Defining the molecular pathology of pancreatic body and tail adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing.

Individuals from three families ascertained in Bogota, Colombia, showing syndromic phenotypes, including cleft lip and/or palate, were exome-sequenced. In each case, sequencing revealed the underlying causal variation confirming or establishing diagnoses. The findings include very rare and novel variants providing insights into genotype and phenotype relationships. These include the molecular diagnosis of an individual with Nager syndrome and a family exhibiting an atypical incontinentia pigmenti phenotype with a missense mutation in IKBKG. IKBKG mutations are typically associated with preterm male death, but this variant is associated with survival for 8-15 days. The third family exhibits unusual phenotypic features and the proband received a provisional diagnosis of Pierre Robin sequence (PRS). Affected individuals share a novel deleterious mutation in IRF6. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndrome and contribute to nonsyndromic cleft lip phenotypes but have not previously been associated with a PRS phenotype. Exome sequencing followed by in silico screening to identify candidate causal variant(s), and functional assay in some cases offers a powerful route to establishing molecular diagnoses. This approach is invaluable for conditions showing phenotypic and/or genetic heterogeneity including cleft lip and/or palate phenotypes where many underlying causal genes have not been identified.

Methane and nitrous oxide fluxes in the polluted Adyar River and estuary, SE India.

We measured dissolved N(2)O, CH(4), O(2), NH(4)(+), NO(3)(-) and NO(2)(-) on 7 transects along the polluted Adyar River-estuary, SE India and estimated N(2)O and CH(4) emissions using a gas exchange relation and a floating chamber. High NO(2)(-) implied some nitrification of a large anthropogenic NH(4)(+) pool. In the lower catchment CH(4) was maximal (6.3+/-4.3 x 10(4)nM), exceeding the ebullition threshold, whereas strong undersaturation of N(2)O and O(2) implied intense denitrification. Emissions fluxes for the whole Adyar system approximately 2.5 x 10(8) g CH(4)yr(-1) and approximately 2.4 x 10(6)gN(2)O yr(-1) estimated with a gas exchange relation and approximately 2 x 10(9) g CH(4)yr(-1) derived with a floating chamber illustrate the importance of CH(4) ebullition. An equivalent CO(2) flux approximately 1-10 x 10(10)gy r(-1) derived using global warming potentials is equivalent to total Chennai motor vehicle CO(2) emissions in one month. Studies such as this may inform more effective waste management and future compliance with international emissions agreements.

Simulating estuarine nitrous oxide production by means of a dynamic model.

We describe a dynamic model developed from a commercially available modeling package (ECoS-III) to simulate estuarine dissolved inorganic nitrogen (DIN) dynamics, and consequent N(2)O production and atmospheric flux on the timescale of tidal cycles. Simulated model state variables were NH(4)(+), NO(3)(-) and N(2)O concentrations, and salinity. Model outputs were evaluated through comparison with summer field data for the Tyne estuary, UK. The model adequately reproduced the observed axial profiles of NH(4)(+), NO(3)(-) and N(2)O concentrations. Nitrification was shown to be the dominant N(2)O source and estimates of the ratios nitrification to DIN load and N(2)O emission to DIN load are considerably lower than the corresponding values adopted in global scale models of estuarine N(2)O emissions based on DIN transformations. Hence our results are consistent with the requirement imposed by atmospheric N(2)O growth rate constraints that the amount of atmospheric N(2)O arising from agriculturally related sources, including estuarine transformations of N, be revised downward.