The success of molecular targeted therapy in cancer may depend on the selection of appropriate tumor types whose survival depends on the drug target, so-called ''oncogene addiction.'' Preclinical approaches to defining drug-responsive subsets are needed if initial clinical trials are to be directed at the most susceptible patient population. Here, we show that gastric cancer cells with high-level stable chromosomal amplification of the growth factor receptor MET are extraordinarily susceptible to the selective inhibitor PHA-665752. Although MET activation has primarily been linked with tumor cell migration and invasiveness, the amplified wild-type MET in these cells is constitutively activated, and its continued signaling is required for cell survival. Treatment with PHA-665752 triggers massive apoptosis in 5 of 5 gastric cancer cell lines with MET amplification but in 0 of 12 without increased gene copy numbers (P ‫؍‬ 0.00016). MET amplification may thus identify a subset of epithelial cancers that are uniquely sensitive to disruption of this pathway and define a patient group that is appropriate for clinical trials of targeted therapy using MET inhibitors.gene amplification ͉ molecular marker ͉ oncogene addiction ͉ targeted therapy

Development of materials that deliver more energy at high rates is important for high-power applications, including portable electronic devices and hybrid electric vehicles. For lithium-ion (Li+) batteries, reducing material dimensions can boost Li+ ion and electron transfer in nanostructured electrodes. By manipulating two genes, we equipped viruses with peptide groups having affinity for single-walled carbon nanotubes (SWNTs) on one end and peptides capable of nucleating amorphous iron phosphate(a-FePO4) fused to the viral major coat protein. The virus clone with the greatest affinity toward SWNTs enabled power performance of a-FePO4 comparable to that of crystalline lithium iron phosphate (c-LiFePO4) and showed excellent capacity retention upon cycling at 1C. This environmentally benign low-temperature biological scaffold could facilitate fabrication of electrodes from materials previously excluded because of extremely low electronic conductivity.

Wilms tumor is a pediatric kidney cancer associated with inactivation of the WT1 tumor-suppressor gene in 5 to 10% of cases. Using a high-resolution screen for DNA copy-number alterations in Wilms tumor, we identified somatic deletions targeting a previously uncharacterized gene on the X chromosome. This gene, which we call WTX, is inactivated in approximately one-third of Wilms tumors (15 of 51 tumors). Tumors with mutations in WTX lack WT1 mutations, and both genes share a restricted temporal and spatial expression pattern in normal renal precursors. In contrast to biallelic inactivation of autosomal tumor-suppressor genes, WTX is inactivated by a monoallelic "single-hit" event targeting the single X chromosome in tumors from males and the active X chromosome in tumors from females.

No abstract

The cellular stress response (SR) is a phylogenetically conserved protection mechanism that involves inhibition of protein synthesis through recruitment of translation factors such as eIF4G into insoluble stress granules (SGs) and blockade of proinflammatory responses by interruption of the signaling pathway from tumor necrosis factor alpha (TNF-␣) to nuclear factor-B (NF-B) activation. However, the link between these two physiological phenomena has not been clearly elucidated. Here we report that eIF4GI, which is a scaffold protein interacting with many translation factors, interacts with TRAF2, a signaling molecule that plays a key role in activation of NF-B through TNF-␣. These two proteins colocalize in SGs during cellular exposure to stress conditions. Moreover, TRAF2 is absent from TNFR1 complexes under stress conditions even after TNF-␣ treatment. This suggests that stressed cells lower their biological activities by sequestration of translation factors and TRAF2 into SGs through a protein-protein interaction.Virtually all organisms, from prokaryotes to humans, are capable of mounting the stress response (SR) for cellular survival under stress conditions. Pretreatment of an organism with a sublethal stress can protect that organism from subsequent lethal shock responses to a more severe stress. For instance, high-temperature preconditioning reduces acute lung injury, septic shock, and liver damage caused by ischemia reperfusion injury in mice, resulting in a dramatic increase in survival rate (19,30,40). These phenomena are attributed to the inhibition of the proinflammatory nuclear factor-B (NF-B) signal transduction pathway by hyperthermia preconditioning (30,31,44). Hsp70 was suggested to be responsible for heat-induced protection against tumor necrosis factor alpha (TNF-␣)-induced lethal inflammatory shock (32,38,46,47), although inhibition of TNF signaling was also demonstrated in the absence of Hsp70 expression in cells preconditioned with heat (30, 44) or sodium arsenite (SA) treatments (18).At the cellular level, discrete cytoplasmic foci called stress granules (SGs) are formed in environmentally stressed eukaryotic cells (1,2,21,23,24,26,29,36,41), perhaps through the action of translation factor eIF2␣ (24, 29). In heat-, thapsigargin-, or arsenite-treated cells, the SGs contain most of the components of the translational 48S preinitiation complex (i.e., small, but not large, ribosomal subunits, eIF3, eIF4E, eIF4G, eIF2, and eIF2B), other RNA-binding proteins such as T-cellrestricted intracellular antigens-1 (TIA-1) and T-cell-restricted intracellular antigen-related protein (TIAR), and untranslated mRNAs (1,2,23,24,26). As a consequence, mRNA translation is generally inhibited under stress conditions (14, 43). However, the relationship between the translational blockage and the anti-inflammatory response has not been clearly elucidated in previous work (13). Here we demonstrate a molecular link between these two physiological phenomena. MATERIALS AND METHODSPlasmid construction. To obtain the sp...