Genome-wide characterization reveals complex interplay between TP53 and TP63 in response to genotoxic stress

In response to genotoxic stress the TP53 tumour suppressor activates target gene expression to induce cell cycle arrest or apoptosis depending on the extent of DNA damage. These canonical activities can be repressed by TP63 in normal stratifying epithelia to maintain proliferative capacity or drive proliferation of squamous cell carcinomas, where TP63 is frequently overexpressed/amplified. Here we use ChIP-sequencing, integrated with microarray analysis, to define the genome-wide interplay between TP53 and TP63 in response to genotoxic stress in normal cells. We reveal that TP53 and TP63 bind to overlapping, but distinct cistromes of sites through utilization of distinctive consensus motifs and that TP53 is constitutively bound to a number of sites. We demonstrate that cisplatin and adriamycin elicit distinct effects on TP53 and TP63 binding events, through which TP53 can induce or repress transcription of an extensive network of genes by direct binding and/or modulation of TP63 activity. Collectively, this results in a global TP53-dependent repression of cell cycle progression, mitosis and DNA damage repair concomitant with activation of anti-proliferative and pro-apoptotic canonical target genes. Further analyses reveal that in the absence of genotoxic stress TP63 plays an important role in maintaining expression of DNA repair genes, loss of which results in defective repair.

First comprehensive peat depositional records for tin, lead and copper associated with the antiquity of Europe's largest cassiterite deposits

Tin, as a constituent of bronze, was central to the technological development of early societies, but cassiterite (SnO2) deposits were scarce and located distantly from the centres of Mediterranean civilizations. As Britain had the largest workable ore deposits in the ancient Western world, this has led to much historical speculation and myth regarding the long-distance trading of tin from the Bronze Age onwards. Here we establish the first detailed chronology for tin, along with lead and copper deposition, into undisturbed ombrotrophic (rain-fed) peat bogs located at Bodmin Moor and Dartmoor in the centre of the British tin ore fields. Sustained elevated tin deposition is demonstrated clearly, with peaks occurring at 100-400 and 700-1000 calendar years AD - contemporaneous with the Roman and Anglo-Saxon periods respectively. While pre-Roman Iron Age tin exploitation undoubtedly took place, it was on a scale that did not result in convincingly enhanced deposition of the metal. The deposition of lead in the peat record provides evidence of a pre-Roman metal-based economy in southwest Britain. Emerging in the 4th century BC, this was centred on copper and lead ore processing that expanded exponentially and then collapsed upon Roman colonization during the 1st century AD. (C) 2011 Elsevier Ltd. All rights reserved.

PICan: An integromics framework for dynamic cancer biomarker discovery

Modern cancer research on prognostic and predictive biomarkers demands the integration of established and emerging high-throughput technologies. However, these data are meaningless unless carefully integrated with patient clinical outcome and epidemiological information. Integrated datasets hold the key to discovering new biomarkers and therapeutic targets in cancer. We have developed a novel approach and set of methods for integrating and interrogating phenomic, genomic and clinical data sets to facilitate cancer biomarker discovery and patient stratification. Applied to a known paradigm, the biological and clinical relevance of TP53, PICan was able to recapitulate the known biomarker status and prognostic significance at a DNA, RNA and protein levels.

POU2F1 activity regulates HOXD10 and HOXD11 promoting a proliferative and invasive phenotype in head and neck cancer

HOX genes are master regulators of organ morphogenesis and cell differentiation during embryonic development, and continue to be expressed throughout post-natal life. To test the hypothesis that HOX genes are dysregulated in head and neck squamous cell carcinoma (HNSCC) we defined their expression profile, and investigated the function, transcriptional regulation and clinical relevance of a subset of highly expressed HOXD genes. Two HOXD genes, D10 and D11, showed strikingly high levels in HNSCC cell lines, patient tumor samples and publicly available datasets. Knockdown of HOXD10 in HNSCC cells caused decreased proliferation and invasion, whereas knockdown of HOXD11 reduced only invasion. POU2F1 consensus sequences were identified in the 5' DNA of HOXD10 and D11. Knockdown of POU2F1 significantly reduced expression of HOXD10 and D11 and inhibited HNSCC proliferation. Luciferase reporter constructs of the HOXD10 and D11 promoters confirmed that POU2F1 consensus binding sites are required for optimal promoter activity. Utilizing patient tumor samples a significant association was found between immunohistochemical staining of HOXD10 and both the overall and the disease-specific survival, adding further support that HOXD10 is dysregulated in head and neck cancer. Additional studies are now warranted to fully evaluate HOXD10 as a prognostic tool in head and neck cancers.

Non-invasive ventilation for cystic fibrosis.

Non-invasive ventilation may be a means to temporarily reverse or slow the progression of respiratory failure in cystic fibrosis. To compare the effect of non-invasive ventilation versus no non-invasive ventilation in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches, handsearching relevant journals and abstract books of conference proceedings. We searched the reference lists of each trial for additional publications possibly containing other trials.Most recent search: 22 February 2013. Randomised controlled trials comparing a form of pressure preset or volume preset non-invasive ventilation to no non-invasive ventilation in people with acute or chronic respiratory failure in cystic fibrosis. Three reviewers independently assessed trials for inclusion criteria and methodological quality, and extracted data. Fifteen trials were identified; seven trials met the inclusion criteria with a total of 106 participants. Six trials evaluated single treatment sessions and one evaluated a six-week intervention.Four trials (79 participants) evaluated non-invasive ventilation for airway clearance compared with an alternative chest physiotherapy method and showed that airway clearance may be easier with non-invasive ventilation and people with cystic fibrosis may prefer it. We were unable to find any evidence that NIV increases sputum expectoration, but it did improve some lung function parameters.Three trials (27 participants) evaluated non-invasive ventilation for overnight ventilatory support, measuring lung function, validated quality of life scores and nocturnal transcutaneous carbon dioxide. Due to the small numbers of participants and statistical issues, there were discrepancies in the results between the RevMan and the original trial analyses. No clear differences were found between non-invasive ventilation compared with oxygen or room air except for exercise performance, which significantly improved with non-invasive ventilation compared to room air over six weeks. Non-invasive ventilation may be a useful adjunct to other airway clearance techniques, particularly in people with cystic fibrosis who have difficulty expectorating sputum. Non-invasive ventilation, used in addition to oxygen, may improve gas exchange during sleep to a greater extent than oxygen therapy alone in moderate to severe disease. These benefits of non-invasive ventilation have largely been demonstrated in single treatment sessions with small numbers of participants. The impact of this therapy on pulmonary exacerbations and disease progression remain unclear. There is a need for long-term randomised controlled trials which are adequately powered to determine the clinical effects of non-invasive ventilation in cystic fibrosis airway clearance and exercise.

Victorius vs Dionysius: the Irish Easter controversy of AD 689

Over the past few decades, the early medieval Easter controversy has increasingly been portrayed as a conflict between the ‘Celtic’ and the ‘Roman’ churches, limiting the geographical extent of this most vibrant debate to Britain and Ireland (with the exception of the disputes caused by Columbanus’ appearance on the Continent). Both are not the case. Before c.AD 800, there was no unanimity within the ‘Roman’ cause. Two ‘Roman’ Easter reckonings existed, which could not be reconciled, one invented by Victorius of Aquitaine in AD 457, the other being the Alexandrian system as translated into Latin by Dionysius Exiguus in AD 525. The conflict between followers of Victorius and adherents of Dionysius occurred in Visigothic Spain first, reached Ireland in the second half of the 7th century, and finally dominated the intellectual debate in Francia in the 8th century. This article will focus on the Irish dimension of this controversy. It is argued that the southern Irish clergy introduced the Victorian reckoning in the AD 630s and strictly adhered to that system until the end of the 7th century. When Adomnan, the abbot of Iona, converted to Dionysius in the late AD 680s and convinced most of the northern Irish churches to follow his example, this caused considerable tension with southern Irish followers of Victorius, as is impressively witnessed by the computistical literature of the time, especially the texts produced in AD 689. From this literature, the issues debated at the time are reconstructed. This analysis has serious consequences for how we read Irish history towards the end of the 7th century; rather than bringing the formerly ‘Celtic’ northern Irish clergy in line with southern Irish ‘Roman’ practise, Adomnan added a new dimension to the conflict.

Phytoplankton and microbial plankton of the Bay of Biscay and Western Iberian Shelf

The region of the Northeast Atlantic represents a gradient between two oceanographic regimes: (i) the subtropical waters of southern Portugal and southwestern Spain, and (ii) the temperate waters characterizing the northwestern and northern Iberian coasts (Cantabrian Sea) and the rest of the Bay of Biscay along the French coast.

Genome-wide Association Study Identifies SESTD1 as a Novel Risk Gene for Lithium Responsive Bipolar Disorder

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10-8). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.