BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations

Background: Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process. Methods and Findings: To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis. Conclusions: Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFRmutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinibinduced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors

Dynamic scaling for 2D superconductors, Josephson junction arrays and superfluids

The value of the dynamic critical exponent $z$ is studied for two-dimensional superconducting, superfluid, and Josephson Junction array systems in zero magnetic field via the Fisher-Fisher-Huse dynamic scaling. We find $z\simeq5.6\pm0.3$, a relatively large value indicative of non-diffusive dynamics. Universality of the scaling function is tested and confirmed for the thinnest samples. We discuss the validity of the dynamic scaling analysis as well as the previous studies of the Kosterlitz-Thouless-Berezinskii transition in these systems, the results of which seem to be consistent with simple diffusion ($z=2$). Further studies are discussed and encouraged.Comment: 19 pages in two-column RevTex, 8 embedded EPS figure

A Performance Evaluation of Hyper Text Transfer Protocols

Version 1.1 of the Hyper Text Transfer Protocol (HTTP) was principally developed as a means for reducing both document transfer latency and network traffic. The rationale for the performance enhancements in HTTP/1.1 is based on the assumption that the network is the bottleneck in Web transactions. In practice, however, the Web server can be the primary source of document transfer latency. In this paper, we characterize and compare the performance of HTTP/1.0 and HTTP/1.1 in terms of throughput at the server and transfer latency at the client. Our approach is based on considering a broader set of bottlenecks in an HTTP transfer# we examine how bottlenecks in the network, CPU, and in the disk system affect the relative performance of HTTP/1.0 versus HTTP/1.1. We show that the network demands under HTTP/1.1 are somewhat lower than HTTP/1.0, and we quantify those differences in terms of packets transferred, server congestion window size and data bytes per packet. We show that when the CPU is the bottleneck, there is relatively little difference in performance between HTTP/1.0 and HTTP/1.1. Surprisingly, we show that when the disk system is the bottleneck, performance using HTTP/1.1 can be much worse than with HTTP/1.0. Based on these observations, we suggest a connection management policy for HTTP/1.1 that can improve throughput, decrease latency, and keep network traffic low when the disk system is the bottleneck