ALBERT

Description: The geology of the Channel Western Approaches is a key to understand the post-rift evolution of the NW European continental margin in relation with the Europe/Africa collision. Despite considerable evidence of Tertiary tectonic inversion throughout the Channel basin, the structures and amplitudes of the tectonic movements remain poorly documented across the French sector of the Western Approaches. The effect of the tectonic inversion for the evolution of the "Channel River", the major system that flowed into the English Channel during the Plio-Quaternary eustatic lowstands, also needs to be clarified. Its drainage basin was larger than the present-day English Channel and constituted the source of terrigenous fluxes of the Armorican and Celtic deep sea fans. A lack of high-resolution seismic data motivated the implementation of the GEOMOC and GEOBREST cruises, whose main results are presented in this paper. The new observations highlight the diachronism and the contrast in amplitudes of the deformations involved in the inversion of the French Western Approaches. The tectonic inversion can be described in two stages: a paroxysmal Paleogene stage including two episodes, Eocene (probably Ypresian) and Oligocene, and a more moderate Neogene stage subdivided into Miocene and Pliocene episodes, driven by the reactivation of the same faults. The deformations along the North Iroise fault (NIF) located at the termination of the Medio-Manche fault produced forced folds in the sedimentary cover above the deeper faults. The tectonic inversion generated uplift of about 700 m of the mid-continental shelf south of the NIF. The isochron map of the reflectors bounding the identified seismic sequences clearly demonstrates a major structural control on the geometry of the Neogene deposits. First, the uplift of the eastern part of the Iroise basin during the upper Miocene favoured the onset of a broad submarine delta system that developed towards the subsiding NW outer shelf. The later evolution of the 'palaeovalley' network corresponding to the western termination of the "Channel River" exhibits a 'bayonet' pattern marked by a zigzagging pattern of valleys, with alternating segments orientated N040oE and N070oE, controlled by Neogene faulting. The palaeovalley network could have begun during Reurevian or Pre-Tiglian sea-level lowstands, which exposed the entire shelf below the shelf edge. The amplitude of the sea-level fall is assumed to have been magnified by uplift of the Iroise basin, followed by later tilting of the outer shelf, as observed in many other examples documented along the North Atlantic margins.

Description: 〈div data-abstract-type="normal"〉〈p〉The Brittany region of France is located in a low seismicity intraplate zone. Most of the instrumented earthquakes are limited to a shallow crustal depth without surface rupture. A paleoseismological analysis was performed on deposits on the Crozon Peninsula and in the Elorn estuary. We highlight hydroplastic deformations induced by liquefaction leading to clay diapirism, which were likely triggered by past earthquakes. This diapirism seems to be frequent in continental nonconsolidated sediments and to develop on the inherited tectonic structures, when a shallow water table and confining layers exist. Timing of deformation is dated using paleoenvironmental data, and electron spin resonance and infrared-stimulated luminescence dating methods. Two seismic periods were identified in western Europe during early Marine Oxygen Isotope Stage (MIS) 10 (~380 ka) and early MIS 8 (~280–265 ka). The lack of similar deformations affecting the Holocene tidal deposits in the Bay of Brest suggests that the magnitude of the triggering paleoearthquakes is probably higher (〈span〉M〈/span〉〈span〉〈span〉w〈/span〉〈/span〉 ~6) than the recent events (〈span〉M〈/span〉〈span〉〈span〉w〈/span〉〈/span〉 5.4). These unusual intraplate major paleoearthquakes need specific factors affecting the far-field crustal stress loading to be triggered, such as a brief acceleration of the Africa-Eurasia lithospheric plate convergence, glacio-isostatic stress perturbations associated with the onset of major glaciations in northern Europe, or other processes induced by orbital forcing.〈/p〉〈/div〉

Description: Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

Description: Weight loss and worsening of nutritional state is a frequent downfall of acute hospitalization in older people. It is usually accepted that acute inflammation is responsible for hypercatabolism. However, several studies suggest, on the contrary, a reduction in resting energy expenditure (REE). This study aimed to obtain a reliable measure of REE and total energy expenditure (TEE) in older patients hospitalized for an acute episode in order to better assess patients’ energy requirements and help understand the mechanisms of weight loss in this situation. Nineteen hospitalized older patients (mean age 83 years) with C-reactive protein (CRP) level 〉20mg/L were recruited. REE and TEE were measured using gold standard methods of indirect calorimetry and doubly labeled water (DLW), respectively. REE was then compared to data from a previous study on aged volunteers from nursing homes who were free of an acute stressor event. Energy requirements measured by DLW were confirmed at 1.3 × REE. Energy intake covered the needs but did not prevent weight loss in these patients. TEE was not increased in hospitalized patients and was not influenced by inflammation, while the relationship between REE and inflammation was uncertain. Our results suggest that lean mass remains the major determinant of REE in hospitalized older people and that weight loss may not be explained solely by a state of hypercatabolism.

Description: Abstract 2933 Poster Board II-909 The challenge of clinical proteomic is to link protein expression profile variations to specific disease phenotypes and identify relevant biomarkers in order to develop straightforward diagnostic or prognosis tools. Blood, a tissue that interfaces with virtually every part of the body, is considered to be a deep source of native and secreted diagnostic analytes. Despite this great potential, the first decade of the proteomics era met with little success, not only because of the vast and complex nature of the proteome but also due to proteins dynamic range and complex degradation pathways, and to the heterogeneity of plasma protein profiles in the human population. Altogether, progress in clinical proteomics will reside in the elaboration of standardized preanalytic procedures, cross-comparisons between samples and independent validation. In aggressive diffuse large B-cell lymphomas (DLBCL), diagnostic and prognostic biomarkers are mandatory to optimize treatment, and include patients in future trials. The aim of the present study was first to identify diagnostic blood biomarkers of DLBCL based on the 075 French GOELAMS ongoing trial -which involved adults younger than 60 suffering from an aggressive form of DLBCL- that randomized patients between CHOP-14 Rituximab or intensive chemotherapy plus Rituximab including autologous stem-cell support. This protocol was built after our group demonstrated the high efficiency of high-dose chemotherapy and autologous stem-cell transplantation as frontline therapy in this disease compared to conventional CHOP (New Engl J Med, 2004). In this study, 200 patients were compared to 100 controls matched for sex and age. Well-defined pre-analytic steps were applied and plasma was collected, at the time of diagnosis, on the specific anti-proteasic P100v1.1 tube from Becton Dickinson. All samples were centralized and aliquoted in a unique platform prior to analytic steps. The whole series of 300 samples was randomly assigned on chips to be analyzed with SELDI-TOF/MS using three different chemistry protocols (CM10, Q10 & IMAC30) and two beam intensities (2000 and 4000, respectively). There was a longer delay in the process of patient's samples before plasma isolation compared to controls; this time had to be considered since it could participate to the protein degradation process and lead to proteomic modifications. Statistical analyses were implemented with the R package software [R development core team. R: A Language for Environmental and Statistical Computing. Vienna: R Foundation, 2008.]. Univariate analyses comparison resulted in 185 peaks differential of the case-control status (t-test, FDR=5%). Multivariate analyses were then performed according to chemistry and beam intensity using stepforward logistic regression. This resulted in 78 peaks related to DLBCL diagnosis. In order to reduce dimension, partial least square regression [A. L. Boulesteix and K. Strimmer (2005). Predicting Transcription Factor Activities from Combined Analysis of Microarray and ChIP Data: A Partial Least Squares Approach] was applied, resulting in two components corresponding to a weighted sum of the 78 peaks. These two components were introduced as covariates in logistic regression so that the 78 peaks could be ranked according to their global coefficient, allowing then top peaks to be studied. Sparse partial least square was also considered as another approach to reduce dimension and select peaks among the 78 identified. These two approaches were compared and proteins studied in greater detail. Altogether, this study allowed to identify promising candidate cancer biomarkers that are currently being validated through the analysis of additional plasma issued from other types of lymphoma (follicular, mantle cell and low burden DLBCL) and non-cancerous septic patients. Highly specific peak combinations will be considered before peptide characterization in order to end up with a diagnostic set of proteins useful for the diagnosis and management of aggressive DLBCLs. Disclosures: No relevant conflicts of interest to declare.

Description: Systemic release of tumor necrosis factor (TNF) and lymphotoxin-α (LTα) has been found to contribute to the severity of non-Hodgkin's lymphoma (NHL). We investigated whether genetic polymorphisms in the TNF locus, previously shown to influence TNF and LTα genes expression, might contribute to these cytokines production and to the clinical course of NHL. Genomic DNA from 273 lymphoma patients was typed for TNF (−308) polymorphism using an allele-specific polymerase chain reaction (PCR) and for LTα (+252) polymorphism with a PCR-based restriction fragment length polymorphism. The presence of the TNF allele involved in increased TNF gene transcription was associated with higher plasma levels of this cytokine at the time of lymphoma diagnosis (χ2 test, P = .013). An extended haplotype analysis showed that the presence of at least two TNF or LTα high-producer alleles constituted a risk factor for first-line treatment failure (χ2 test, P = .021), shorter progression-free survival (log-rank test, P = .0007), and overall survival (log-rank test, P = .012). In the subgroup of 126 patients with diffuse large-cell lymphoma, the presence of two or more TNF/LTα high producing alleles contributed significantly to a higher rate of relapse and progression (log-rank test, P = .045 and P = .027). In multivariate Cox regression models including the variables of the International Prognostic Index, the TNF/LTα haplotype status was found to be an independent risk factor for progression-free survival (relative risk 2.33, 95% confidence interval [1.17 to 4.64], P = .0053) and overall survival (relative risk 1.92, 95% confidence interval [0.63 to 5.80],P = .081) of large-cell lymphoma patients. These results indicate that genetic polymorphism leading to increased TNF production influences the outcome of NHL and suggest a pathophysiological role for the genetic control of the immune response in lymphoid malignancies.

Description: Background. Natural regulatory T cells (nTregs) are key players in immune homeostasis and protection towards autoimmunity. There is also strong evidence that Tregs are involved in the immune recognition of tumor-related antigens. However, little is known about the role of nTregs in Chronic Myelogenous leukaemia (CML), an immunogenic tumor. Aims. The aim of this study is to determine if the proportions of nTregs are significantly modified in CML patients at diagnosis or during imatinib mesylate (IM) treatment when compared to healthy counterparts, and if they correlate with prognosis factors and/or tumor burden. Patients. Fourty-three CML patients were enrolled, 12 at diagnosis (median age 55 (range 32–77) years) and 31 during IM treatment (median age 56 (29–84) years) alone (n=21) or in combination with cytarabine (n=4) or Peg-interferon (n=6). Four patients received interferon before IM. They were compared to 13 healthy donors (median age 42 (21–56) years). We also analysed if the proportion of nTregs correlates with diagnosis (Sokal was low for 6, intermediate for 6 for the 12 patients analysed at diagnosis) or on-going prognosis factors (normalized bcr-abl/abl ratio using PB RQ-PCR). Methods. Mononuclear cells were separated from PB by density gradient centrifugation and subsequently frozen until flow cytometry analysis. Before use, the CD4+ T-cell population was positively purified with immunomagnetic microbeads. Using a sequential gating strategy, nTregs were identified as CD4+CD25+Foxp3+ T-cells and proportions were expressed as a percentage of total CD4+ T-cells. Statistical analyses are based on at least 30,000 events gated on CD4+CD25+ T-cells. All comparisons were adjusted with patients or donors age at sample collection. Results. We confirm that nTregs percentages increase with age both in patients and healthy donors (p=0.023). At diagnosis, whilst there is no significant difference in nTregs between patients and healthy donors, the percentage of nTregs is found to correlate with Sokal score with a marked increase of nTregs for patients with aggressive disease compared to patients with less aggressive disease at diagnosis (p