Global and local controlson continental margin stratigraphy

Integrated Ocean Drilling Program (IODP) Expedition 317 was devoted to understanding the relative importance of global sea level (eustasy) versus local tectonic and sedimentary processes in controlling continental margin sedimentary cycles. The expedition recovered sediments from the Eocene to recent period, with a particular focus on the sequence stratigraphy of the late Miocene to recent, when global sea level change was dominated by glacioeustasy. Drilling in the Canterbury Basin, on the eastern margin of the South Island of New Zealand, takes advantage of high rates of Neogene sediment supply, which preserves a high-frequency (0.1–0.5 m.y.) record of depositional cyclicity. The Canterbury Basin provides an opportunity to study the complex interactions between processes responsible for the preserved stratigraphic record of sequences because of the proximity of an uplifting mountain chain, the Southern Alps, and strong ocean currents. Currents have locally built large, elongate sediment drifts within the prograding Neogene section. Expedition 317 did not drill into one of these elongate drifts, but currents are inferred to have strongly influenced deposition across the basin, including in locations lacking prominent mounded drifts. Upper Miocene to recent sedimentary sequences were cored in a transect of three sites on the continental shelf (landward to basinward, Sites U1353, U1354, and U1351) and one on the continental slope (Site U1352). The transect provides a stratigraphic record of depositional cycles across the shallow-water environment most directly affected by relative sea level change. Lithologic boundaries, provisionally correlative with seismic sequence boundaries, have been identified in cores from each site and provide insights into the origins of seismically resolvable sequences. This record will be used to estimate the timing and amplitude of global sea level change and to document the sedimentary processes that operate during sequence formation. Sites U1353 and U1354 provide significant, double-cored, high-recovery sections through the Holocene and late Quaternary for high-resolution study of recent glacial cycles in a continental shelf setting. Continental slope Site U1352 represents a complete section from modern slope terrigenous sediment to hard Eocene limestone, with all the associated lithologic, biostratigraphic, physical, geochemical, and microbiological transitions. The site also provides a record of ocean circulation and fronts during the last ~35 m.y. The early Oligocene (~30 Ma) Marshall Paraconformity was the deepest drilling target of Expedition 317 and is hypothesized to represent intensified current erosion or nondeposition associated with the initiation of thermohaline circulation following the separation of Australian and Antarctica. Expedition 317 set a number of scientific ocean drilling records: (1) deepest hole drilled in a single expedition and second deepest hole in the history of scientific ocean drilling (Hole U1352C, 1927 m); (2) deepest hole and second deepest hole drilled by the R/V JOIDES Resolution on a continental shelf (Hole U1351B, 1030 m; Hole U1353B, 614 m); (3) shallowest water depth for a site drilled by the JOIDES Resolution for scientific purposes (Site U1353, 84.7 m water depth); and (4) deepest sample taken by scientific ocean drilling for microbiological studies (1925 m, Site U1352). Expedition 317 supplements previous drilling of sedimentary sequences for sequence stratigraphic and sea level objectives, particularly drilling on the New Jersey margin (Ocean Drilling Program [ODP] Legs 150, 150X, 174A, and 174AX and IODP Expedition 313) and in the Bahamas (ODP Leg 166), but includes an expanded Pliocene section. Completion of at least one transect across a geographically and tectonically distinct siliciclastic margin was the necessary next step in deciphering continental margin stratigraphy. Expedition 317 also complements ODP Leg 181, which focused on drift development in more distal parts of the Eastern New Zealand Oceanic Sedimentary System (ENZOSS).Integrated Ocean Drilling Program Management InternationalPublished2.2. Laboratorio di paleomagnetismorestricte

Properties of resistant cells generated from lung cancer cell lines treated with EGFR inhibitors

<p>Abstract</p> <p>Background</p> <p>Epidermal growth factor receptor (EGFR) signaling plays an important role in non-small cell lung cancer (NSCLC) and therapeutics targeted against EGFR have been effective in treating a subset of patients bearing somatic EFGR mutations. However, the cancer eventually progresses during treatment with EGFR inhibitors, even in the patients who respond to these drugs initially. Recent studies have identified that the acquisition of resistance in approximately 50% of cases is due to generation of a secondary mutation (T790M) in the EGFR kinase domain. In about 20% of the cases, resistance is associated with the amplification of MET kinase. In the remaining 30-40% of the cases, the mechanism underpinning the therapeutic resistance is unknown.</p> <p>Methods</p> <p>An erlotinib resistant subline (H1650-ER1) was generated upon continuous exposure of NSCLC cell line NCI-H1650 to erlotinib. Cancer stem cell like traits including expression of stem cell markers, enhanced ability to self-renew and differentiate, and increased tumorigenicity <it>in vitro </it>were assessed in erlotinib resistant H1650-ER1 cells.</p> <p>Results</p> <p>The erlotinib resistant subline contained a population of cells with properties similar to cancer stem cells. These cells were found to be less sensitive towards erlotinib treatment as measured by cell proliferation and generation of tumor spheres in the presence of erlotinib.</p> <p>Conclusions</p> <p>Our findings suggest that in cases of NSCLC accompanied by mutant EGFR, treatment targeting inhibition of EGFR kinase activity in differentiated cancer cells may generate a population of cancer cells with stem cell properties.</p

Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells

<p>Abstract</p> <p>Background</p> <p>Although lung cancer is among the few malignancies for which we know the primary etiological agent (i.e., cigarette smoke), a precise understanding of the temporal sequence of events that drive tumor progression remains elusive. In addition to finding that cigarette smoke (CS) impacts the functioning of key pathways with significant roles in redox homeostasis, xenobiotic detoxification, cell cycle control, and endoplasmic reticulum (ER) functioning, our data highlighted a defensive role for the unfolded protein response (UPR) program. The UPR promotes cell survival by reducing the accumulation of aberrantly folded proteins through translation arrest, production of chaperone proteins, and increased degradation. Importance of the UPR in maintaining tissue health is evidenced by the fact that a chronic increase in defective protein structures plays a pathogenic role in diabetes, cardiovascular disease, Alzheimer's and Parkinson's syndromes, and cancer.</p> <p>Methods</p> <p>Gene and protein expression changes in CS exposed human cell cultures were monitored by high-density microarrays and Western blot analysis. Tissue arrays containing samples from 110 lung cancers were probed with antibodies to proteins of interest using immunohistochemistry.</p> <p>Results</p> <p>We show that: 1) CS induces ER stress and activates components of the UPR; 2) reactive species in CS that promote oxidative stress are primarily responsible for UPR activation; 3) CS exposure results in increased expression of several genes with significant roles in attenuating oxidative stress; and 4) several major UPR regulators are increased either in expression (i.e., BiP and eIF2α) or phosphorylation (i.e., phospho-eIF2α) in a majority of human lung cancers.</p> <p>Conclusion</p> <p>These data indicate that chronic ER stress and recruitment of one or more UPR effector arms upon exposure to CS may play a pivotal role in the etiology or progression of lung cancers, and that phospho-eIF2α and BiP may have diagnostic and/or therapeutic potential. Furthermore, we speculate that upregulation of UPR regulators (in particular BiP) may provide a pro-survival advantage by increasing resistance to cytotoxic stresses such as hypoxia and chemotherapeutic drugs, and that UPR induction is a potential mechanism that could be attenuated or reversed resulting in a more efficacious treatment strategy for lung cancer.</p

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