Carbon isotope alteration during the thermal maturation of non-flowering plant species representative of those found within the geological record

Rationale The carbon isotope (δ13C value) composition of fossil plant material is routinely used as a proxy of past climate and environment change. However, palaeoclimate interpretation requires assumptions about the stability of δ13C values in plant material during its decomposition and incorporation into sediments. Previous work on modern angiosperm species shows δ13C changes of several per mille during simulated decomposition experiments. However, no such tests have been undertaken on non-flowering plants, which are found extensively within the geological record. These plants have distinctly different cellulose-to-lignin ratios from those of their angiosperm counterparts, potentially creating hitherto unknown variations in the original to fossil δ13C signatures. Methods To test the extent of δ13C change during decomposition we have subjected a number of plants, representing more basal, non-flowering plant lineages (cycads, ferns, horsetails and dawn redwood), to artificial decay using a hydrothermal maturation technique at two temperatures over periods of up to 273 hours. Subsamples were extracted every 12–16 hours and analysed for their δ13C and %C values using a Carlo Erba 1500 elemental analyser, and VG TripleTrap and Optima mass spectrometers. Results The %C values increased for all samples through the maturation process at both temperatures with the largest increases observed within the first 24 hours. Decreases in δ13C values were observed for all plants at 300°C and for two of the species at the lower temperature (200°C). The maximum shift in the δ13C value related to experimental decomposition was −0.90‰ (horsetail), indicating a preferential loss of 13C during thermal maturation. Conclusions The reduction in the δ13C value potentially suggests a preferential loss of isotopically heavier cellulose in relation to the isotopically lighter lignin component during maturation. The isotopic offset observed here (<0.9‰) means that palaeoclimatic interpretation of δ13C values from non-flowering plant material within the geological record remains robust, but only where interpretations are based on variations in δ13C values greater than 1

Perception versus reality: A National Cohort Analysis of the surgery-first approach for resectable pancreatic cancer

INTRODUCTION: Although surgical resection is necessary, it is not sufficient for long-term survival in pancreatic ductal adenocarcinoma (PDAC). We sought to evaluate survival after up-front surgery (UFS) in anatomically resectable PDAC in the context of three critical factors: (A) margin status; (B) CA19-9; and (C) receipt of adjuvant chemotherapy. METHODS: The National Cancer Data Base (2010-2015) was reviewed for clinically resectable (stage 0/I/II) PDAC patients. Surgical margins, pre-operative CA19-9, and receipt of adjuvant chemotherapy were evaluated. Patient overall survival was stratified based on these factors and their respective combinations. Outcomes after UFS were compared to equivalently staged patients after neoadjuvant chemotherapy on an intention-to-treat (ITT) basis. RESULTS: Twelve thousand and eighty-nine patients were included (n = 9197 UFS, n = 2892 ITT neoadjuvant). In the UFS cohort, only 20.4% had all three factors (median OS = 31.2 months). Nearly 1/3rd (32.7%) of UFS patients had none or only one factor with concomitant worst survival (median OS = 14.7 months). Survival after UFS decreased with each failing factor (two factors: 23 months, one factor: 15.5 months, no factors: 7.9 months) and this persisted after adjustment. Overall survival was superior in the ITT-neoadjuvant cohort (27.9 vs. 22 months) to UFS. CONCLUSION: Despite the perceived benefit of UFS, only 1-in-5 UFS patients actually realize maximal survival when known factors highly associated with outcomes are assessed. Patients are proportionally more likely to do worst, rather than best after UFS treatment. Similarly staged patients undergoing ITT-neoadjuvant therapy achieve survival superior to the majority of UFS patients. Patients and providers should be aware of the false perception of \u27optimal\u27 survival benefit with UFS in anatomically resectable PDAC

Rate-dependence of the compressive and tensile strength of granites

The strength and rupture of geomaterials are integral to subsurface engineering practices, such as those required to optimise geothermal energy extraction. Of particular importance is the time- and strain-rate-dependence of material strength, which dictates the energy released upon failure, and impacts the magnitude of induced seismicity, fracture architecture and thus hydraulic conductivity and system permeability. Here, we performed a series of uniaxial compression and Brazilian tensile strength measurements at a range of deformation rates in order to constrain the impact of strain rate on the strength of G603 granite. The dense, low permeability, medium-grained granites were mechanically tested at 4 strain rates (or diametric equivalent strain rates in the case of Brazilian tests) from 10−5 to 10−2 s−1, such that sample failure was achieved in anything from below 1s at the fastest rate in tension, to over 1000s at the slowest rate in compression. The applied rates encompassed those recommended by ISRM and ASTM material testing standards for compressive and Brazilian tensile testing. We found a significant rate strengthening effect, whereby compressive and tensile strength both increased by approximately 35 % across the 4 orders of magnitude of strain rate tested. We found that the static Young's modulus remained relatively constant across this range of deformation rates, however variability was reduced at faster rates, owing to the reduced time for equilibration of the system to imposed stresses. The lower strength at slower strain rates causes smaller stress drops, indicating that rocks driven to compressive and tensile failure at slower rates release less energy upon failure. Such constraints of the strain-rate-dependence of material strength, in contrast to the use of standardised material characteristics conventionally used in Engineering Geology applications, will prove useful as we develop increasingly sophisticated strategies such as cyclic soft stimulation to access resources using less energy, whilst reducing environmental risk and producing less waste

Process evaluation for complex interventions in primary care: understanding trials using the normalization process model

Background: the Normalization Process Model is a conceptual tool intended to assist in understanding the factors that affect implementation processes in clinical trials and other evaluations of complex interventions. It focuses on the ways that the implementation of complex interventions is shaped by problems of workability and integration.Method: in this paper the model is applied to two different complex trials: (i) the delivery of problem solving therapies for psychosocial distress, and (ii) the delivery of nurse-led clinics for heart failure treatment in primary care.Results: application of the model shows how process evaluations need to focus on more than the immediate contexts in which trial outcomes are generated. Problems relating to intervention workability and integration also need to be understood. The model may be used effectively to explain the implementation process in trials of complex interventions.Conclusion: the model invites evaluators to attend equally to considering how a complex intervention interacts with existing patterns of service organization, professional practice, and professional-patient interaction. The justification for this may be found in the abundance of reports of clinical effectiveness for interventions that have little hope of being implemented in real healthcare setting

Clinical quantification of the integrin αvβ6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study)

© 2019, The Author(s). Purpose: The RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [18F]FB-A20FMDV2 PET ligand. Methods: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvβ6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvβ6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. Results: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. Conclusions: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvβ6, was markedly increased in subjects with PF compared with healthy subjects

Influence of the ratio of planktonic to benthic diatoms on lacustrine organic matter δ13C from Erlongwan maar lake, northeast China

Carbon isotope ratio (δ13Corg) values of organic matter in lake sediments are commonly used to reconstruct environmental change, but the factors which influence change are varied and complex. Here we report δ13C values for sediments from Erlongwan maar lake in northeast China. In this record, changes in δ13C cannot be explained by simple changes in aquatic productivity. Instead, values were likely influenced by differences in the ratio between planktonic and benthic algae, as indicated by the remains of diatoms. This is because the variation of δ13Corg in algae from different habitats is controlled by the thickness of the diffusive boundary layer, which is dependent on the turbulence of the water. Compared with benthic algae, which grow in relatively still water, pelagic algae are exposed to greater water movement. This is known to dramatically reduce the thickness of the boundary layer and was found to cause even more severe δ13C depletion. In Erlongwan maar lake, low values were linked to the dominance of planktonic diatoms during the period commonly known as the Medieval Warm Period. Values gradually increased with the onset of the Little Ice Age, which we interpret as being driven by an increase in the proportion of benthic taxa, due to effect of the colder climate. The increase in planktonic diatoms at the end of the Little Ice Age, linked to higher temperature and a reduction in ice cover, resulted in a further decline in δ13Corg

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment