Interferon signaling patterns in peripheral blood lymphocytes may predict clinical outcome after high-dose interferon therapy in melanoma patients

<p>Abstract</p> <p>Background</p> <p>High-dose Interferon (HDI) therapy produces a clinical response and achieves relapse-free survival in 20-33% of patients with operable high risk or metastatic melanoma. However, patients may develop significant side effects frequently necessitating dose reduction or discontinuation of therapy. We recently showed that peripheral blood lymphocytes (PBL) from some melanoma patients have impaired interferon (IFN) signaling which could be restored with high concentrations of IFN. This exploratory study evaluated IFN signaling in PBL of melanoma patients to assess whether the restoration of PBL IFN signaling may predict a beneficial effect for HDI in melanoma patients.</p> <p>Methods</p> <p>PBL from 14 melanoma patients harvested on Day 0 and Day 29 of neoadjuvant HDI induction therapy were analyzed using phosflow to assess their interferon signaling patterns through IFN-α induced phosphorylation of STAT1-Y701.</p> <p>Results</p> <p>Patients who had a clinical response to HDI showed a lower PBL interferon signaling capacity than non-responders at baseline (Day 0). Additionally, clinical responders and patients with good long-term outcome showed a significant increase in their PBL interferon signaling from Day 0 to Day 29 compared to clinical non-responders and patients that developed metastatic disease. The differences in STAT1 activation from pre- to post- HDI treatment could distinguish between patients who were inclined to have a favorable or unfavorable outcome.</p> <p>Conclusion</p> <p>While the sample size is small, these results suggest that interferon signaling patterns in PBL correlate with clinical responses and may predict clinical outcome after HDI in patients with melanoma. A larger confirmatory study is warranted, which may yield a novel approach to select patients for HDI therapy.</p

Optical Polarization and Spectral Variability in the M87 Jet

During the last decade, M87's jet has been the site of an extraordinary variability event, with one knot (HST-1) increasing by over a factor 100 in brightness. Variability was also seen on timescales of months in the nuclear flux. Here we discuss the optical-UV polarization and spectral variability of these components, which show vastly different behavior. HST-1 shows a highly significant correlation between flux and polarization, with P increasing from $\sim 20$ at minimum to >40% at maximum, while the orientation of its electric vector stayed constant. HST-1's optical-UV spectrum is very hard ($\alpha_{UV-O}\sim0.5$, $F_\nu\propto\nu^{-\alpha}$), and displays "hard lags" during epochs 2004.9-2005.5, including the peak of the flare, with soft lags at later epochs. We interpret the behavior of HST-1 as enhanced particle acceleration in a shock, with cooling from both particle aging and the relaxation of the compression. We set 2$\sigma$ upper limits of $0.5 \delta$ parsecs and 1.02$c$ on the size and advance speed of the flaring region. The slight deviation of the electric vector orientation from the jet PA, makes it likely that on smaller scales the flaring region has either a double or twisted structure. By contrast, the nucleus displays much more rapid variability, with a highly variable electric vector orientation and 'looping' in the $(I,P)$ plane. The nucleus has a much steeper spectrum ($\alpha_{UV-O} \sim 1.5$) but does not show UV-optical spectral variability. Its behavior can be interpreted as either a helical distortion to a steady jet or a shock propagating through a helical jet.Comment: 14 pages, 7 figures, ApJ, in pres

Novel model-based dosing guidelines for gentamicin and tobramycin in preterm and term neonates

Objectives In the heterogeneous group of preterm and term neonates, gentamicin and tobramycin are mainly dosed according to empirical guidelines, after which therapeutic drug monitoring and subsequent dose adaptation are applied. In view of the variety of neonatal guidelines available, the purpose of this study was to evaluate target concentration attainment of these guidelines, and to propose a new model-based dosing guideline for these drugs in neonates. Methods Demographic characteristics of 1854 neonates (birth weight 390-5200 g, post-natal age 0-27 days) were extracted from earlier studies and sampled to obtain a test dataset of 5000 virtual patients. Monte Carlo simulations on the basis of validated models were undertaken to evaluate the attainment of target peak (5-12 mg/L) and trough (<0.5 mg/L) concentrations, and cumulative AUC, with the existing and proposed guidelines. Results Across the entire neonatal age and weight range, the Dutch National Formulary for Children, the British National Formulary for Children, Neofax and the Red Book resulted in adequate peak but elevated trough concentrations (63%-90% above target). The proposed dosing guideline (4.5 mg/kg gentamicin or 5.5 mg/kg tobramycin) with a dosing interval based on birth weight and post-natal age leads to adequate peak concentrations with only 33%-38% of the trough concentrations above target, and a constant AUC across weight and post-natal age. Conclusions The proposed neonatal dosing guideline for gentamicin and tobramycin results in improved attainment of target concentrations and should be prospectively evaluated in clinical studies to evaluate the efficacy and safety of this treatmen

Carbohydrate-aromatic interactions: a computational and IR spectroscopic investigation of the complex, methyl alpha-L-fucopyranoside·toluene, isolated in the gas phase

a b s t r a c t A carbohydrate-aromatic complex, methyl a-L-fucopyranoside Á toluene, which provides a model for probing the physical basis of carbohydrate-protein &apos;stacking&apos; interactions, has been created in a molecular beam and probed through IR ion dip spectroscopy in the CH and OH regions. The results are interpreted in the light of DFT calculations using the MO5-2X functional. They indicate the creation of stacked structures with the aromatic molecule bonded either to the upper or to the lower face of the pyranoside ring, through CH 3,4 -p (upper) or CH 1 -p (lower) interactions leading to binding energies 618 kJ mol À1

Predominant Asymmetrical Stem Cell Fate Outcome Limits the Rate of Niche Succession in Human Colonic Crypts.

Stem cell (SC) dynamics within the human colorectal crypt SC niche remain poorly understood, with previous studies proposing divergent hypotheses on the predominant mode of SC self-renewal and the rate of SC replacement. Here we use age-related mitochondrial oxidative phosphorylation (OXPHOS) defects to trace clonal lineages within human colorectal crypts across the adult life-course. By resolving the frequency and size distribution of OXPHOS-deficient clones, quantitative analysis shows that, in common with mouse, long-term maintenance of the colonic epithelial crypt relies on stochastic SC loss and replacement mediated by competition for limited niche access. We find that the colonic crypt is maintained by ~5 effective SCs. However, with a SC loss/replacement rate estimated to be slower than once per year, our results indicate that the vast majority of individual SC divisions result in asymmetric fate outcome. These findings provide a quantitative platform to detect and study deviations from human colorectal crypt SC niche homeostasis during the process of colorectal carcinogenesis.Wellcome Trus

Heterogeneous coupling of the Sumatran megathrust constrained by geodetic and paleogeodetic measurements

Geodetic and paleogeodetic measurements of interseismic strain above the Sumatran portion of the Sunda subduction zone reveal a heterogeneous pattern of coupling. Annual banding in corals provides vertical rates of deformation spanning the last half of the 20th century, and repeated GPS surveys between 1991 and 2001 and continuous measurements at GPS stations operated since 2002 provide horizontal velocities. Near the equator, the megathrust is locked over a narrow width of only a few tens of kilometers. In contrast, the locked fault zone is up to about 175 km wide in areas where great interplate earthquakes have occurred in the past. Formal inversion of the data reveals that these strongly coupled patches are roughly coincident with asperities that ruptured during these events. The correlation is most spectacular for rupture of the M_w 8.7 Nias-Simeulue earthquake of 2005, which released half of the moment deficit that had accumulated since its previous rupture in 1861, suggesting that this earthquake was overdue. Beneath the Mentawai islands, strong coupling is observed within the overlapping rupture areas of the great earthquakes of 1797 and 1833. The accumulated slip deficit since these events is slowly reaching the amount of slip that occurred during the 1833 earthquake but already exceeds the slip that occurred during the 1797 earthquake. Thus, rerupture of part of the Mentawai patch in September 2007 was not a surprise. In contrast, coupling is low below the Batu islands near the equator and around Enggano island at about 5°S, where only moderate earthquakes (M_w < 8.0) have occurred in the past two centuries. The correlation of large seismic asperities with patches that are locked during the interseismic period suggests that they are persistent features. This interpretation is reinforced by the fact that the large locked patches and great ruptures occur beneath persistent geomorphologic features, the largest outer arc islands. Depth- and convergence-rate-dependent temperature might influence the pattern of coupling, through its effect on the rheology of the plate interface, but other influences are required to account for the observed along-strike heterogeneity of coupling. In particular, subduction of the Investigator Fracture Zone could be the cause for the low coupling near the equator

Simulation fails to replicate stress in trainees performing a technical procedure in the clinical environment

Introduction: Simulation-based training (SBT) has become an increasingly important method by which doctors learn. Stress has an impact upon learning, performance, technical, and non-technical skills. However, there are currently no studies that compare stress in the clinical and simulated environment. We aimed to compare objective (heart rate variability, HRV) and subjective (state trait anxiety inventory, STAI) measures of stress theatre with a simulated environment.Methods: HRV recordings were obtained from eight anesthetic trainees performing an uncomplicated rapid sequence induction at pre-determined procedural steps using a wireless Polar RS800CX monitor © in an emergency theatre setting. This was repeated in the simulated environment. Participants completed an STAI before and after the procedure.Results: Eight trainees completed the study. The theatre environment caused an increase in objective stress vs baseline (p = .004). There was no significant difference between average objective stress levels across all time points (p = .20) between environments. However, there was a significant interaction between the variables of objective stress and environment (p = .045). There was no significant difference in subjective stress (p = .27) between environments.Discussion: Simulation was unable to accurately replicate the stress of the technical procedure. This is the first study that compares the stress during SBT with the theatre environment and has implications for the assessment of simulated environments for use in examinations, rating of technical and non-technical skills, and stress management training

Crop Updates 2005 Oilseeds

This session covers fifteen papers from different authors: 1. ACKNOWLEDGEMENTS, Douglas Hamilton, FARMING SYSTEMS DEVELOPMENT OFFICER CROP AGRONOMY AND NUTRITION 2. Canola workshop at Crop Updates 2005, Oilseeds WA, John Duff, EXECUTIVE OFFICER OILSEEDS WA 3. Comparison of IT and TT canola varieties in geographic zones of WA, 2003-4, Graham Walton and Hasan Zaheer, Department of Agriculture 4. Farmer scale canola variety trials in WA, 2004, Graham Walton, John Duff, Neil Harris and Heather Cosgriff, Oilseeds WA 5. Oilseed crops for industrial uses, Margaret C. Campbell, Centre for Legumes in Mediterranean Agriculture (CLIMA), Graham Walton,Department of Agriculture 6. Weed control opportunities with GM canola, Bill Crabtree, Independent Consultant, Northam 7. Soil and tissue tests for the sulfur requirements of canola, R.F. Brennan and M.D.A. Bolland, Department of Agriculture 8. Tests to predict the potassium requirements of canola, R.F. Brennan and M.D.A. Bolland, Department of Agriculture 9. Genotypic variation in potassium efficiency of canola, P.M. Damon and Z. Rengel, Faculty of Natural and Agricultural Sciences, UWA 10. Atrazine contamination of groundwater in the agricultural region of Western Australia, Russell Speed1, Neil Rothnie2, John Simons1, Ted Spadek2 and John Moore1;1Department of Agriculture, 2Chemistry Centre (WA) PESTS AND DISEASES 11. Controlling aphids and Beet western yellows virus in canola using imidacloprid seed dressing, Brenda Coutts and Roger Jones; Department of Agriculture 12. Managing sclerotinia in canola, Neil Harris, Dovuro Seeds Western Australia 13. Slugs, the trail of destruction in canola, Neil Harris, Dovuro Seeds Western Australia 14. Blackleg risk assessment and strategies for risk management in canola during 2005 and beyond, Moin Salam, Ravjit Khanguraand Art Diggle, Department of Agriculture 15. Modelling: BRAT – Blackleg Risk Appraisal Tool, Moin Salam, Ravjit KhanguraDepartment of Agricultur