signaling machinery, potentially allowing for the establishment of an autocrine and paracrine pro‐tumorigenic signaling loop. As such, TGFβ1 inhibitors might impede localized OS progression in dogs.
We present measurements of the E -mode ( E E ) polarization power spectrum and temperatureE -mode ( T E ) cross-power spectrum of the cosmic microwave background using data collected by SPT-3G, the ...latest instrument installed on the South Pole Telescope. This analysis uses observations of a 1500 deg2 region at 95, 150, and 220 GHz taken over a four-month period in 2018. We report binned values of the E E and T E power spectra over the angular multipole range 300 ≤ ℓ < 3000 , using the multifrequency data to construct six semi-independent estimates of each power spectrum and their minimum-variance combination. These measurements improve upon the previous results of SPTpol across the multipole ranges 300 ≤ ℓ ≤ 1400 for E E and 300 ≤ ℓ ≤ 1700 for T E , resulting in constraints on cosmological parameters comparable to those from other current leading ground-based experiments. We find that the SPT-3G data set is well fit by a Λ CDM cosmological model with parameter constraints consistent with those from Planck and SPTpol data. From SPT-3G data alone, we find H0= 68.8 ± 1.5 km s−1 Mpc−1 and σ8= 0.789 ± 0.016 , with a gravitational lensing amplitude consistent with the Λ CDM prediction ( AL= 0.98 ± 0.12 ). We combine the SPT-3G and the Planck data sets and obtain joint constraints on the Λ CDM model. The volume of the 68% confidence region in six-dimensional Λ CDM parameter space is reduced by a factor of 1.5 compared to Planck-only constraints, with no significant shifts in central values. We note that the results presented here are obtained from data collected during just half of a typical observing season with only part of the focal plane operable, and that the active detector count has since nearly doubled for observations made with SPT-3G after 2018.
BACKGROUND: Canine osteosarcoma (OS) is an aggressive sarcoma characterized by pathologic skeletal resorption and pulmonary metastases. A number of negative prognostic factors, including bone ...alkaline phosphatase, have been identified in dogs with OS, but the underlying biologic factors responsible for such observations have not been thoroughly investigated. Endothelin‐1‐mediated signaling is active during bone repair, and is responsible for osteoblast migration, survival, proliferation, and bone alkaline phosphatase expression. HYPOTHESIS: The endothelin‐1 signaling axis is active in canine OS cells, and this pathway is utilized by malignant osteoblasts for promoting cellular migration, survival, proliferation, and bone alkaline phosphatase activities. ANIMALS: 45 dogs with appendicular OS. METHODS: The expressions of endothelin‐1 and endothelin A receptor were studied in OS cell lines and in samples from spontaneously occurring tumors. Activities mediated by endothelin‐1 signaling were investigated by characterizing responses in 3 OS cell lines. In 45 dogs with OS, bone alkaline phosphatase concentrations were correlated with primary tumor osteoproductivity. RESULTS: Canine OS cells express endothelin‐1 and endothelin A receptor, and this signaling axis mediates OS migration, survival, proliferation, and bone alkaline phosphatase activities. In OS‐bearing dogs, circulating bone alkaline phosphatase activities were positively correlated with primary tumor relative bone mineral densities. CONCLUSIONS AND CLINICAL IMPORTANCE: Canine OS cells express endothelin‐1 and functional endothelin A receptors, with the potential for a protumorigenic signaling loop. Increases in bone alkaline phosphatase activity are associated with osteoblastic OS lesions, and might be an epiphenomenon of active endothelin‐1 signaling or excessive osteoproduction within the localized bone microenvironment.
Background
Cobalt chloride (CoCl2) is administered to racehorses to enhance performance. The purpose of this study was to evaluate the clinical, cardiovascular, and endocrine effects of parenterally ...administered CoCl2.
Objectives
To describe the effects of weekly intravenous doses of CoCl2 on Standardbred horses.
Animals
Five, healthy Standardbred mares.
Methods
Prospective, randomized, experimental dose‐escalation pilot. Five Standardbred mares were assigned to receive 1 of 5 doses of CoCl2 (4, 2, 1, 0.5, or 0.25 mg/kg) weekly IV for 5 weeks. Physical examination, blood pressure, cardiac output, and electrocardiography (ECG) were evaluated for 4 hours after administration of the first and fifth doses. Blood and urine samples were collected for evaluation of cobalt concentration, CBC and clinical chemistry, and hormone concentrations.
Results
All mares displayed pawing, nostril flaring, muscle tremors, and straining after CoCl2 infusion. Mares receiving 4, 2, or 1 mg/kg doses developed tachycardia after dosing (HR 60–126 bpm). Ventricular tachycardia was noted for 10 minutes after administration of the 4 mg/kg dose. Increases in systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) occurred after administration of all doses (4, 2, 1, 0.5, and 0.25 mg/kg). Profound hypertension was observed after the 4 mg/kg dose (SAP/DAP, MAP mmHg = 291–300/163–213, 218–279). Hemodynamics normalized by 1–2 hours after administration. ACTH and cortisol concentrations increased within 30 minutes of administration of all CoCl2 doses, and cardiac troponin I concentration increased after administration of the 4 and 2 mg/kg doses.
Conclusions and Clinical Importance
The degree of hypertension and arrhythmia observed after IV CoCl2 administration raises animal welfare and human safety concerns.
We present observations of the dwarf galaxies Draco and Ursa Minor, the Local Group galaxies M32 and M33, and the globular cluster M15 conducted with the Whipple 10 m gamma-ray telescope to search ...for the gamma-ray signature of self-annihilating weakly interacting massive particles (WIMPs), which may constitute astrophysical dark matter (DM). We review the motivations for selecting these sources based on their unique astrophysical environments and report the results of the data analysis that produced upper limits on the excess rate of gamma rays for each source. We consider models for the DM distribution in each source based on the available observational constraints and discuss possible scenarios for the enhancement of the gamma-ray luminosity. Limits on the thermally averaged product of the total self- annihilation cross section and velocity of the WIMP, image, are derived using conservative estimates for the magnitude of the astrophysical contribution to the gamma-ray flux. Although these limits do not constrain predictions from the currently favored theoretical models of supersymmetry (SUSY), future observations with VERITAS will probe a larger region of the WIMP parameter phase space, image, and WIMP particle mass.
In this paper, we describe the optimization of transition-edge-sensor (TES) detector arrays for the third-generation camera for the South Pole Telescope. The camera, which contains ~16 000 detectors, ...will make high-angular-resolution maps of the temperature and polarization of the cosmic microwave background. Our key results are scatter in the transition temperature of Ti/Au TESs is reduced by fabricating the TESs on a thin Ti(5 nm)/Au(5 nm) buffer layer and the thermal conductivity of the legs that support our detector islands is dominated by the SiOx dielectric in the microstrip transmission lines that run along the legs.
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