Biogenic Tracers Through the Holocene on the Alaskan Shelf

Dramatic environmental changes in the Arctic Ocean have been observed for the last two decades including changing the amount of sea ice thickness and extent, and increased river discharge. In order to put these and other current day observations into historical context and perhaps reveal mechanisms controlling them, a suite of paleo-proxies were used to analyze two high resolution cores collected on the 2005 HOTRAX expedition. The goals of this research were: (1) develop an analytical method for determining biogenic calcite, (2) identify the major sources of biogenic matter into the system over the Holocene, and (3) assemble the history of depositional events that have occurred in the Alaskan shelf over the Holocene. The C/N and δ13C in the very earliest record at Station 5, 12,000 ybp, suggest marine conditions prior to the inundation of glacial outwash and terrestrial organic matter. From 12,000 to 9600 ybp abundant amounts of terrestrially-derived materials were delivered to the Alaskan shelf, confirmed by dolomite, high C/N ratios, heavy δ13C signatures, and low sulfur. Immediately following these terrestrial inputs, a thousand year transition period re-established marine conditions like those found in the late Holocene. In the mid-Holocene, 6000–1000 ybp, increased concentrations of pyrite occurred at this time because enough labile organic matter was deposited for anoxic conditions to occur, and sufficient amounts of sulfate and iron were available. The most recent record, 1000 ybp to present, shows much different biogeochemical conditions than in the mid to early Holocene, organic carbon concentrations are 50% higher, but anoxic conditions do not appear to be present likely due to high amounts of bioturbation, enhancing oxygen penetration into the upper sediments. In terms of the marine sources of organic matter in the mid and late Holocene, their origin appears to be diatoms or other siliceous organisms. The recent observations of cocolithophores in the Bering Sea suggest that other phytoplankton species could be present in high latitude waters, but they were not found in the Holocene records examined here. With respect to other environmental changes occurring in the Arctic at present, it will interesting to see if increased river discharges shift the Alaskan shelf to a more terrestrially-dominated system as seen in the earliest Holocene

Significance of Population Centers As Sources of Gaseous and Dissolved PAHs in the Lower Great Lakes

Polyethylene passive samplers (PEs) were used to measure concentrations of gaseous and dissolved polycyclic aromatic hydrocarbons (PAHs) in the air and water throughout the lower Great Lakesduring summer and fall of 2011. Atmospheric Σ15PAH­ concentrations ranged from 2.1 ng/m3 in Cape Vincent (NY) to 76.4 ng/m3 in downtown Cleveland (OH). Aqueous Σ18PAH concentrations ranged from 2.4 ng/L at an offshoreLake Erie site to 30.4 ng/L in Sheffield Lake (OH). Gaseous PAH concentrations correlated strongly with population within 3-40 km of the sampling site depending on the compound considered, suggesting that urban centers are a primary source of gaseous PAHs (except retene) in the lowerGreat Lakes region. The significance of distant population (within 20 km) versus local population (within 3 km) increased with sub-cooled liquid vapor pressure. Most dissolved aqueous PAHs did not correlate significantly with population, nor were they consistently related to river discharge, wastewater effluents, or precipitation. Air-water exchange calculations implied that diffusive exchange was a source of phenanthrene to surface waters, while acenaphthylene volatilized out of the lakes. Comparison of air-water fluxes with temperature suggested that the significance of urban centers as sources of dissolved PAHs via diffusive exchange may decrease in warmer months

A Hindbrain Inhibitory Microcircuit Mediates Vagally-Coordinated Glucose Regulation

Neurons in the brainstem dorsal vagal complex integrate neural and humoral signals to coordinate autonomic output to viscera that regulate a variety of physiological functions, but how this circuitry regulates metabolism is murky. We tested the hypothesis that premotor, GABAergic neurons in the nucleus tractus solitarius (NTS) form a hindbrain micro-circuit with preganglionic parasympathetic motorneurons of the dorsal motor nucleus of the vagus (DMV) that is capable of modulating systemic blood glucose concentration. In vitro, neuronal activation or inhibition using either excitatory or inhibitory designer receptor exclusively activated by designer drugs (DREADDs) constructs expressed in GABAergic NTS neurons increased or decreased, respectively, action potential firing of GABAergic NTS neurons and downstream synaptic inhibition of the DMV. In vivo, DREADD-mediated activation of GABAergic NTS neurons increased systemic blood glucose concentration, whereas DREADD-mediated silencing of these neurons was without effect. The DREADD-induced hyperglycemia was abolished by blocking peripheral muscarinic receptors, consistent with the hypothesis that altered parasympathetic drive mediated the response. This effect was paralleled by elevated serum glucagon and hepatic phosphoenolpyruvate carboxykinase 1 (PEPCK1) expression, without affecting insulin levels or muscle metabolism. Activity in a hindbrain inhibitory microcircuit is sufficient to modulate systemic glucose concentration, independent of insulin secretion or utilization

Clinical significance of circulating anti-p53 antibodies in European patients with hepatocellular carcinoma

p53 alterations are considered to be predictive of poor prognosis in hepatocellular carcinoma (HCC) and may induce a humoral response. Anti-p53 serum antibodies were assessed by enzyme-linked immunosorbent assay (ELISA) using purified recombinant human p53 on 130 European HCC patients before treatment and during the clinical course of the disease. p53 immunohistochemistry was performed on tumours from the 52 patients who underwent surgery, and DNA sequencing analysis was initiated when circulating anti-p53 antibodies were detected. Nine (7%) HCC patients had anti-p53 serum antibodies before treatment. During a mean period of 30 months of follow-up, all the negative patients remained negative, even when recurrence was observed. Of the nine positive patients, eight were still positive 12–30 months after surgery. The presence of anti-p53 serum antibodies was correlated neither with mutation of the p53 gene nor the serum alpha-fetoprotein levels and clinicopathological characterics of the tumours. However, a greater incidence of vascular invasion and accumulation of p53 protein were observed in the tumours of these patients (P < 0.03 and P < 0.01 respectively) as well as a better survival rate without recurrence (P = 0.05). In conclusion, as was recently shown in pancreatic cancer, anti-p53 serum antibodies may constitute a marker of relative ‘good prognosis’ in a subgroup of patients exhibiting one or several markers traditionally thought to be of bad prognosis. © 1999 Cancer Research Campaig

Differential Carbohydrate Recognition by Campylobacter jejuni Strain 11168: Influences of Temperature and Growth Conditions

The pathogenic clinical strain NCTC11168 was the first Campylobacter jejuni strain to be sequenced and has been a widely used laboratory model for studying C. jejuni pathogenesis. However, continuous passaging of C. jejuni NCTC11168 has been shown to dramatically affect its colonisation potential. Glycan array analysis was performed on C. jejuni NCTC11168 using the frequently passaged, non-colonising, genome sequenced (11168-GS) and the infrequently passaged, original, virulent (11168-O) isolates grown or maintained under various conditions. Glycan structures recognised and bound by C. jejuni included terminal mannose, N-acetylneuraminic acid, galactose and fucose. Significantly, it was found that only when challenged with normal oxygen at room temperature did 11168-O consistently bind to sialic acid or terminal mannose structures, while 11168-GS bound these structures regardless of growth/maintenance conditions. Further, binding of un-capped galactose and fucosylated structures was significantly reduced when C. jejuni was maintained at 25°C under atmospheric oxygen conditions. These binding differences identified through glycan array analysis were confirmed by the ability of specific lectins to competitively inhibit the adherence of C. jejuni to a Caco-2 intestinal cell line. Our data suggests that the binding of mannose and/or N-acetylneuraminic acid may provide the initial interactions important for colonisation following environmental exposure

RADVAN: a randomised phase 2 trial of WBRT plus vandetanib for melanoma brain metastases - results and lessons learnt

BACKGROUND: Brain metastases occur in up to 75% of patients with advanced melanoma. Most are treated with whole-brain radiotherapy (WBRT), with limited effectiveness. Vandetanib, an inhibitor of vascular endothelial growth factor receptor, epidermal growth factor receptor and rearranged during transfection tyrosine kinases, is a potent radiosensitiser in xenograft models. We compared WBRT with WBRT plus vandetanib in the treatment of patients with melanoma brain metastases. METHODS: In this double-blind, multi-centre, phase 2 trial patients with melanoma brain metastases were randomised to receive WBRT (30 Gy in 10 fractions) plus 3 weeks of concurrent vandetanib 100 mg once daily or placebo. The primary endpoint was progression-free survival in brain (PFS brain). The main study was preceded by a safety run-in phase to confirm tolerability of the combination. A post-hoc analysis and literature review considered barriers to recruiting patients with melanoma brain metastases to clinical trials. RESULTS: Twenty-four patients were recruited, six to the safety phase and 18 to the randomised phase. The study closed early due to poor recruitment. Median PFS brain was 3.3 months (90% confidence interval (CI): 1.6-5.6) in the vandetanib group and 2.5 months (90% CI: 0.2-4.8) in the placebo group (P=0.34). Median overall survival (OS) was 4.6 months (90% CI: 1.6-6.3) and 2.5 months (90% CI: 0.2-7.2), respectively (P=0.54). The most frequent adverse events were fatigue, alopecia, confusion and nausea. The most common barrier to study recruitment was availability of alternative treatments. CONCLUSIONS: The combination of WBRT plus vandetanib was well tolerated. Compared with WBRT alone, there was no significant improvement in PFS brain or OS, although we are unable to provide a definitive result due to poor accrual. A review of barriers to trial accrual identified several factors that affect study recruitment in this difficult disease area