Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.

Drug resistance presents a challenge to the treatment of cancer patients. Many studies have focused on cell-autonomous mechanisms of drug resistance. By contrast, we proposed that the tumour micro-environment confers innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anticancer drugs. We found that stroma-mediated resistance is common, particularly to targeted agents. We characterized further the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibitors because most patients with this type of cancer show some degree of innate resistance. Proteomic analysis showed that stromal cell secretion of hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-OH kinase (PI(3)K)-AKT signalling pathways, and immediate resistance to RAF inhibition. Immunohistochemistry experiments confirmed stromal cell expression of HGF in patients with BRAF-mutant melanoma and showed a significant correlation between HGF expression by stromal cells and innate resistance to RAF inhibitor treatment. Dual inhibition of RAF and either HGF or MET resulted in reversal of drug resistance, suggesting RAF plus HGF or MET inhibitory combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, this study indicates that the systematic dissection of interactions between tumours and their micro-environment can uncover important mechanisms underlying drug resistance

A comparative assessment of the information technology services sector in India and China

The purpose of this paper is to assess the nature of competition in the information technology (IT) services sector between India and China. Using primary and secondary data sources, we compare and contrast the strengths and weaknesses of the IT services sector in the two countries along the main dimensions of Porter&rsquo;s competitive advantage model. The principal findings indicate that the IT services sectors in the two countries are distinctively different, have developed along different paths and are highly complementary to each other. China has a well established hardware sector and its IT services sector focuses mostly on servicing its domestic market. India&rsquo;s IT services sector is predominantly export orientated with focus on the US and Western European markets. Contrary to popular beliefs, given the complementary characteristics of the IT services sectors in India and China, it is unlikely for the two countries to compete against each other in the near future and greater strategic co-operation between IT service providers in the two countries is a more likely outcome.<br /

Tumor microenvironment induces innate RAF-inhibitor resistance through HGF secretion

Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anti-cancer drugs. We found that stroma-mediated resistance is surprisingly common – particularly to targeted agents. We further characterized the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most of these patients exhibit some degree of innate resistance1-4. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed stromal HGF expression in patients with BRAF-mutant melanoma and a statistically significant correlation between stromal HGF expression and innate resistance to treatment. Dual inhibition of RAF and MET resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance

A human PrM antibody that recognizes a novel cryptic epitope on dengue E glycoprotein

10.1371/journal.pone.0033451PLoS ONE74

Opposing effects of final population density and stress on Escherichia coli mutation rate

Evolution depends on mutations. For an individual genotype, the rate at which mutations arise is known to increase with various stressors (stress-induced mutagenesis-SIM) and decrease at high final population density (density-associated mutation-rate plasticity-DAMP). We hypothesised that these two forms of mutation-rate plasticity would have opposing effects across a nutrient gradient. Here we test this hypothesis, culturing Escherichia coli in increasingly rich media. We distinguish an increase in mutation rate with added nutrients through SIM (dependent on error-prone polymerases Pol IV and Pol V) and an opposing effect of DAMP (dependent on MutT, which removes oxidised G nucleotides). The combination of DAMP and SIM results in a mutation rate minimum at intermediate nutrient levels (which can support 7 × 10  cells ml ). These findings demonstrate a strikingly close and nuanced relationship of ecological factors-stress and population density-with mutation, the fuel of all evolution

Phaseless Auxiliary-Field Quantum Monte Carlo on Graphical Processing Units

We present an implementation of phaseless Auxiliary-Field Quantum Monte Carlo (ph-AFQMC) utilizing graphical processing units (GPUs). The AFQMC method is recast in terms of matrix operations which are spread across thousands of processing cores and are executed in batches using custom Compute Unified Device Architecture kernels and the hardware-optimized cuBLAS matrix library. Algorithmic advances include a batched Sherman-Morrison-Woodbury algorithm to quickly update matrix determinants and inverses, density-fitting of the two-electron integrals, an energy algorithm involving a high-dimensional precomputed tensor, and the use of single-precision floating point arithmetic. These strategies result in dramatic reductions in wall-times for both single- and multi-determinant trial wavefunctions. For typical calculations we find speed-ups of roughly two orders of magnitude using just a single GPU card. Furthermore, we achieve near-unity parallel efficiency using 8 GPU cards on a single node, and can reach moderate system sizes via a local memory-slicing approach. We illustrate the robustness of our implementation on hydrogen chains of increasing length, and through the calculation of all-electron ionization potentials of the first-row transition metal atoms. We compare long imaginary-time calculations utilizing a population control algorithm with our previously published correlated sampling approach, and show that the latter improves not only the efficiency but also the accuracy of the computed ionization potentials. Taken together, the GPU implementation combined with correlated sampling provides a compelling computational method that will broaden the application of ph-AFQMC to the description of realistic correlated electronic systems

Emergent mesoscale correlations in active solids with noisy chiral dynamics

Theoretical Physic