Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen

The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.Peer reviewe

Downregulation of glial glutamate transporters after dopamine denervation in the striatum of 6-hydroxydopamine-lesioned rats

Overactivity of glutamatergic neurotransmission in the basal ganglia is known to be closely related to the onset and pathogenesis of Parkinson's disease. Glutamate homeostasis around glutamatergic synapses is tightly regulated by two groups of glutamate transporters: glial glutamate transporters GLT1 (EAAT2) and GLAST (EAAT1), and neuronal glutamate transporter EAAC1. In order to investigate the changes of glutamate transporters after the onset of Parkinson's disease, unilateral 6-hydroxydopamine-lesioned rat, an animal model of Parkinson's disease, was employed. By immunofluorescence and Western blot analyses, GLT1 and GLAST proteins were significantly reduced in the striatum with lesion. No change in GLT1 and GLAST protein was found in the substantia nigra. The reduction of GLT1 protein in the striatum was more prominent than that of GLAST protein (∼40% vs. 20%). In addition, EAAC1 protein was found to be increased in the substantia nigra pars reticulata of the lesioned rats but not in the striatum. The present results indicate that reductions of GLT1 and GLAST may impair glutamate homeostasis around glutamatergic synapses in the striatum and contribute to over-spills of glutamate in the system. An increase in the EAAC1 level in the substantia nigra pars reticulata may increase GABA synthesis and enhance GABAergic neurotransmission. These results indicate that there are differential and distinct modulations of glutamate transporters after dopamine denervation in the 6-hydroxydopamine-lesioned rat. © 2008 Wiley-Liss, Inc.link_to_subscribed_fulltex

Up-regulation in expression of vesicular glutamate transporter 3 in substantia nigra but not in striatum of 6-hydroxydopamine-lesioned rats

Overactivity of the glutamatergic system is suggested to be closely related to the onset and pathogenesis of Parkinson's disease. Vesicular glutamate transporters (VGLUT1, T2 and T3) are a group of glutamate transporters in neurons that are responsible for transporting glutamate into synaptic vesicles and they are key elements for homeostasis of glutamate neurotransmission. The present study was aimed to investigate the expression of VGLUT1, T2 and T3 proteins after the onset of Parkinson's disease. A rat model of Parkinson's disease, the 6-hydroxydopamine-lesioned rat, was employed. Immunocytochemistry revealed that VGLUT1, T2 and T3 immunoreactivity was not modulated in the striatum of the lesioned rat. Western blotting analyses also showed that there was no change in the expression of T1, T2 and T3 proteins in the striatum. In contrast, no VGLUT1 protein was detected in the substantia nigra. After the lesion, levels of VGLUT2 immunoreactivity and protein were not modulated. Significant increase of VGLUT3 immunoreactivity was observed in the perikarya of GABAergic substantia nigra pars reticulata neurons (+14.7%) although VGLUT3 protein was not modulated in the nigral tissues. VGLUT3 in GABAergic neurons is suggested to play a role in GABA synthesis. The present results may therefore implicate that VGLUT1 and T2 are not modulated in the striatum and the substantia nigra of the 6-hydroxydopamine-lesioned rat and only VGLUT3 plays a role in pathogenesis of Parkinson's disease. Copyright © 2007 S. Karger AG.link_to_subscribed_fulltex

Export-led growth and the Japanese economy: evidence from VAR and directed acyclic graphs

This paper explores the causal relationship between real exports and GDP growth in Japan using two recently developed causal modelling approaches. Using Japanese time series, the paper employed the augmented VAR methodology developed by Toda and Yamamoto to test for Granger non-causality. Then, a more recently developed technique of directed acyclic graphs (DAG) was also used in providing over-identifying restrictions on the innovations from a vector autoregression (VAR). In contrast to prior analyses, the application of DAG techniques allows for the examination of both contemporaneous and dynamic causal structure of the exports-productivity nexus. The empirical results reveal that the causal path between exports and GDP growth in Japan is bi-directional. Furthermore, other variables such as capital and foreign output are also significant determinants of productivity growth in Japan.

Global Discourses and Local Politics in the Production of Power Policy in India

Waquar Ahmed examines the evolution of electric-power policy in India by drawing linkages between global and local national discourses, of development. He focuses on the objectives and goals of the developmental state of India after the end of colonial occupation, and how the transition from Keynesianism to neo-liberalism as the dominant developmental discourse at the global level has impacted India's power policy. He focuses on the dynamic nature of state-society coalition in India in order to understand how changing coalitions at different points of time in history, have impacted India's power policy. Development (2006) 49, 94–100. doi:10.1057/palgrave.development.1100275

Age structure of the workforce in growing and declining industries: evidence from Hong Kong

Industry-specific human capital, Industry upgrading, Sectoral shifts, J10, J23, J24,