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

Generation of a non-small cell lung cancer transcriptome microarray

<p>Abstract</p> <p>Background</p> <p>Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. At present no reliable biomarkers are available to guide the management of this condition. Microarray technology may allow appropriate biomarkers to be identified but present platforms are lacking disease focus and are thus likely to miss potentially vital information contained in patient tissue samples.</p> <p>Methods</p> <p>A combination of large-scale in-house sequencing, gene expression profiling and public sequence and gene expression data mining were used to characterise the transcriptome of NSCLC and the data used to generate a disease-focused microarray – the Lung Cancer DSA research tool.</p> <p>Results</p> <p>Built on the Affymetrix GeneChip platform, the Lung Cancer DSA research tool allows for interrogation of ~60,000 transcripts relevant to Lung Cancer, tens of thousands of which are unavailable on leading commercial microarrays.</p> <p>Conclusion</p> <p>We have developed the first high-density disease specific transcriptome microarray. We present the array design process and the results of experiments carried out to demonstrate the array's utility. This approach serves as a template for the development of other disease transcriptome microarrays, including non-neoplastic diseases.</p

Expression and clinical significance of Glucose Regulated Proteins GRP78 (BiP) and GRP94 (GP96) in human adenocarcinomas of the esophagus

<p>Abstract</p> <p>Background</p> <p>Glucose regulated proteins (GRPs) are main regulators of cellular homeostasis due to their role as molecular chaperones. Moreover, the functions of GRPs suggest that they also may play important roles in cancer biology. In this study we investigated the glucose regulated proteins GRP78 (BiP) and GRP94 (GP96) in a series of human esophageal adenocarcinomas to determine their implications in cancer progression and prognosis.</p> <p>Methods</p> <p>Formalin-fixed, paraffin-embedded tissues of primary resected esophageal (Barrett) adenocarcinomas (n = 137) and corresponding normal tissue were investigated. mRNA-gene expression levels of GRP78 and GRP94 were determined by quantitative real-time RT-PCR after mRNA extraction. Protein expression analysis was performed with immunohistochemical staining of the cases, assembled on a tissue micorarray. The results were correlated with pathologic features (pT, pN, G) and overall survival.</p> <p>Results</p> <p>GRP78 and GRP94 mRNA were expressed in all tumors. The relative gene expression of GRP78 was significantly higher in early cancers (pT1m and pT1sm) as compared to more advanced stages (pT2 and pT3) and normal tissue (p = 0.031). Highly differentiated tumors showed also higher GRP78 mRNA levels compared to moderate and low differentiated tumors (p = 0.035). In addition, patients with higher GRP78 levels tended to show a survival benefit (p = 0.07). GRP94 mRNA-levels showed no association to pathological features or clinical outcome.</p> <p>GRP78 and GRP94 protein expression was detectable by immunohistochemistry in all tumors. There was a significant correlation between a strong GRP78 protein expression and early tumor stages (pT1m and pT1sm, p = 0.038). For GRP94 low to moderate protein expression was significantly associated with earlier tumor stage (p = 0.001) and less lymph node involvement (p = 0.036). Interestingly, the patients with combined strong GRP78 and GRP94 protein expression exclusively showed either early (pT1m or pT1sm) or advanced (pT3) tumor stages and no pT2 stage (p = 0.031).</p> <p>Conclusion</p> <p>We could demonstrate an association of GRP78 and GRP94 mRNA and protein expression with tumor stage and behaviour in esophageal adenocarcinomas. Increased expression of GRP78 may be responsible for controlling local tumor growth in early tumor stages, while high expression of GRP78 and GRP94 in advanced stages may be dependent from other factors like cellular stress reactions due to glucose deprivation, hypoxia or the hosts' immune response.</p

FOXM1 Induces a Global Methylation Signature That Mimics the Cancer Epigenome in Head and Neck Squamous Cell Carcinoma

The oncogene FOXM1 has been implicated in all major types of human cancer. We recently showed that aberrant FOXM1 expression causes stem cell compartment expansion resulting in the initiation of hyperplasia. We have previously shown that FOXM1 regulates HELLS, a SNF2/helicase involved in DNA methylation, implicating FOXM1 in epigenetic regulation. Here, we have demonstrated using primary normal human oral keratinocytes (NOK) that upregulation of FOXM1 suppressed the tumour suppressor gene p16INK4A (CDKN2A) through promoter hypermethylation. Knockdown of HELLS using siRNA re-activated the mRNA expression of p16INK4A and concomitant downregulation of two DNA methyltransferases DNMT1 and DNMT3B. The dose-dependent upregulation of endogenous FOXM1 (isoform B) expression during tumour progression across a panel of normal primary NOK strains (n = 8), dysplasias (n = 5) and head and neck squamous cell carcinoma (HNSCC) cell lines (n = 11) correlated positively with endogenous expressions of HELLS, BMI1, DNMT1 and DNMT3B and negatively with p16INK4A and involucrin. Bisulfite modification and methylation-specific promoter analysis using absolute quantitative PCR (MS-qPCR) showed that upregulation of FOXM1 significantly induced p16INK4A promoter hypermethylation (10-fold, P<0.05) in primary NOK cells. Using a non-bias genome-wide promoter methylation microarray profiling method, we revealed that aberrant FOXM1 expression in primary NOK induced a global hypomethylation pattern similar to that found in an HNSCC (SCC15) cell line. Following validation experiments using absolute qPCR, we have identified a set of differentially methylated genes, found to be inversely correlated with in vivo mRNA expression levels of clinical HNSCC tumour biopsy samples. This study provided the first evidence, using primary normal human cells and tumour tissues, that aberrant upregulation of FOXM1 orchestrated a DNA methylation signature that mimics the cancer methylome landscape, from which we have identified a unique FOXM1-induced epigenetic signature which may have clinical translational potentials as biomarkers for early cancer screening, diagnostic and/or therapeutic interventions

Unfolded protein response in cancer: the Physician's perspective

The unfolded protein response (UPR) is a cascade of intracellular stress signaling events in response to an accumulation of unfolded or misfolded proteins in the lumen of the endoplasmic reticulum (ER). Cancer cells are often exposed to hypoxia, nutrient starvation, oxidative stress and other metabolic dysregulation that cause ER stress and activation of the UPR. Depending on the duration and degree of ER stress, the UPR can provide either survival signals by activating adaptive and antiapoptotic pathways, or death signals by inducing cell death programs. Sustained induction or repression of UPR pharmacologically may thus have beneficial and therapeutic effects against cancer. In this review, we discuss the basic mechanisms of UPR and highlight the importance of UPR in cancer biology. We also update the UPR-targeted cancer therapeutics currently in clinical trials