Tracing tetraether lipids from source to sink in the Rhône River system (NW Mediterranean)

In this study, we investigated soils and river suspended particulate matter (SPM) collected in the Rhône and its tributary basins as well as marine surface sediments taken in the Rhône prodelta (Gulf of Lions, NW Mediterranean). Thereby, we traced the signal of branched glycerol dialkyl glycerol tetraethers (brGDGTs) from the source to sink via the Rhône River and its tributaries and identified sources of brGDGTs in rivers and marine sediments. Soil pH rather than the mean annual air temperature (MAAT) explains most of the observed variances of the brGDGT distribution in our soil dataset. The observed changes in the distribution of brGDGTs in the river SPM indicate that brGDGTs brought by the river to the sea are primarily derived from the lower Rhône and its tributary soils, even though in situ production in the river itself cannot be excluded. In marine surface sediments, it appears that the input of riverine brGDGTs is the primary source of brGDGTs in the Rhône prodelta, although the brGDGT composition may be further modified by the in situ production in the marine environment. More work is required to assess fully whether brGDGTs can be used to reconstruct the terrestrial paleoenvironmental changes using marine sediment cores taken in the Rhône prodelta close to the river mouth

Distribution and lability of land-derived organic matter in the surface sediments of the Rhône prodelta and the adjacent shelf (Mediterranean Sea, France): a multi proxy study

The Gulf of Lions is a river-dominated ocean margin that receives high loads of nutrients and particulate matter from the Rhône River but most particulate materials settle rapidly on the nearshore seafloor. One question is raised on the fate of these large quantities of organic carbon delivered by the river to the coastal marine environment. Surface sediments (0–0.5 cm) were collected in the Rhône prodelta and its adjacent shelf during a period of low river discharge (April 2007, 16 stations). The sources, distribution and lability of sedimentary organic matter were examined using bulk (organic carbon, total nitrogen, stable carbon isotope ratios, and grain size) and molecular-level (pigments, amino acids, fatty acids, and δ<sup>13</sup>C of individual fatty acids) analyses. Our results confirmed previous observations of a southwestward Rhodanian imprint in the nearshore sediments, with 97% of terrigenous inputs of organic matter near the river mouth. Isotopic values of bulk organic carbon, as well as fatty acid biomarkers and compound-specific δ<sup>13</sup>C signatures of most fatty acids clearly indicate that the Rhône inputs consist of a mixture of organic matter (OM) from different origins with a strong contribution from terrestrial sources (soil and plant debris), and a smaller input from freshwater microalgae, mostly diatoms. The influence of the Rhône River was prominent within the first ten kilometers, but may still be observed on the outer shelf (~21 km) as indicated by the occurrence of long chain fatty acids, which are derived from vascular plants, and their δ<sup>13</sup>C signatures. In the proximal prodelta, bacteria-specific fatty acids were abundant (1.65 mg g<sup>−1</sup> OC at the mouth site) and were relatively depleted in δ<sup>13</sup>C confirming that bacteria mostly utilize land-derived OM. In the shelf area, the inputs of marine OM and its predominant utilization by the bacteria was confirmed, but the coupling between the pelagic and the benthic compartments appeared limited at this period of the year. <br><br> Overall, degradation indexes based on amino acids (Dauwe's degradation index) and pigments (ratio of intact chlorophyll-<I>a</I> to the sum of chlorophyll-<I>a</I> + phaeopigment-<I>a</I>), as well as isotopic enrichment of source-specific fatty acids reveal an offshore gradient of OM decay reflecting the rapid deposition of the terrestrial material in the prodelta, the low mixing with OM deriving from marine sources and the efficient degradation of the OM. The OM delivered by the Rhône is relatively labile based on the intermediary value of Dauwe's degradation index, the high proportion of bio-available nitrogen and the occurrence of polyunsaturated fatty acids. Deltaic sediments off the Rhône River should thus be of sufficiently high nutritional quality to sustain dense macrofaunal communities

Temporal variability of live (stained) benthic foraminiferal faunas in a river-dominated shelf – Faunal response to rapid changes of the river influence (Rhône prodelta, NW Mediterranean)

In the context of the French research project CHACCRA (Climate and Human-induced Alterations in Carbon Cycling at the River-seA connection), living (rose Bengal-stained) benthic foraminifera were investigated at two stations (24 and 67 m depth) in the Rhône prodelta (NW Mediterranean, Gulf of Lions). The aim of this study was to precise the response of benthic foraminiferal faunas to temporal changes of the Rhône River inputs (e.g. organic and terrigeneous material). Each site was sampled in April 2007, September 2007, May 2008 and December 2008, permitting to observe foraminiferal faunas of the 63–150 and >150 μm size fractions under a wide range of environmental conditions. Obvious variations in foraminiferal faunal composition were observed during the four investigated periods at the shallowest Station A located in the close vicinity of the Rhône River mouth. After major Rhône River flood events, different colonisation stages were observed with foraminiferal faunas responding with an opportunistic strategy few days to weeks after the creation of a peculiar sedimentary environment (<i>Leptohalysis scottii</i>, May 2008) or high organic matter supplies (<i>Ammonia tepida</i>, December 2008). Under more stable conditions, relatively diverse and equilibrated faunas grew in the sediments. Species benefited from noticeable input of riverine phytodetritus to the sediment during spring bloom conditions (April 2007; e.g. <i>Bolivina dilatata</i>, <i>Nonionella stella</i>, <i>Stainforthia fusiformis</i>), or high amounts of still bio-available organic matter under more oligotrophic conditions (September 2007; e.g. <i>Ammonia tepida</i>, <i>Psammosphaera fusca</i>). The reduced influence of the Rhône River input at the farther Station N led to less contrasted environmental conditions during the four sampling periods, and so to less obvious variations in foraminiferal faunal composition. During reduced riverine influence (i.e. low Rhône discharge), species able to feed on fresh phytodetritus (e.g. <i>Clavulina cylindrica</i>, <i>Hopkinsina atlantica</i>, <i>Nonionella iridea</i> and <i>Nonionella turgida</i>) benefited from eutrophic conditions of the spring bloom (April 2007, May 2008). Conversely, the occurrence of <i>Nouria polymorphinoides</i> under oligotrophic conditions (September 2007, December 2008) was indicative of a benthic environment potentially disturbed by bottom currents. This study put into evidence the extremely rapid response of benthic foraminiferal faunas to strong variations in environmental conditions mostly induced by the Rhône dynamics

Use of H19 Gene Regulatory Sequences in DNA-Based Therapy for Pancreatic Cancer

Pancreatic cancer is the eighth most common cause of death from cancer in the world, for which palliative treatments are not effective and frequently accompanied by severe side effects. We propose a DNA-based therapy for pancreatic cancer using a nonviral vector, expressing the diphtheria toxin A chain under the control of the H19 gene regulatory sequences. The H19 gene is an oncofetal RNA expressed during embryo development and in several types of cancer. We tested the expression of H19 gene in patients, and found that 65% of human pancreatic tumors analyzed showed moderated to strong expression of the gene. In vitro experiments showed that the vector was effective in reducing Luciferase protein activity on pancreatic carcinoma cell lines. In vivo experiment results revealed tumor growth arrest in different animal models for pancreatic cancer. Differences in tumor size between control and treated groups reached a 75% in the heterotopic model (P = .037) and 50% in the orthotopic model (P = .007). In addition, no visible metastases were found in the treated group of the orthotopic model. These results indicate that the treatment with the vector DTA-H19 might be a viable new therapeutic option for patients with unresectable pancreatic cancer

Live (stained) benthic foraminifera from the Cap-Ferret Canyon (Bay of Biscay, NE Atlantic): A comparison between the canyon axis and the surrounding areas

Living (Rose Bengal stained) benthic foraminiferal faunas were investigated at 13 deep-sea stations sampled in the Cap-Ferret Canyon area (NE Atlantic). One station (151 m) is located on the continental shelf close to the canyon head. All other stations are located along 2 bathymetric transects: 7 sites along the canyon axis with depths ranging from 300 to 3000 m and 5 stations along the adjacent flank with depths ranging from 300 m to 2000 m. Sedimentological analyses indicate that the Cap-Ferret Canyon is at present inactive in terms of sediment gravity flow. Compared to stations on the adjacent flank, canyon-axis stations are generally characterised by shallow oxygen penetration depths, high diffusive oxygen uptakes (DOU) and high lipid contents. Higher mineralisation rates recorded in the canyon axis are likely due to a preferential focusing of labile organic matter in the canyon axis. Foraminiferal standing stocks do not exhibit any straightforward correlation with the different descriptors of organic matter available in the sediment. However, foraminiferal standing stock and diversity along the canyon axis are generally higher than on the adjacent flank. Canyon axis sites yield dominant species that are similar to those at adjacent flank and open slope stations located at comparable water depths. However, intermediate and deep infaunal species were only recorded in the lower canyon axis, where high amounts of organic matter were observed in deeper sediment layers. Finally, the faunal composition in the Cap-Ferret Canyon is different compared to the nearby Cap-Breton Canyon, where sediment gravity flows are active. The absence of pioneer species and the occurrence of highly specialized taxa are both consistent with the much more stable conditions in terms of hydro-sedimentary conditions prevailing in the Cap-Ferret Canyon

Tumor growth rate as a metric of progression, response, and prognosis in pancreatic and intestinal neuroendocrine tumors

Background: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo. Methods: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR0); 12-24 weeks before randomization versus baseline; each treatment visit versus baseline (TGRTx-0); between consecutive treatment visits (TGRTx-Tx). To assess TGR as a measure of prognosis, PFS was compared for TGR0 subgroups stratified by optimum TGR0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS. Results: TGR0 revealed tumors growing during pre-treatment (median [interquartile range] TGR0: lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR0-12 of - 2.9 [- 5.1, - 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR0 > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5-6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR0, hepatic tumor load, and primary tumor type were independently associated with PFS. Conclusions: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity. Trial registration: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496

Somatostatin receptors 2 and 5 are preferentially expressed in proliferating endothelium

Angiogenesis is characterised by activation, migration and proliferation of endothelial cells and is central to the pathology of cancer, cardiovascular disease and chronic inflammation. Somatostatin is an inhibitory polypeptide that acts through five receptors (sst 1, 2, 3, 4, 5). Sst has previously been reported in endothelium, but their role remains obscure. Here, we report the expression of sst in human umbilical vein endothelial cells (HUVECs) in vitro, during proliferation and quiescence. A protocol for culturing proliferating and quiescent HUVECs was established, and verified by analysing cell cycle distribution in propidium-iodide-stained samples using flow cytometry. Sst mRNA was then quantified in nine proliferating and quiescent HUVEC lines using quantitative reverse transcriptase–polymerase chain reaction. Sst 2 and 5 were preferentially expressed in proliferating HUVECs. All samples were negative for sst 4. Sst 1 and 3 expression and cell cycle progression were unrelated. Immunostaining for sst 2 and 5 showed positivity in proliferating but not quiescent cells, confirming sst 2 and 5 protein expression. Inhibition of proliferating cells with somatostatin analogues Octreotide and SOM230, which have sst 5 activity, was found (Octreotide 10−10–10−6 M: 48.5–70.2% inhibition; SOM230 10−9–10−6 M: 44.9–65.4% inhibition) in a dose-dependent manner, suggesting that sst 5 may have functional activity in proliferation. Dynamic changes in sst 2 and 5 expression during the cell cycle and the inhibition of proliferation with specific analogues suggest that these receptors may have a role in angiogenesis

Crystal Structure of the PAC1R Extracellular Domain Unifies a Consensus Fold for Hormone Recognition by Class B G-Protein Coupled Receptors

Pituitary adenylate cyclase activating polypeptide (PACAP) is a member of the PACAP/glucagon family of peptide hormones, which controls many physiological functions in the immune, nervous, endocrine, and muscular systems. It activates adenylate cyclase by binding to its receptor, PAC1R, a member of class B G-protein coupled receptors (GPCR). Crystal structures of a number of Class B GPCR extracellular domains (ECD) bound to their respective peptide hormones have revealed a consensus mechanism of hormone binding. However, the mechanism of how PACAP binds to its receptor remains controversial as an NMR structure of the PAC1R ECD/PACAP complex reveals a different topology of the ECD and a distinct mode of ligand recognition. Here we report a 1.9 Å crystal structure of the PAC1R ECD, which adopts the same fold as commonly observed for other members of Class B GPCR. Binding studies and cell-based assays with alanine-scanned peptides and mutated receptor support a model that PAC1R uses the same conserved fold of Class B GPCR ECD for PACAP binding, thus unifying the consensus mechanism of hormone binding for this family of receptors