Urinary Neutrophil Gelatinase-Associated Lipocalin Measured on Admission to the Intensive Care Unit Accurately Discriminates between Sustained and Transient Acute Kidney Injury in Adult Critically Ill Patients

Background: First we aimed to evaluate the ability of neutrophil gelatinase-associated lipocalin (NGAL) and cystatin-C (CyC) in plasma and urine to discriminate between sustained, transient and absent acute kidney injury (AKI), and second to evaluate their predictive performance for sustained AKI in adult intensive care unit (ICU) patients. Methods: A prospective cohort study of 700 patients was studied. Sample collection was performed over 8 time points starting on admission. Results: After exclusion 510 patients remained for the analysis. All biomarkers showed significant differentiation between sustained and no AKI at all time points (p ≤ 0.0002) except for urine CyC (uCyC) on admission (p = 0.06). Urine NGAL (uNGAL) was the only biomarker significantly differentiating sustained from transient AKI on ICU admission (p = 0.02). Individually, uNGAL performed better than the other biomarkers (area under the curves, AUC = 0.80, 95% confidence interval, CI = 0.72–0.88) for the prediction of sustained AKI. The combination with plasma NGAL (pNGAL) showed a nonsignificant improvement (AUC = 0.83, 95% CI = 0.75–0.91). The combination of individual markers with a model of clinical characteristics (MDRD eGFR, HCO3– and sepsis) did not improve its performance significantly. However, the integrated discrimination improvement showed significant improvement when uNGAL was added (p = 0.04). Conclusions: uNGAL measured on ICU admission differentiates patients with sustained AKI from transient or no-AKI patients. Combining biomarkers such as pNGAL, uNGAL and plasma CyC with clinical characteristics adds some value to the predictive model

The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1. Arterial flow regulates artery diameter but other mechanisms may also affect this. Here, the authors show that the guanine nucleotide exchange factor Trio and GTPases Rac1 and RhoG, triggers F-actin remodeling in arterial endothelial cells, independent of flow, to enhance lumen diameter in zebrafish and cell models.Peer reviewe

Long non-coding RNA LASSIE regulates shear stress sensing and endothelial barrier function

Blood vessels are constantly exposed to shear stress, a biomechanical force generated by blood flow. Normal shear stress sensing and barrier function are crucial for vascular homeostasis and are controlled by adherens junctions (AJs). Here we show that AJs are stabilized by the shear stress-induced long non-coding RNA LASSIE (linc00520). Silencing of LASSIE in endothelial cells impairs cell survival, cell-cell contacts and cell alignment in the direction of flow. LASSIE associates with junction proteins (e.g. PECAM-1) and the intermediate filament protein nestin, as identified by RNA affinity purification. The AJs component VE-cadherin showed decreased stabilization, due to reduced interaction with nestin and the microtubule cytoskeleton in the absence of LASSIE. This study identifies LASSIE as link between nestin and VE-cadherin, and describes nestin as crucial component in the endothelial response to shear stress. Furthermore, this study indicates that LASSIE regulates barrier function by connecting AJs to the cytoskeleton

Dynamic flow synthesis of porous organic cages

The dynamic covalent synthesis of two imine-based porous organic cages was successfully transferred from batch to continuous flow. The same flow reactor was then used to scramble the constituents of these two cages in differing ratios to form cage mixtures. Preparative HPLC purification of one of these mixtures allowed rapid access to a desymmetrised cage molecule.We thank the Engineering and Physical Sciences Research Council (EPSRC) for financial support under the Grants EP/H000925/1 (AIC), EP/K009494/1 (SVL) and EP/M004120/1 (SVL), and Pfizer Worldwide Research & Development (CB). The authors would like to thank EPSRC Dial-a-Molecule Grand Challenge Network (EP/K004840/1) for funding a placement with SVL via the Interdisciplinary Mobility Funding scheme (AGS).This is the author accepted manuscript. The final version is available from RSC via http://dx.doi.org/10.1039/C5CC07447

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Sodium bicarbonate prophylactic therapy in the prevention of contrast-induced nephropathy in patients admitted to the intensive care unit of a teaching hospital: a retrospective cohort study

BACKGROUND: Intravenously administered iodine-containing contrast medium (CM) is associated with the development of contrast-induced nephropathy (CIN). Data on the effectiveness of sodium bicarbonate therapy in the prevention of CIN are controversial. Furthermore, the incidence of and risk factors for CIN in intensive care unit (ICU) patients are poorly defined. We investigated the effectiveness of sodium bicarbonate prophylaxis and the incidence of and risk factors for CIN in a heterogeneous ICU population. METHODS: This retrospective cohort study included patients admitted to the ICU in 2009–2011 who received CM for computed tomography (CT). RESULTS: Two hundred eleven CT scans with CM, performed in 170 patients, were included in the study. Contrast prophylaxis with sodium bicarbonate was administered in 48 of the 211 cases. CIN developed in 19 of the 48 cases receiving prophylaxis and in 39 of 163 cases not receiving prophylaxis (p = 0.03). In 115 CTs performed in patients with a glomerular filtration rate (GFR) >60 mL/min, prophylaxis was administered 15 times (13 %) and no prophylaxis was administered 100 times (87 %). CIN developed in 12 and 13 % of these cases, respectively (NS). In 96 CTs in patients with a GFR <60 mL/min, 17 of 33 (51.5 %) cases receiving prophylaxis developed CIN and 27 of 63 (42.9 %) cases not receiving prophylaxis developed CIN (NS). Prophylactic sodium bicarbonate therapy did not prevent CIN in our patients, irrespective of pre-existing renal failure. Pre-existing renal impairment (odds ratio 4.41), an elevated Acute Physiology and Chronic Health Evaluation (APACHE) IV score (odds ratio 1.02), and higher haemoglobin levels (odds ratio 0.64) were significant and independent risk factors associated with the development of CIN. CONCLUSIONS: Prophylactic isotonic sodium bicarbonate was not associated with a decreased incidence of CIN in ICU patients. Current sodium bicarbonate prophylaxis guidelines cannot be generalized to a heterogeneous ICU population. Pre-existing renal impairment was associated with the highest CIN risk