Early and late effects of pharmacological ALK inhibition on the neuroblastoma transcriptome

Background: Neuroblastoma is an aggressive childhood malignancy of the sympathetic nervous system. Despite multi-modal therapy, survival of high-risk patients remains disappointingly low, underscoring the need for novel treatment strategies. The discovery of ALK activating mutations opened the way to precision treatment in a subset of these patients. Previously, we investigated the transcriptional effects of pharmacological ALK inhibition on neuroblastoma cell lines, six hours after TAE684 administration, resulting in the 77-gene ALK signature, which was shown to gradually decrease from 120 minutes after TAE684 treatment, to gain deeper insight into the molecular effects of oncogenic ALK signaling. Aim: Here, we further dissected the transcriptional dynamic profiles of neuroblastoma cells upon TAE684 treatment in a detailed timeframe of ten minutes up to six hours after inhibition, in order to identify additional early targets for combination treatment. Results: We observed an unexpected initial upregulation of positively regulated MYCN target genes following subsequent downregulation of overall MYCN activity. In addition, we identified adrenomedullin (ADM), previously shown to be implicated in sunitinib resistance, as the earliest response gene upon ALK inhibition. Conclusions: We describe the early and late effects of ALK inhibitor TAE684 treatment on the neuroblastoma transcriptome. The observed unexpected upregulation of ADM warrants further investigation in relation to putative ALK resistance in neuroblastoma patients currently undergoing ALK inhibitor treatment

Workplace Job Satisfaction in Britain: Evidence from Linked Employer-Employee Data

This paper examines the determinants of job satisfaction in Britain using nationally representative linked employer-employee data (WERS2004) and alternative econometric techniques. It uses eight facets of job satisfaction for the purpose. As well as underscoring the importance of accounting for unobserved workplace heterogeneity, the paper is able to highlight some new findings that relate to differential effects of dependent children and other dependents, type of employment contract and gaps between employees' skill and skills requirements of their job. Working long hours is found to be positively associated with intrinsic aspect of jobs. Public sector employment is positively associated with all facets of job satisfaction except satisfaction with pay.job satisfaction, linked employer-employee data, Britain

The Effect of the Northeast Dairy Compact on Producers and Consumers, with Implications of Compact Contagion

Balagtas andSumnermodel and measure the effects of the Northeast Dairy Compact on prices, quantities, and producer and consumer welfare, underscoring the distribution of these effects across regions and among producer and buyers. Using 1999 as a base year, simulations show that the Compact raised the farm price of milk in the Northeast by $0.45/cwt., lowered the farm price of milk in the rest of the country by$0.02/cwt., and transferred income from producers outside the Compact region and buyers in the Compact region to producers in the Compact region. Non-Compact producer losses exceeded Compact producer gains. Similar results are found for a scenario of Compact contagion, extension of the Compact to include additional states. In both cases, the Compact changed the distribution of the costs and benefits of price discrimination as practiced by milk marketing orders. The implication is that the regional distribution of the Compact's welfare effects raises again the question of the organization of a government-sponsored milk marketing plan such as the federal milk marketing order system.Health and Safety, Regulatory Reform

Nanoscale fluid flows in the vicinity of patterned surfaces

Molecular dynamics simulations of dense and rarefied fluids comprising small chain molecules in chemically patterned nano-channels predict a novel switching from Poiseuille to plug flow along the channel. We also demonstrate behavior akin to the lotus effect for a nanodrop on a chemically patterned substrate. Our results show that one can control and exploit the behavior of fluids at the nanoscale using chemical patterning.Comment: Phys. Rev. Lett. in pres

Bariatric surgery and brain health: A longitudinal observational study investigating the effect of surgery on cognitive function and gray matter volume

Dietary modifications leading to weight loss have been suggested as a means to improve brain health. In morbid obesity, bariatric surgery (BARS)—including different procedures, such as vertical sleeve gastrectomy (VSG), gastric banding (GB), or Roux-en-Y gastric bypass (RYGB) surgery—is performed to induce rapid weight loss. Combining reduced food intake and malabsorption of nutrients, RYGB might be most effective, but requires life-long follow-up treatment. Here, we tested 40 patients before and six months after surgery (BARS group) using a neuropsychological test battery and compared them with a waiting list control group. Subsamples of both groups underwent structural MRI and were examined for differences between surgical procedures. No substantial differences between BARS and control group emerged with regard to cognition. However, larger gray matter volume in fronto-temporal brain areas accompanied by smaller volume in the ventral striatum was seen in the BARS group compared to controls. RYGB patients compared to patients with restrictive treatment alone (VSG/GB) had higher weight loss, but did not benefit more in cognitive outcomes. In sum, the data of our study suggest that BARS might lead to brain structure reorganization at long-term follow-up, while the type of surgical procedure does not differentially modulate cognitive performance

Intestine‐Specific Expression of Human Chimeric Intestinal Alkaline Phosphatase Attenuates Western Diet‐Induced Barrier Dysfunction and Glucose Intolerance

Intestinal epithelial cell derived alkaline phosphatase (IAP) dephosphorylates/detoxifies bacterial endotoxin lipopolysaccharide (LPS) in the gut lumen. We have earlier demonstrated that consumption of high‐fat high‐cholesterol containing western type‐diet (WD) significantly reduces IAP activity, increases intestinal permeability leading to increased plasma levels of LPS and glucose intolerance. Furthermore, oral supplementation with curcumin that increased IAP activity improved intestinal barrier function as well as glucose tolerance. To directly test the hypothesis that targeted increase in IAP would protect against WD‐induced metabolic consequences, we developed intestine‐specific IAP transgenic mice where expression of human chimeric IAP is under the control of intestine‐specific villin promoter. This chimeric human IAP contains domains from human IAP and human placental alkaline phosphatase, has a higher turnover number, narrower substrate specificity, and selectivity for bacterial LPS. Chimeric IAP was specifically and uniformly overexpressed in these IAP transgenic (IAPTg) mice along the entire length of the intestine. While IAP activity reduced from proximal P1 segment to distal P9 segment in wild‐type (WT) mice, this activity was maintained in the IAPTg mice. Dietary challenge with WD impaired glucose tolerance in WT mice and this intolerance was attenuated in IAPTg mice. Significant decrease in fecal zonulin, a marker for intestinal barrier dysfunction, in WD fed IAPTg mice and a corresponding decrease in translocation of orally administered nonabsorbable 4 kDa FITC dextran to plasma suggests that IAP overexpression improves intestinal barrier function. Thus, targeted increase in IAP activity represents a novel strategy to improve WD‐induced intestinal barrier dysfunction and glucose intolerance

Correlative Spectral Analysis of Gamma-Ray Bursts using Swift-BAT and GLAST-GBM

We discuss the preliminary results of spectral analysis simulations involving anticipated correlated multi-wavelength observations of gamma-ray bursts (GRBs) using Swift's Burst Alert Telescope (BAT) and the Gamma-Ray Large Area Space Telescope's (GLAST) Burst Monitor (GLAST-GBM), resulting in joint spectral fits, including characteristic photon energy (Epeak) values, for a conservative annual estimate of ~30 GRBs. The addition of BAT's spectral response will (i) complement in-orbit calibration efforts of GBM's detector response matrices, (ii) augment GLAST's low energy sensitivity by increasing the ~20-100 keV effective area, (iii) facilitate ground-based follow-up efforts of GLAST GRBs by increasing GBM's source localization precision, and (iv) help identify a subset of non-triggered GRBs discovered via off-line GBM data analysis. Such multi-wavelength correlative analyses, which have been demonstrated by successful joint-spectral fits of Swift-BAT GRBs with other higher energy detectors such as Konus-WIND and Suzaku-WAM, would enable the study of broad-band spectral and temporal evolution of prompt GRB emission over three energy decades, thus potentially increasing the science return without placing additional demands upon mission resources throughout their contemporaneous orbital tenure over the next decade.Comment: 5 pages. Adapted from a contribution to the Proceedings of the 2008 Nanjing GRB Conference. Edited by Y. F. Huang, Z. G. Dai and B. Zhan

Transport properties of strongly correlated electrons in quantum dots using a simple circuit model

Numerical calculations are shown to reproduce the main results of recent experiments involving nonlocal spin control in nanostructures (N. J. Craig et al., Science 304, 565 (2004)). In particular, the splitting of the zero-bias-peak discovered experimentally is clearly observed in our studies. To understand these results, a simple "circuit model" is introduced and shown to provide a good qualitative description of the experiments. The main idea is that the splitting originates in a Fano anti-resonance, which is caused by having one quantum dot side-connected in relation to the current's path. This scenario provides an explanation of Craig et al.'s results that is alternative to the RKKY proposal, which is here also addressed.Comment: 5 pages, 5 figure