Cirmtuzumab inhibits Wnt5a-induced Rac1 activation in chronic lymphocytic leukemia treated with ibrutinib.

Signaling via the B cell receptor (BCR) plays an important role in the pathogenesis and progression of chronic lymphocytic leukemia (CLL). This is underscored by the clinical effectiveness of ibrutinib, an inhibitor of Bruton's tyrosine kinase (BTK) that can block BCR-signaling. However, ibrutinib cannot induce complete responses (CR) or durable remissions without continued therapy, suggesting alternative pathways also contribute to CLL growth/survival that are independent of BCR-signaling. ROR1 is a receptor for Wnt5a, which can promote activation of Rac1 to enhance CLL-cell proliferation and survival. In this study, we found that CLL cells of patients treated with ibrutinib had activated Rac1. Moreover, Wnt5a could induce Rac1 activation and enhance proliferation of CLL cells treated with ibrutinib at concentrations that were effective in completely inhibiting BTK and BCR-signaling. Wnt5a-induced Rac1 activation could be blocked by cirmtuzumab (UC-961), an anti-ROR1 mAb. We found that treatment with cirmtuzumab and ibrutinib was significantly more effective than treatment with either agent alone in clearing leukemia cells in vivo. This study indicates that cirmtuzumab may enhance the activity of ibrutinib in the treatment of patients with CLL or other ROR1+ B-cell malignancies

A high incidence of native portal vein thrombosis in veterans undergoing liver transplantation

The incidence of native portal vein thrombosis (PVT) in liver transplant recipients has been reported to range from 2.1 to 13.8%. We have identified an inordinately high incidence of PVT in a consecutive series of U.S. veterans receiving liver transplants. Between October 1989 and February 1994, 88 consecutive U.S. veterans received 99 orthotopic liver transplants under primary Tacrolimus (Prograf, formerly FK506) based immunosuppression. A number of clinical features were examined in an effort to identify risk factors for PVT and outcome was compared to patients without PVT. Native PVT was present in 23/88 (26%) patients. All of these patients were male U.S. veterans with a mean age of 47 years. When compared to the 65 patients without PVT, we found no significant difference with respect to underlying liver disease, age, Childs-Pugh score (mean = 12), UNOS status as defined prior to April 1995 (95% UNOS 3 or 4), previous abdominal surgery, or liver volume. Median blood loss for patients with PVT (21 units of packed red blood cells) was greater than for those without PVT (14 units, P = 0.04). Portal thrombectomy was performed in 11 patients, 11 patients required mesoportal jump grafts, and 1 patient had an interposition graft. Standard veno-venous bypass was used in 10 patients with single bypass utilized for the remainder. Actuarial patient survival for all patients at 1, 2, and 4 years was 88, 85, and 79%, respectively. There was no significant difference in patients with or without PVT. Patients with PVT had poorer graft survival than patients without PVT (86% vs 65%, 1 year; 81% vs 65%, 2 years; 81% vs 61%, 4 years; P = 0.03); however, this was not related to technical problems with the portal venous inflow. PVT occurred in 26% of U.S. veterans undergoing liver transplantation. These patients bad significantly higher operative blood loss and poorer graft survival. The high incidence of postnecrotic cirrhosis in a predominantly male group of patients with advanced disease, as is evident by the high mean Childs-Pugh score and UNOS status, perhaps accounts for our observations

Comparison of algorithms for incoming atmospheric long-wave radiation

While numerous algorithms exist for predicting incident atmospheric long-wave radiation under clear (Lclr) and cloudy skies, few comparisons have been published to assess the accuracy of the different algorithms. Virtually no comparisons have been made for both clear and cloudy skies across multiple sites. This study evaluates the accuracy of 13 algorithms for predicting incident long-wave radiation under clear skies, ten cloud correction algorithms, and four algorithms for all-sky conditions using data from 21 sites across North America and China. Data from five research sites were combined with publicly available data from nine sites in the AmeriFlux network for initial evaluation and optimization of cloud cover estimates; seven additional AmeriFlux sites were used as an independent test of the algorithms. Clear-sky algorithms that excelled in predicting Lclr were the Dilley, Prata, and Angström algorithms. Root mean square deviation (RMSD) between predicted and measured 30-minute or hourly Lclr averaged approximately 23 W m-2 for these three algorithms across all sites, while RMSD of daily estimates was as low as 14 W m-2. Cloud-correction algorithms of Kimball, Unsworth, and Crawford described the data best when combined with the Dilley clear-sky algorithm. Average RMSD across all sites for these three cloud corrections was approximately 24 to 25 W m -2 for 30-minute or hourly estimates and approximately 15 to 16 W m-2 for daily estimates. The Kimball and Unsworth cloud corrections require an estimate of cloud cover, while the Crawford algorithm corrects for cloud cover directly from measured solar radiation. Optimum limits in the clearness index, defined as the ratio of observed solar radiation to theoretical terrestrial solar radiation, for complete cloud cover and clear skies were suggested for the Kimball and Unsworth algorithms. Application of the optimized algorithms to seven independent sites yielded similar results. On the basis of the results, the recommended algorithms can be applied with reasonable accuracy for a wide range of climates, elevations, and latitudes. © 2009 by American Geophysical Union

Off-axis electron holography of bacterial cells and magnetic nanoparticles in liquid

The mapping of electrostatic potentials and magnetic fields in liquids usingelectron holography has been considered to be unrealistic. Here, we showthat hydrated cells ofMagnetospirillum magneticumstrain AMB-1 and assem-blies of magnetic nanoparticles can be studied using off-axis electronholography in a fluid cell specimen holder within the transmission electronmicroscope. Considering that the holographic object and reference waveboth pass through liquid, the recorded electron holograms show sufficientinterference fringe contrast to permit reconstruction of the phase shift ofthe electron wave and mapping of the magnetic induction from bacterialmagnetite nanocrystals. We assess the challenges of performingin situmagne-tization reversal experiments using a fluid cell specimen holder, discussapproaches for improving spatial resolution and specimen stability, and outlinefuture perspectives for studying scientific phenomena, ranging from interpar-ticle interactions in liquids and electrical double layers at solid–liquidinterfaces to biomineralization and the mapping of electrostatic potentialsassociated with protein aggregation and folding

A modeling investigation of canopy-air oxygen isotopic exchange of water vapor and carbon dioxide in a soybean field

The oxygen isotopes of CO2 and H2O ( 18O-CO2 and 18O-H2O) provide unique information regarding the contribution of terrestrial vegetation to the global CO2 and H2O cycles. In this paper, a simple isotopic land surface model was used to investigate processes controlling the isotopic exchange of 18O-H2O and 18O-CO2 between a soybean ecosystem and the atmosphere. We included in a standard land surface model a nonsteady state theory of leaf water isotopic composition, a canopy kinetic fractionation factor, and a big-leaf parameterization of the 18O-CO2 isoforcing on the atmosphere. Our model simulations showed that the Pclet effect was less important than the nonsteady state effect on the temporal dynamics of the water isotopic exchange. The model reproduced the highly significant and negative correlation between relative humidity and the ecosystem-scale 18O-CO2 isoforcing measured with eddy covariance. But the model-predicted isoforcing was biased high in comparison to the observations. Model sensitivity analysis suggested that the CO2 hydration efficiency must have been much lower in the leaves of soybean in field conditions than previously reported. Understanding environmental controls on the hydration efficiency and the scaling from the leaf to the canopy represents an area in need of more research. Copyright 2010 by the American Geophysical Union

Lifting the burden of headache in China: managing migraine in a SMART way

With support from Lifting The Burden , a UK-registered charitable organization, a nationwide survey of headache disorders in the Chinese adult population was conducted in 2008–2009. This project, which was within the Global Campaign against Headache, showed that headache disorders have a major adverse impact on public health in China. Subsequently, as essential support for implementing headache services around the country, an enactment of stage 3 (intervention) of the Global Campaign against Headache − the continuing medical education (CME) program Headache Schools − was established. ‘SMART’ (Screen, Migraine, Aura, Red flag and Treatment), a systematic and operational disease management model, was introduced with the aims of enhancing neurologists’ knowledge of migraine, standardizing their diagnostic and treatment approaches, and improving their practices and outcomes. To date, 615 neurologists have been trained and 135 headache clinics have been established. In future, as we promote SMART in CME, we can use the database of our computerized clinical decision support systems to evaluate the impact on treatment outcomes

Treat the patient by the recognized toxidrome when the ingested herbal juice is non-toxic

This is the case of 63-year-old mother and her 35-year-old daughter who drank herbal juice (Rhizoma Dioscoreae Nipponicae and Ficus formosana Maxim) and then developed diarrhea, cold sweating, and myoclonus. On physical examination, the mother had a normal consciousness level, a normal respiratory rate, and bilateral miosis. After the administration of 2 g of pralidoxime (PAM) and 0.5 mg of atropine, the mother felt better. The daughter only had mild symptoms of sweating and vomiting before arrival at the emergency department (ED)

Characterising and predicting the relationship between translaminar fracture toughness and pull-out length distributions under distinct temperatures

The translaminar fracture toughness reflects the damage tolerance of a fibre-reinforced composite under longitudinal tension, which often governs the final failure of structures. One of the main energy-dissipation mechanisms that contributes to the translaminar toughness of composites is the fibre pull-out process. The present study aims to quantify and model the statistical distribution of fibre pull-out lengths formed on the translaminar fracture surface of composites, for the first time in the literature; this is done under different temperatures, so that the relationship between pull-out length distributions, micromechanical properties and the translaminar fracture toughness can be established. The fracture surfaces of cross-ply compact tension specimens tested under three different temperatures have been scanned through X-ray computed tomography to quantify the extent of fibre pull-out on the fracture surfaces; the distribution of pull-out lengths showed alarger average and larger variability with an increase in temperature, which also lead to an increase in translaminar fracture toughness. A similar trend has been captured by the proposed analytical model, which predicts the pull-out length distribution based on the analysis of quasi-fractal idealizations of the fracture surface, yielding an overall accuracy of more than 85%. This article is part of the theme issue 'Ageing and durability of composite materials'