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BACKGROUND: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. METHODS AND FINDINGS: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. CONCLUSIONS: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

The sensitivity of conventional DNA sequencing in tumor biopsies is limited by stromal contamination and by genetic heterogeneity within the cancer. Here, we show that microreactor-based pyrosequencing can detect rare cancer-associated sequence variations by independent and parallel sampling of multiple representatives of a given DNA fragment. This technology can thereby facilitate accurate molecular diagnosis of heterogeneous cancer specimens and enable patient selection for targeted cancer therapies. NOTE:: In the version of this article initially published, it should have been acknowledged that Jan F. Simons, in addition to Roman K. Thomas and Elizabeth Nickerson, contributed equally to this work. The error has been corrected in the HTML and PDF versions of the article., Author(s): Roman K Thomas [1, 2, 12]; Elizabeth Nickerson [3, 12]; Jan F Simons [3, 11, 12]; Pasi A Janne [1]; Torstein Tengs [1, 2]; Yuki Yuza [1]; Levi A [...]

Glioblastomas (EGFRvIII) and phosphatase and tensin homologue deleted in chromosome 10 (PTEN) at the gene and protein levels in glioblastomas from patients before treatment with epidermal growth factor receptor (EGFR) kinase inhibitors are analyzed. Coexpression of EGFRvIII and PTEN by glioblastoma cells is associated with responsiveness to EGFR kinase inhibitors.

A two-step postsynthetic functionalization reaction of zeolite HZSM-5 that proceeds with high selectivity at room temperature is reported. The theoretical modeling using density functional theory and cluster models of the zeolite acid site has shown that both steps are exothermic and has provided theoretical chemical shift values in agreement with the experiment.

The Australian Federal Court case of Universal Music Australia Pty Ltd v Sharman License Holdings Ltd (`Sharman') is the latest in a series of peer-to-peer (P2P) filesharing cases from various jurisdictions that has found the software distributor/technology provider liable for copyright infringement. Sharman followed a few months after the groundbreaking US Supreme Court case of MGM Studios v Grokster Ltd' (`Grokster') that had acknowledged the Sony safe harbour for technology providers but also introduced an inducement of infringement doctrine to deal with reprehensible conduct of infringers. While both cases involved similar technology and shared a number of similarities on the facts and legal principles, a closer examination of Sharman shows that the net of copyright infringement in P2P filesharing is cast wider than that in Groksler. The effect of Sharman is an increased burden on the technology provider and the potentially tremendous consequences on innovation due to the lack of a clear safe harbour as well as the widening of the design obligation. [ABSTRACT FROM AUTHOR]

The interfacial reactions of solder joints between the Sn-4Ag-0.5Cu solder ball and the Sn-7Zn-A1 (30 ppm) presoldered paste were investigated in a wafer level chip scale package (WLCSP). After appropriate surface mount technology (SMT) reflow process on the printed circuit board (PCB) with organic solderability preservative (Cu/OSP) and Cu/Ni/Au surface finish, samples were subjected to 150°C high-temperature storage (HTS), 1,000 h aging. Sequentially, the cross-sectional analysis is scrutinized using a scanning electron microscope (SEM)/energy-dispersive spectrometer (EDS) and energy probe microanalysis (EPMA) to observe the metallurgical evolution in the interface and solder buck itself. It was found that Zn-enriched intermetallic compounds (IMCs) without Sn were formed and migrated from the presolder paste region into the solder after reflow and 150°C HTS test. [ABSTRACT FROM AUTHOR]

Background: Protein tyrosine kinases are important regulators of cellular homeostasis with tightly controlled catalytic activity. Mutations in kinase-encoding genes can relieve the autoinhibitory constraints on kinase activity, can promote malignant transformation, and appear to be a major determinant of response to kinase inhibitor therapy. Missense mutations in the EGFR kinase domain, for example, have recently been identified in patients who showed clinical responses to EGFR kinase inhibitor therapy. Methods and Findings: Encouraged by the promising clinical activity of epidermal growth factor receptor (EGFR) kinase inhibitors in treating glioblastoma in humans, we have sequenced the complete EGFR coding sequence in glioma tumor samples and cell lines. We identified novel missense mutations in the extracellular domain of EGFR in 13.6% (18/132) of glioblastomas and 12.5% (1/ 8) of glioblastoma cell lines. These EGFR mutations were associated with increased EGFR gene dosage and conferred anchorage-independent growth and tumorigenicity to NIH-3T3 cells. Cells transformed by expression of these EGFR mutants were sensitive to small-molecule EGFR kinase inhibitors. Conclusions: Our results suggest extracellular missense mutations as a novel mechanism for oncogenic EGFR activation and may help identify patients who can benefit from EGFR kinase inhibitors for treatment of glioblastoma.

A correction to the article "High-throughput oncogene mutation profiling in human cancer" that was published in the previous issue is presented.

The interfacial reactions of solder joints between Sn-4Ag-0.5Cu solder ball and a couple of presoldered pastes (Sn-7Zn-Al(30ppm) and Sn-3Ag-0.5Cu) were investigated in wafer-level chip-scale package (WLCSP). After appropriate surface mount technology reflow processes on printed circuit boards with a Cu/OSP (organic solderability preservative) surface finish, samples were subjected to 150°C high-temperature storage (HTS) for 1,000 h of aging or 1,000 cycles of a thermal cycling test (TCT). Sequentially, cross-section analysis is scrutinized by scanning electron microscopy/energy dispersive spectrometry and energy probe microanalysis to observe metallurgical evolution in the interface and solder buck itself. It was found that the degradation of the joint shear strength after TCT is more pronounced than that of the shear strength after HTS. Fracture surface analyses of the shear tests show that the degradation of the joint strength for HTS is solely due to the influence of the interfacial IMC grain growth, while the shear strength degradation for TCT is mainly due to the coefficient thermal expansion mismatch from the thermal cycling at the chip-solder interface and can lead to the occurrence of the crack. [ABSTRACT FROM AUTHOR]

Receptor tyrosine kinase genes were sequenced in non-small cell lung cancer (NSCLC) and matched normal tissue. Somatic mutations of the epidermal growth factor receptor gene ECFR were found in 15 of 58 unselected tumors from Japan and 1 of 61 from the United States. Treatment with the EGFR kinase inhibitor gef itinib (Iressa) causes tumor regression in some patients with NSCLC, more frequently in Japan. ECFR mutations were found in additional lung cancer samples from D.S. patients who responded to gefitinib therapy and in a lung adenocarcinoma cell line that was hypersensitive to growth inhibition by gefitinib, but not in gefitinib-insensitive tumors or cell lines. These results suggest that ECFR mutations may predict sensitivity to gefitinib. [ABSTRACT FROM AUTHOR]

Major efforts are underway to systematically define the somatic and germline genetic variations causally associated with disease. Genome-wide genetic analysis of actual clinical samples is, however, limited by the paucity of genomic DNA available. Here we have tested the fidelity and genome representation of phi29 polymerase-based genome amplification (phi29MDA) using direct sequencing and high density oligonucleotide arrays probing >10,000 SNP alleles. Genome representation was comprehensive and estimated to be 99.82% complete, although six regions encompassing a maximum of 5.62 Mb failed to amplify. There was no degradation in the accuracy of SNP genotyping and, in direct sequencing experiments sampling 500,000 bp, the estimated error rate (9.5 x 10(-6)) was the same as in paired unamplified samples. The detection of cancer-associated loss of heterozygosity and copy number changes, including homozygous deletion and gene amplification, were similarly robust. These results suggest that phi29MDA yields high fidelity, near-complete genome representation suitable for high resolution genetic analysis.