Highlights from the 13th St Gallen International Breast Cancer Conference 2013. Access to innovation for patients with breast cancer: how to speed it up?

The recognition that early breast cancer is a spectrum of diseases each requiring a specific systemic therapy guided the 13th St Gallen International Breast Cancer Consensus Conference [1]. The meeting assembled 3600 participants from nearly 90 countries worldwide. Educational content has been centred on the primary and multidisciplinary treatment approach of early breast cancer. The meeting culminated on the final day, with the St Gallen Breast Cancer Treatment Consensus, established by 40-50 of the world's most experienced opinion leaders in the field of breast cancer treatment. The major issue that arose during the consensus conference was the increasing gap between what is theoretically feasible in patient risk stratification, in treatment, and in daily practice management. We need to find new paths to access innovations to clinical research and daily practice. To ensure that continued innovation meets the needs of patients, the therapeutic alliance between patients and academic-led research should to be extended to include relevant pharmaceutical companies and drug regulators with a unique effort to bring innovation into clinical practice. We need to bring together major players from the world of breast cancer research to map out a coordinated strategy on an international scale, to address the disease fragmentation, to share financial resources, and to integrate scientific data. The final goal will be to improve access to an affordable, best standard of care for all patients in each country.

BMP signaling in the development of the mouse esophagus and forestomach.

The stratification and differentiation of the epidermis are known to involve the precise control of multiple signaling pathways. By contrast, little is known about the development of the mouse esophagus and forestomach, which are composed of a stratified squamous epithelium. Based on prior work in the skin, we hypothesized that bone morphogenetic protein (BMP) signaling is a central player. To test this hypothesis, we first used a BMP reporter mouse line harboring a BRE-lacZ allele, along with in situ hybridization to localize transcripts for BMP signaling components, including various antagonists. We then exploited a Shh-Cre allele that drives recombination in the embryonic foregut epithelium to generate gain- or loss-of-function models for the Bmpr1a (Alk3) receptor. In gain-of-function (Shh-Cre;Rosa26(CAG-loxpstoploxp-caBmprIa)) embryos, high levels of ectopic BMP signaling stall the transition from simple columnar to multilayered undifferentiated epithelium in the esophagus and forestomach. In loss-of-function experiments, conditional deletion of the BMP receptor in Shh-Cre;Bmpr1a(flox/flox) embryos allows the formation of a multilayered squamous epithelium but this fails to differentiate, as shown by the absence of expression of the suprabasal markers loricrin and involucrin. Together, these findings suggest multiple roles for BMP signaling in the developing esophagus and forestomach.

Postoperative statin use and risk of biochemical recurrence following radical prostatectomy: results from the Shared Equal Access Regional Cancer Hospital (SEARCH) database.

OBJECTIVE: To investigate the effect of statin use after radical prostatectomy (RP) on biochemical recurrence (BCR) in patients with prostate cancer who never received statins before RP. PATIENTS AND METHODS: We conducted a retrospective analysis of 1146 RP patients within the Shared Equal Access Regional Cancer Hospital (SEARCH) database. Multivariable Cox proportional hazards analyses were used to examine differences in risk of BCR between post-RP statin users vs nonusers. To account for varying start dates and duration of statin use during follow-up, post-RP statin use was treated as a time-dependent variable. In a secondary analysis, models were stratified by race to examine the association of post-RP statin use with BCR among black and non-black men. RESULTS: After adjusting for clinical and pathological characteristics, post-RP statin use was significantly associated with 36% reduced risk of BCR (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.47-0.87; P = 0.004). Post-RP statin use remained associated with reduced risk of BCR after adjusting for preoperative serum cholesterol levels. In secondary analysis, after stratification by race, this protective association was significant in non-black (HR 0.49, 95% CI 0.32-0.75; P = 0.001) but not black men (HR 0.82, 95% CI 0.53-1.28; P = 0.384). CONCLUSION: In this retrospective cohort of men undergoing RP, post-RP statin use was significantly associated with reduced risk of BCR. Whether the association between post-RP statin use and BCR differs by race requires further study. Given these findings, coupled with other studies suggesting that statins may reduce risk of advanced prostate cancer, randomised controlled trials are warranted to formally test the hypothesis that statins slow prostate cancer progression.

The island-scale internal wave climate of Moorea, French Polynesia

Analysis of five-year records of temperatures and currents collected at Moorea reveal strong internal wave activity at predominantly semi-diurnal frequencies impacting reef slopes at depths 30m around the entire island. Temperature changes of 1.5C to 3C are accompanied by surges of upward and onshore flow and vertical shear in onshore currents. Superimposed on annual temperature changes of approximately 3C, internal wave activity is high from Oct-May and markedly lower from Jun-Sep. The offshore pycnocline is broadly distributed with continuous stratification to at least 500m depth, and a subsurface fluorescence maximum above the strong nutricline at approximately 200m. Minimum buoyancy periods range from 4.8 to 6min, with the maximum density gradient occurring at 50 to 60m depth in summer and deepening to approximately 150 to 200m in winter. The bottom slope angle around all of Moorea is super-critical relative to the vertical stratification angle suggesting that energy propagating into shallow water is only a portion of total incident internal wave energy. Vertical gradient Richardson numbers indicate dominance by density stability relative to current shear with relatively limited diapycnal mixing. Coherence and lagged cross-correlation of semi-diurnal temperature variation indicate complex patterns of inter-site arrival of internal waves and no clear coherence or lagged correlation relationships among island sides. Semi-diurnal and high frequency internal wave packets likely arrive on Moorea from a combination of local and distant sources and may have important impacts for nutrient and particle fluxes in deep reef environments. © 2012 American Geophysical Union. All Rights Reserved.

Utilisation de la Calorimétrie à Titrage Isotherme pour l'étude des interactions entre (bio)molécules

info:eu-repo/semantics/published

Comparison of the thermodynamics and base-pair dynamics of a full LNA:DNA duplex and of the isosequential DNA:DNA duplex

Locked nucleic acids (LNA), conformationally restricted nucleotide analogues, are known to enhance pairing stability and selectivity toward complementary strands. With the aim to contribute to a better understanding of the origin of these effects, the structure, thermal stability, hybridization thermodynamics, and base-pair dynamics of a full-LNA:DNA heteroduplex and of its isosequential DNA:DNA homoduplex were monitored and compared. CD measurements highlight differences in the duplex structures: the homoduplex and heteroduplex present B-type and A-type helical conformations, respectively. The pairing of the hybrid duplex is characterized, at all temperatures monitored (between 15 and 37 degrees C), by a larger stability constant but a less favorable enthalpic term. A major contribution to this thermodynamic profile emanates from the presence of a hairpin structure in the LNA single strand which contributes favorably to the entropy of interaction but leads to an enthalpy penalty upon duplex formation. The base-pair opening dynamics of both systems was monitored by NMR spectroscopy via imino protons exchange measurements. The measurements highlight that hybrid G-C base-pairs present a longer base-pair lifetime and higher stability than natural G-C base-pairs, but that an LNA substitution in an A-T base-pair does not have a favorable effect on the stability. The thermodynamic and dynamic data confirm a more favorable stacking of the bases in the hybrid duplex. This study emphasizes the complementarities between dynamic and thermodynamical studies for the elucidation of the relevant factors in binding events.

Immunological Signatures Identifying Different Stages of Latent Mycobacterium tuberculosis Infection and Discriminating Latent from Active Tuberculosis in Humans

Objectives: One third of the world population is considered latently infected with Mycobacterium tuberculosis(LTBI) and sterilizing this reservoir of bacteria that may reactivate is required for tuberculosis (TB) elimination. Thegroup of individuals with LTBI is heterogeneous with some of them being more at risk to develop TB disease thanothers. Improved diagnosis of subjects with LTBI is needed, allowing to differentiate subjects with LTBI from thosewith active TB, and to select among LTBI subjects those who are more at risk to develop active TB. We havecharacterized at the cellular level both the quantitative and qualitative T cell responses to different mycobacterialantigens in selected populations of infected subjects in order to identify new biomarkers that could help to identify M.tuberculosis-infected subjects and to stratify them in risk groups for reactivation of the infection.Methods: Lymphoblast frequencies and cytokine production (IFN-γ, TNF-α, IL-2) among CD4+ and CD8+ T cellswere analyzed by flow cytometry after in vitro stimulation with the latency antigen heparin-binding haemagglutinin(HBHA) or early-secreted antigen Target-6 (ESAT-6) of peripheral blood mononuclear cells from clinically wellcharacterized M. tuberculosis-infected humans (28 LTBI, 22 TB disease,12 controls). The LTBI group definedaccording to the Center for Disease Control guidelines was subdivided into QuantiFERON-TB Gold in-Tube (QFT)positive and negative subgroups.Results: Similar to TB patients, QFT+ LTBI subjects had higher proportions of HBHA-induced TNF-αsingle+ CD4+lymphocytes than QFT- LTBI subjects (p<0.05). Compared to LTBI subjects, TB patients had higher frequencies ofESAT-6-induced CD8+ lymphoblasts (p<0.001), higher proportions of ESAT-6-induced IFN-γ+TNF-α+ CD4+ Tlymphocytes (p<0.05), and lower proportions of HBHA-induced IFN-γ+TNF-α+IL-2+ (p<0.05) CD4+ T lymphocytes.Conclusions: These data provide new biomarkers to discriminate active TB from LTBI, and more interestingly,help to identify LTBI subjects with increased likelihood to develop TB disease.

Catalyse et pot catalytique

Dans la lignée des précédents fascicules de chimie, ce dossier est consacré à la catalyse :qu'est-ce que la catalyse ?Exemples de réactions catalysées, le pot catalytique, quel carburant choisir ?Finie la pollution automobile ?La pile à combustible.

Experimental investigation of thermal structures in regular three-dimensional falling films

Interfacial waves on the surface of a falling liquid film are known to modify heat and mass transfer. Under non-isothermal conditions, the wave topology is strongly influenced by the presence of thermocapillary (Marangoni) forces at the interface which leads to a destabilization of the film flow and potentially to critical film thinning. In this context, the present study investigates the evolution of the surface topology and the evolution of the surface temperature for the case of regularly excited solitary-type waves on a falling liquid film under the influence of a wall-side heat flux. Combining film thickness (chromatic confocal imaging) and surface temperature information (infrared thermography), interactions between hydrodynamics and thermocapillary forces are revealed. These include the formation of rivulets, film thinning and wave number doubling in spanwise direction. Distinct thermal structures on the films’ surface can be associated to characteristics of the surface topology.

Turbulence model performance in continuous casting simulations

This paper concerns the development and validation (using an oil/water system) of a finite volume computer model of the continuous casting process for steel flat products. The emphasis is on hydrodynamic aspects and in particular the dynamic behaviour of the metal/slag interface. Instability and wave action encourage the entrainment of inclusions into the melt affecting product quality. To track the interface between oil and water a new implicit algorithm was developed, called the Counter Diffusion Method. To prevent excessive damping, a time-filtered version of the k-e model, was found necessary, with appropriate density stratification terms representing interface turbulence damping.

Increased blooms of a dinoflagellate in the NW Atlantic

Sampling by the Continuous Plankton Recorder (CPR) over the NW Atlantic from 1960 to 2000 has enabled long-term studies of the larger components of the phytoplankton community, highlighting various changes, particularly during the 1990s. Analysis of an index of phytoplankton biomass, the Phytoplankton Colour Index (PCI) has revealed an increase over the past decade, most marked during the winter (December to February) months. Examination of the structure of the community using multiple linear-regression models indicates that the winter phytoplankton community composition has changed markedly in the 1990s compared to the 1960s. One phytoplankter, the dinoflagellate Ceratium arcticum (Cleve), has undergone dramatic changes in abundance during this period, with pronounced large winter blooms and decreased autumnal levels, and its contribution to the Phytoplankton Colour index values has increased significantly. Other dominant species in the phytoplankton community, both diatoms and dinoflagellates, did not show the same variations over the examined time period. It is suggested that the response of C. arcticum is probably a result of previously reported changes in stratification in the NW Atlantic, due to dynamic hydro-climatic (freshening and cooling) events.

Wind mixing, food availability and mortality of anchovy larvae Engraulis encrasicolus in the northern Adriatic Sea

A study was carried out in June/July 1996 in the River Po outflow in the northern Adriatic to investigate spawning of anchovy Engraulis encrasicolus and survival of larvae in relation to food availability and wind mixing. Hydrographic- and bongo net sampling was carried out on 2 grid surveys; one after a period of low winds and settled weather, and the other after an intervening period of strong winds, which resulted in a decrease in water column stratification. The spawning areas of anchovy and the larval distributions were associated with the river outflow plume (most clearly on the second survey grid, after the period of higher winds). Potential food particles for anchovy larvae, primarily copepod nauplii and copepodite stages, were also concentrated in the area influenced by the river outflow. Although there was a nearly 50% reduction in the mean water column abundance of potential food particles between the 2 survey grids, mostly due to a decline in abundance outside the immediate river plume area, there was no significant change in mortality of anchovy larvae between the 2 grids; the exponential decline in numbers of eggs and larvae to 10 mm in length being equivalent to overall mortality rates of 43.2%/d on the first survey and 44.7%/d on the second. The resilience of larval survival under potentially less favourable feeding conditions, following the period of wind mixing, was ascribed, in part, to the maintenance of local water column stratification by the superficial low salinity input from the River Po. This stratification in the immediate outflow area was associated with the presence of concentrated layers of potential food particles (typically >50 particles/L and 1.5 to 2.8 times the mean water column abundance) in the upper 10 m of the water column, coincident with peak numbers of anchovy larvae. However, since there was no evidence for lower larval survival in areas, less influenced by the immediate river outflow plume, a simple direct relationship between enhanced water column stability, improved feeding conditions and larval survival was not supported.

Macroecology of Calanus finmarchicus and C. helgolandicus in the North Atlantic Ocean and adjacent seas

Global climate change is expected to modify the spatial distribution of marine organisms. However, projections of future changes should be based on robust information on the ecological niche of species. This paper presents a macroecological study of the environmental tolerance and ecological niche (sensu Hutchinson 1957, i.e. the field of tolerance of a species to the principal factors of its environment) of Calanus finmarchicus and C. helgolandicus in the North Atlantic Ocean and adjacent seas. Biological data were collected by the Continuous Plankton Recorder (CPR) Survey, which samples plankton in the North Atlantic and adjacent seas at a standard depth of 7 m. Eleven parameters were chosen including bathymetry, temperature, salinity, nutrients, mixed-layer depth and an index of turbulence compiled from wind data and chlorophyll a concentrations (used herein as an index of available food). The environmental window and the optimum level were determined for both species and for each abiotic factor and chlorophyll concentration. The most important parameters that influenced abundance and spatial distribution were temperature and its correlates such as oxygen and nutrients. Bathymetry and other water-column-related parameters also played an important role. The ecological niche of C. finmarchicus was larger than that of C. helgolandicus and both niches were significantly separated. Our results have important implications in the context of global climate change. As temperature (and to some extent stratification) is predicted to continue to rise in the North Atlantic sector, changes in the spatial distribution of these 2 Calanus species can be expected. Application of this approach to the 1980s North Sea regime shift provides evidence that changes in sea temperature alone could have triggered the substantial and rapid changes identified in the dynamic regimes of these ecosystems. C. finmarchicus appears to be a good indicator of the Atlantic Polar Biome (mainly the Atlantic Subarctic and Arctic provinces) while C. helgolandicus is an indicator of more temperate waters (Atlantic Westerly Winds Biome) in regions characterised by more pronounced spatial changes in bathymetry.

Continuous Plankton Records - Seasonal-Variations In The Distribution And Abundance Of Plankton In The North-Atlantic Ocean And The North-Sea

Charts are presented of the seasonal variations in the distribution of four phytoplankton and five zooplankton taxa in the North Atlantic and the North Sea. The main factors determining the seasonal variations appear to be the distribution of the main overwintering stocks, the current system and, in some instances, temperature control of the rate of population increase. Information is presented about the variation with latitude (over the range from 34° N to 65 ° N) of the seasonal regime of the plankton. On the assumption that there is a relationship between nutrient supply and vertical temperature stratification the main features of this variability can be interpreted. In the south (to about 43° N) nutrient limitation plus grazing appear to be dominant, resulting in a bimodal seasonal cycle of phytoplankton. North of about 60° N the system appears to be limited by the size of the phytoplankton stocks being grazed primarily by Calanus Finmarchicus and Euphausiacea. In an extensive zone, from about 44° N to 60° N, it would appear that the spring bloom of phytoplankton is under-exploited by grazing while in summer the zooplankton graze the daily production of the phytoplankton, the stocks of which are probably maintained by in situ nutrient regeneration. The implications, for at least this mid-latitude zone, that rates and fluxes of processes, as opposed to density dependent interactions between stocks, play a major role in the dynamics of the seasonal cycle is consistent with previously reported observations suggesting that physical environmental factors play a major role in determining year-to-year fluctuations in the abundance of the plankton.

Oceanic controls on the primary production of the northwest European continental shelf: model experiments under recent past conditions and a potential future scenario

In this paper we clearly demonstrate that changes in oceanic nutrients are a first order factor in determining changes in the primary production of the northwest European continental shelf on time scales of 5–10 yr. We present a series of coupled hydrodynamic ecosystem modelling simulations, using the POLCOMS-ERSEM system. These are forced by both reanalysis data and a single example of a coupled ocean-atmosphere general circulation model (OA-GCM) representative of possible conditions in 2080–2100 under an SRES A1B emissions scenario, along with the corresponding present day control. The OA-GCM forced simulations show a substantial reduction in surface nutrients in the open-ocean regions of the model domain, comparing future and present day time-slices. This arises from a large increase in oceanic stratification. Tracer transport experiments identify a substantial fraction of on-shelf water originates from the open-ocean region to the south of the domain, where this increase is largest, and indeed the on-shelf nutrient and primary production are reduced as this water is transported on-shelf. This relationship is confirmed quantitatively by comparing changes in winter nitrate with total annual nitrate uptake. The reduction in primary production by the reduced nutrient transport is mitigated by on-shelf processes relating to temperature, stratification (length of growing season) and recycling. Regions less exposed to ocean-shelf exchange in this model (Celtic Sea, Irish Sea, English Channel, and Southern North Sea) show a modest increase in primary production (of 5–10%) compared with a decrease of 0–20% in the outer shelf, Central and Northern North Sea. These findings are backed up by a boundary condition perturbation experiment and a simple mixing model.