Time, hydrologic landscape and the long‐term storage of peatland carbon in sedimentary basins

Peatland carbon may enter long‐term storage in sedimentary basins preserved as either coal or lignite. The time required to account for the carbon in 1 – 10 m thick coal seams must represent 105 to 106 years, an order of magnitude more than previously assumed. To understand the process by which this happens requires extrapolation of our understanding of peatland carbon accumulation over timescales that greatly exceed those of Holocene peat. We analyse the consequences of extrapolating peat growth to periods of 106 years. We deduce that that key to sustained peat growth are hydrologic landscapes that can maintain a saturated peat body above the level of clastic deposition. Contrary to current stratigraphic frameworks we conclude that the generation of accommodation space at low rates of 0.1 to 0.2 mm/yr can adequately accommodate thick peat accumulation over periods >105 yrs. However, generation of accommodation space at rates >0.5 mm/yr cannot. The low rates that permit accommodation of thick peat are typical of the rates of subsidence in specific tectonic settings, particularly foreland basins, and this has implications for our understanding of the links between terrestrial carbon burial, tectonics and the carbon cycle. The long‐term stability of extensive peatland required to form coal also requires sediment bypass, modifying basin wide sediment transport and deposition. Limits to peatland growth under very low accommodation rates must exist but the relative importance of the limiting process is not understood. Finally, we discuss the consequences of these factors for predicting the future of the peatland carbon reservoir

Improving spatial predictability of petroleum resources within the Central Tertiary Basin, Spitsbergen: a geochemical and petrographic study of coals from the eastern and western coalfields

Central Tertiary Basin (CTB) coals from a variety of palaeogeographic conditions within the Longyear and Verkhnij seams, were sampled to assess the relationship between the petroleum present, the remaining generation potential and coal geochemistry in order to improve the spatial predictability of petroleum resources within the basin. Vitrinite reflectance (VR) values from the CTB coals have been shown to be suppressed (Marshall et al., 2015a). This study attempts to quantify and correct for this suppression effect by applying the Lo (1993) method (LoVR), which uses Hydrogen Index (HI) values to modify VR data, and the coal Rank(Sr) scale of Suggate (2000, 2002), a technique not affected by suppression. In addition, the oil generation and expulsion thresholds for the CTB coals were investigated

Inhibition of Chk1 Kills Tetraploid Tumor Cells through a p53-Dependent Pathway

Tetraploidy constitutes an adaptation to stress and an intermediate step between euploidy and aneuploidy in oncogenesis. Tetraploid cells are particularly resistant against genotoxic stress including radiotherapy and chemotherapy. Here, we designed a strategy to preferentially kill tetraploid tumor cells. Depletion of checkpoint kinase-1 (Chk1) by siRNAs, transfection with dominant-negative Chk1 mutants or pharmacological Chk1 inhibition killed tetraploid colon cancer cells yet had minor effects on their diploid counterparts. Chk1 inhibition abolished the spindle assembly checkpoint and caused premature and abnormal mitoses that led to p53 activation and cell death at a higher frequency in tetraploid than in diploid cells. Similarly, abolition of the spindle checkpoint by knockdown of Bub1, BubR1 or Mad2 induced p53-dependent apoptosis of tetraploid cells. Chk1 inhibition reversed the cisplatin resistance of tetraploid cells in vitro and in vivo, in xenografted human cancers. Chk1 inhibition activated p53-regulated transcripts including Puma/BBC3 in tetraploid but not in diploid tumor cells. Altogether, our results demonstrate that, in tetraploid tumor cells, the inhibition of Chk1 sequentially triggers aberrant mitosis, p53 activation and Puma/BBC3-dependent mitochondrial apoptosis

Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model

<p>Abstract</p> <p>Background</p> <p>There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).</p> <p>Methods</p> <p>We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed <it>in vitro</it>. <it>In vivo </it>experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.</p> <p>Results</p> <p>Lapatinib dramatically reduced cell proliferation (<it>P </it>< 0.0001), DNA synthesis (<it>P </it>< 0.006), and colony formation capacity (<it>P </it>< 0.0001) in A549 cells <it>in vitro</it>. Furthermore, lapatinib induced G1 cell cycle arrest (<it>P </it>< 0.0001) and apoptotic cell death (<it>P </it>< 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. <it>In vivo </it>experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (<it>P </it>< 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (<it>P </it>< 0.0001).</p> <p>Conclusion</p> <p>Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.</p

Prognostic impact of vitamin B6 metabolism in lung cancer

Patients with non-small cell lung cancer (NSCLC) are routinely treated with cytotoxic agents such as cisplatin. Through a genome-wide siRNA-based screen, we identified vitamin B6 metabolism as a central regulator of cisplatin responses in vitro and in vivo. By aggravating a bioenergetic catastrophe that involves the depletion of intracellular glutathione, vitamin B6 exacerbates cisplatin-mediated DNA damage, thus sensitizing a large panel of cancer cell lines to apoptosis. Moreover, vitamin B6 sensitizes cancer cells to apoptosis induction by distinct types of physical and chemical stress, including multiple chemotherapeutics. This effect requires pyridoxal kinase (PDXK), the enzyme that generates the bioactive form of vitamin B6. In line with a general role of vitamin B6 in stress responses, low PDXK expression levels were found to be associated with poor disease outcome in two independent cohorts of patients with NSCLC. These results indicate that PDXK expression levels constitute a biomarker for risk stratification among patients with NSCLC.publishedVersio

Divergent Genomic and Epigenomic Landscapes of Lung Cancer Subtypes Underscore the Selection of Different Oncogenic Pathways during Tumor Development

For therapeutic purposes, non-small cell lung cancer (NSCLC) has traditionally been regarded as a single disease. However, recent evidence suggest that the two major subtypes of NSCLC, adenocarcinoma (AC) and squamous cell carcinoma (SqCC) respond differently to both molecular targeted and new generation chemotherapies. Therefore, identifying the molecular differences between these tumor types may impact novel treatment strategy. We performed the first large-scale analysis of 261 primary NSCLC tumors (169 AC and 92 SqCC), integrating genome-wide DNA copy number, methylation and gene expression profiles to identify subtype-specific molecular alterations relevant to new agent design and choice of therapy. Comparison of AC and SqCC genomic and epigenomic landscapes revealed 778 altered genes with corresponding expression changes that are selected during tumor development in a subtype-specific manner. Analysis of >200 additional NSCLCs confirmed that these genes are responsible for driving the differential development and resulting phenotypes of AC and SqCC. Importantly, we identified key oncogenic pathways disrupted in each subtype that likely serve as the basis for their differential tumor biology and clinical outcomes. Downregulation of HNF4α target genes was the most common pathway specific to AC, while SqCC demonstrated disruption of numerous histone modifying enzymes as well as the transcription factor E2F1. In silico screening of candidate therapeutic compounds using subtype-specific pathway components identified HDAC and PI3K inhibitors as potential treatments tailored to lung SqCC. Together, our findings suggest that AC and SqCC develop through distinct pathogenetic pathways that have significant implication in our approach to the clinical management of NSCLC

Africa’s Indian Ocean in Yvette Christiansë’s Unconfessed

Yvette Christianë’s novel Unconfessed approaches the history of slavery at the Cape through the story of Sila, a slave woman incarcerated on Robben Island for the murder of her son Baro. The author’s note at the end of the novel places the narrative within a context of the colonial archive in the form of court records which contain the information that Sila was sentenced to death in 1823 but discovered in a Cape Town gaol by the Superintendent of Police for the Cape Colony in 1825. She was subsequently moved to Robben Island and, through the intervention of the Superintendent, granted a full pardon