Polymorphisms, Mutations, and Amplification of the EGFR Gene in Non-Small Cell Lung Cancers

Masaharu Nomura and colleagues examine the distribution ofEGFR polymorphisms in different populations and find differences that might explain different responses to tyrosine kinase inhibitors in lung cancer patients

Alterations in Genes of the EGFR Signaling Pathway and Their Relationship to EGFR Tyrosine Kinase Inhibitor Sensitivity in Lung Cancer Cell Lines

Deregulation of EGFR signaling is common in non-small cell lung cancers (NSCLC) and this finding led to the development of tyrosine kinase inhibitors (TKIs) that are highly effective in a subset of NSCLC. Mutations of EGFR (mEGFR) and copy number gains (CNGs) of EGFR (gEGFR) and HER2 (gHER2) have been reported to predict for TKI response. Mutations in KRAS (mKRAS) are associated with primary resistance to TKIs.We investigated the relationship between mutations, CNGs and response to TKIs in a large panel of NSCLC cell lines. Genes studied were EGFR, HER2, HER3 HER4, KRAS, BRAF and PIK3CA. Mutations were detected by sequencing, while CNGs were determined by quantitative PCR (qPCR), fluorescence in situ hybridization (FISH) and array comparative genomic hybridization (aCGH). IC50 values for the TKIs gefitinib (Iressa) and erlotinib (Tarceva) were determined by MTS assay. For any of the seven genes tested, mutations (39/77, 50.6%), copy number gains (50/77, 64.9%) or either (65/77, 84.4%) were frequent in NSCLC lines. Mutations of EGFR (13%) and KRAS (24.7%) were frequent, while they were less frequent for the other genes. The three techniques for determining CNG were well correlated, and qPCR data were used for further analyses. CNGs were relatively frequent for EGFR and KRAS in adenocarcinomas. While mutations were largely mutually exclusive, CNGs were not. EGFR and KRAS mutant lines frequently demonstrated mutant allele specific imbalance i.e. the mutant form was usually in great excess compared to the wild type form. On a molar basis, sensitivity to gefitinib and erlotinib were highly correlated. Multivariate analyses led to the following results: 1. mEGFR and gEGFR and gHER2 were independent factors related to gefitinib sensitivity, in descending order of importance. 2. mKRAS was associated with increased in vitro resistance to gefitinib.Our in vitro studies confirm and extend clinical observations and demonstrate the relative importance of both EGFR mutations and CNGs and HER2 CNGs in the sensitivity to TKIs

Local Resistance in Early Medieval Chinese Historiography and the Problem of Religious Overinterpretation

Official Chinese historiography is a treasure trove of information on local resistance to the centralised empire in early medieval China (third to sixth century). Sinologists specialised in the study of Chinese religions commonly reconstruct the religious history of the era by interpreting some of these data. In the process, however, the primary purpose of the historiography of local resistance is often overlooked, and historical interpretation easily becomes ‘overinterpretation’—that is, ‘fabricating false intensity’ and ‘seeing intensity everywhere’, as French historian Paul Veyne proposed to define the term. Focusing on a cluster of historical anecdotes collected in the standard histories of the four centuries under consideration, this study discusses the supposedly ‘religious’ nature of some of the data they contain

The GEOTRACES Intermediate Data Product 2014

The GEOTRACES Intermediate Data Product 2014 (IDP2014) is the first publicly available data product of the international GEOTRACES programme, and contains data measured and quality controlled before the end of 2013. It consists of two parts: (1) a compilation of digital data for more than 200 trace elements and isotopes (TEIs) as well as classical hydrographic parameters, and (2) the eGEOTRACES Electronic Atlas providing a strongly inter-linked on-line atlas including more than 300 section plots and 90 animated 3D scenes. The IDP2014 covers the Atlantic, Arctic, and Indian oceans, exhibiting highest data density in the Atlantic. The TEI data in the IDP2014 are quality controlled by careful assessment of intercalibration results and multi-laboratory data comparisons at cross-over stations. The digital data are provided in several formats, including ASCII spreadsheet, Excel spreadsheet, netCDF, and Ocean Data View collection. In addition to the actual data values the IDP2014 also contains data quality flags and 1-? data error values where available. Quality flags and error values are useful for data filtering. Metadata about data originators, analytical methods and original publications related to the data are linked to the data in an easily accessible way. The eGEOTRACES Electronic Atlas is the visual representation of the IDP2014 data providing section plots and a new kind of animated 3D scenes. The basin-wide 3D scenes allow for viewing of data from many cruises at the same time, thereby providing quick overviews of large-scale tracer distributions. In addition, the 3D scenes provide geographical and bathymetric context that is crucial for the interpretation and assessment of observed tracer plumes, as well as for making inferences about controlling processes

One-Stage Laparoscopic Surgery for Pulmonary Sequestration and Hiatal Hernia in a 2-Year-Old Girl

We herein report a case of one-stage laparoscopic surgery for extralobar pulmonary sequestration (EPS) and hiatal hernia. Our patient was a 2-year-old girl who was diagnosed as a mediastinal mass lesion. Postnatal computed tomography revealed that the mediastinal mass was an EPS. Two weeks after birth, the patient developed gastroesophageal reflux (GER), and esophagography showed a hiatal hernia. At 2 years of age, she underwent one-stage laparoscopic Nissen's fundoplication for GER with resection of the EPS in the posterior mediastinum. The sequestrated lung was grasped via the esophageal hiatus; three aberrant blood vessels were dissected to allow removal of the sequestration through the umbilical port site. The esophageal hiatus was repaired and Nissen's fundoplication was performed laparoscopically. The patient's postoperative course was uneventful, with no recurrence of GER symptoms for 1 year. We conclude that one-stage laparoscopic surgery is useful for patients with EPS and hiatal hernia

Growth inhibition of imatinib-resistant CML cells with the T315I mutation and hypoxia-adaptation by AV65 - a novel Wnt/β-catenin signaling inhibitor.

We investigated the effect of a novel Wnt/β-catenin signaling inhibitor, AV65 on imatinib mesylate (IM)-sensitive and -resistant human chronic myeloid leukemia (CML) cells in vitro. AV65 inhibited the proliferation of various CML cell lines including T315I mutation-harboring cells. AV65 reduced the expression of β-catenin in CML cells, resulting in the induction of apoptosis. Moreover, AV65 inhibited the proliferation of hypoxia-adapted primitive CML cells that overexpress β-catenin. The combination of AV65 with IM had a synergistic inhibitory effect on the proliferation of CML cells. These findings suggest that AV65 could be a novel therapeutic agent for the treatment of CML

Further Studies on the Enzymatic and Chemical Inactivation of Hypothalamic FSH-RH

The effect of chemical and enzymatic treatments on the biological activity of porcine follicle-stimulating hormone-releasing hormone (FSH-RH) was studied. FSH-RH activity was not affected by trypsin, pepsin, neuraminidase, carboxypeptidase A, aminopeptidase M and leucine aminopeptidase. However, incubation with chymotrypsin, subtilisin, papain and pyrrolidone carboxylyl peptidase abolished the FSH-RH activity as did treatment with hydrochloric acid (0.9 m, 1 h, 100 °C), diazotized sulfanilic acid, and N-bromosuccinimide. Nitrous acid, sodium metaperiodate, and ninhydrin did not affect the FSH-RH activity appreciably. Amino acid analyses of the purest FSH-RH preparation showed the following composition: His 1, Arg 1, Ser 1, Glu 1, Pro 1, Gly 2, Leu 1, Trp 1, and Tyr 1. These results and information obtained during purification procedures indicate that a basic polypeptide composed of ten amino acids possesses both LH-RH and FSH-RH activity