A systematic review of platinum and taxane resistance from bench to clinic: an inverse relationship

We undertook a systematic review of the pre-clinical and clinical literature for studies investigating the relationship between platinum and taxane resistance. Medline was searched for (1) cell models of acquired drug resistance reporting platinum and taxane sensitivities and (2) clinical trials of platinum or taxane salvage therapy in ovarian cancer. One hundred and thirty-seven models of acquired drug resistance were identified. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel and 66.7% of paclitaxel-resistant cells were sensitive to cisplatin. A similar inverse pattern was observed for cisplatin vs. docetaxel, carboplatin vs. paclitaxel and carboplatin vs. docetaxel. These associations were independent of cancer type, agents used to develop resistance and reported mechanisms of resistance. Sixty-five eligible clinical trials of paclitaxel-based salvage after platinum therapy were identified. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously recieved paclitaxel had a pooled response rate of 35.3%, n=232, compared to 22% in paclitaxel naïve patients n=1918 (p<0.01, Chi-squared). Suggesting that pre-treatment with paclitaxel may improve the response of salvage paclitaxel therapy. The response rate to paclitaxel/platinum combination regimens in platinum-sensitive ovarian cancer was 79.5%, n=88 compared to 49.4%, n=85 for paclitaxel combined with other agents (p<0.001, Chi-squared), suggesting a positive interaction between taxanes and platinum. Therefore, the inverse relationship between platinum and taxanes resistance seen in cell models is mirrored in the clinical response to these agents in ovarian cancer. An understanding of the cellular and molecular mechanisms responsible would be valuable in predicting response to salvage chemotherapy and may identify new therapeutic targets

A Model for the Strings of Eta Carinae

We propose a model based on ionization shadows to explain the formation of the long and narrow strings of Eta Carinae. Five strings are known, all located along the symmetry axis outside the Homunculus. The model assumes that each string is formed in a shadow behind a dense clump near the symmetry axis. The surrounding gas is ionized first, becomes much hotter, and compresses the gas in the shadow. This leads to the formation of a radial, dense, long, and narrow region, i.e., a string. Later the neutral material in the strings is ionized, and becomes brighter. Still later it re-expands, and we predict that in about 200 years the strings will fade. The condition for the model to work is that the ionization front, due to the diffuse ionizing recombination radiation of the surrounding gas, proceeds into the shadow at a velocity slower than the compression speed. From that we get a condition on the mass loss rate of the mass loss episode that formed the strings, which should be less than 10^{-4} Mo/year. The model can also explain the strings in the planetary nebula NGC 6543.Comment: 8 pages; Submitted to A&

Analysis of Intracellular Trafficking and Interactions of Cytoplasmic HIV-1 Rev Mutants in Living Cells

AbstractThe HIV-1 Rev protein is an essential nuclear regulatory viral protein. Rev mutants that are able to block wild-type (WT) Rev activityin transhave been reported and used in antiviral approaches. Not only nuclear but also cytoplasmic Rev mutants were described and suspected to be transdominant by retaining WT Rev in the cytoplasm. To investigate their potential for cytoplasmic retention, we studied the localization, trafficking, and interactions of cytoplasmic Rev mutants containing mutations in the N-terminal multifunctional domain. Using a novel dual-color autofluorescent protein-tagging system, we found that coexpression of the nucleolar blue-tagged WT Rev protein together with green-labeled cytoplasmic Rev mutants did not result in the retention of WT Rev in the cytoplasm but, on the contrary, in colocalization of the mutants to the nucleolus. A combination of mutations abolished the interaction with WT Rev, defining two domains important for Rev protein interaction. The identified domains were also essential for specific Rev responsive element (RRE) RNA binding and nuclear retention. Inactivation of the nuclear export signal shifted the steady-state distribution of the mutants from the cytoplasm to the nucleus, indicating their capability for nucleo-cytoplasmic shuttling. The cytoplasmic mutants were not transdominant compared to the nuclear mutant RevM10BL. These results emphasize that efficient oligomerization with WT Rev combined with RRE-specific RNA binding are prerequisites for effective transdominance

Ten-year global distribution of downwelling longwave radiation

International audienceDownwelling longwave fluxes, DLFs, have been derived for each month over a ten year period (1984?1993), on a global scale with a resolution of 2.5° × 2.5°. The fluxes were computed using a deterministic model for atmospheric radiation transfer, along with satellite and reanalysis data for the key atmospheric input parameters, i.e. cloud properties, and specific humidity and temperature profiles. The cloud climatologies were taken from the latest released and improved International Satellite Climatology Project D2 series. Specific humidity and temperature vertical profiles were taken from three different reanalysis datasets; NCEP/NCAR, GEOS, and ECMWF (acronyms explained in main text). DLFs were computed for each reanalysis dataset, with differences reaching values as high as 30 Wm?2 in specific regions, particularly over high altitude areas and deserts. However, globally, the agreement is good, with the rms of the difference between the DLFs derived from the different reanalysis datasets ranging from 5 to 7 Wm?2. The results are presented as geographical distributions and as time series of hemispheric and global averages. The DLF time series based on the different reanalysis datasets show similar seasonal and inter-annual variations, and similar anomalies related to the 86/87 El Niño and 89/90 La Niña events. The global ten-year average of the DLF was found to be between 342.2 Wm?2 and 344.3 Wm?2, depending on the dataset. We also conducted a detailed sensitivity analysis of the calculated DLFs to the key input data. Plots are given that can be used to obtain a quick assessment of the sensitivity of the DLF to each of the three key climatic quantities, for specific climatic conditions corresponding to different regions of the globe. Our model downwelling fluxes are validated against available data from ground-based stations distributed over the globe, as given by the Baseline Surface Radiation Network. There is a negative bias of the model fluxes when compared against BSRN fluxes, ranging from ?7 to ?9 Wm?2, mostly caused by low cloud amount differences between the station and satellite measurements, particularly in cold climates. Finally, we compare our model results with those of other deterministic models and general circulation models

Long-term global distribution of earth's shortwave radiation budget at the top of atmosphere

International audienceThe mean monthly shortwave (SW) radiation budget at the top of atmosphere (TOA) was computed on 2.5° longitude-latitude resolution for the 14-year period from 1984 to 1997, using a radiative transfer model with long-term climatological data from the International Satellite Cloud Climatology Project (ISCCP-D2) supplemented by data from the National Centers for Environmental Prediction ? National Center for Atmospheric Research (NCEP-NCAR) Global Reanalysis project, and other global data bases such as TIROS Operational Vertical Sounder (TOVS) and Global Aerosol Data Set (GADS). The model radiative fluxes at TOA were validated against Earth Radiation Budget Experiment (ERBE) S4 scanner satellite data (1985?1989). The model is able to predict the seasonal and geographical variation of SW TOA fluxes. On a mean annual and global basis, the model is in very good agreement with ERBE, overestimating the outgoing SW radiation at TOA (OSR) by 0.93 Wm-2 (or by 0.92%), within the ERBE uncertainties. At pixel level, the OSR differences between model and ERBE are mostly within ±10 Wm-2, with ±5 Wm-2 over extended regions, while there exist some geographic areas with differences of up to 40 Wm-2, associated with uncertainties in cloud properties and surface albedo. The 14-year average model results give a planetary albedo equal to 29.6% and a TOA OSR flux of 101.2 Wm-2. A significant linearly decreasing trend in OSR and planetary albedo was found, equal to 2.3 Wm-2 and 0.6% (in absolute values), respectively, over the 14-year period (from January 1984 to December 1997), indicating an increasing solar planetary warming. This planetary SW radiative heating occurs in the tropical and sub-tropical areas (20° S?20° N), with clouds being the most likely cause. The computed global mean OSR anomaly ranges within ±4 Wm-2, with signals from El Niño and La Niña events or Pinatubo eruption, whereas significant negative OSR anomalies, starting from year 1992, are also detected

Analysis of the decrease in the tropical mean outgoing shortwave radiation at the top of atmosphere for the period 1984-2000

International audienceA decadal-scale trend in the tropical radiative energy budget has been observed recently by satellites, which however is not reproduced by climate models. In the present study, we have computed the outgoing shortwave radiation (OSR) at the top of atmosphere (TOA) at 2.5° longitude-latitude resolution and on a mean monthly basis for the 17-year period 1984-2000, by using a deterministic solar radiative transfer model and cloud climatological data from the International Satellite Cloud Climatology Project (ISCCP) D2 database. Anomaly time series for the mean monthly pixel-level OSR fluxes, as well as for the key physical parameters, were constructed. A significant decreasing trend in OSR anomalies, starting mainly from the late 1980s, was found in tropical and subtropical regions (30° S-30° N), indicating a decadal increase in solar planetary heating equal to 1.9±0.3Wm-2/decade, reproducing well the features recorded by satellite observations, in contrast to climate model results. This increase in solar planetary heating, however, is accompanied by a similar increase in planetary cooling, due to increased outgoing longwave radiation, so that there is no change in net radiation. The model computed OSR trend is in good agreement with the corresponding linear decadal decrease of 2.5±0.4Wm-2/decade in tropical mean OSR anomalies derived from ERBE S-10N non-scanner data (edition 2). An attempt was made to identify the physical processes responsible for the decreasing trend in tropical mean OSR. A detailed correlation analysis using pixel-level anomalies of model computed OSR flux and ISCCP cloud cover over the entire tropical and subtropical region (30° S-30° N), gave a correlation coefficient of 0.79, indicating that decreasing cloud cover is the main reason for the tropical OSR trend. According to the ISCCP-D2 data derived from the combined visible/infrared (VIS/IR) analysis, the tropical cloud cover has decreased by 6.6±0.2% per decade, in relative terms. A detailed analysis of the inter-annual and long-term variability of the various parameters determining the OSR at TOA, has shown that the most important contribution to the observed OSR trend comes from a decrease in low-level cloud cover over the period 1984-2000, followed by decreases in middle and high-level cloud cover. Note, however, that there still remain some uncertainties associated with the existence and magnitude of trends in ISCCP-D2 cloud amounts. Opposite but small trends are introduced by increases in cloud scattering optical depth of low and middle clouds

Global distribution of Earth's surface shortwave radiation budget

International audienceThe monthly mean shortwave (SW) radiation budget at the Earth's surface (SRB) was computed on 2.5-degree longitude-latitude resolution for the 17-year period from 1984 to 2000, using a radiative transfer model accounting for the key physical parameters that determine the surface SRB, and long-term climatological data from the International Satellite Cloud Climatology Project (ISCCP-D2). The model input data were supplemented by data from the National Centers for Environmental Prediction - National Center for Atmospheric Research (NCEP-NCAR) and European Center for Medium Range Weather Forecasts (ECMWF) Global Reanalysis projects, and other global data bases such as TIROS Operational Vertical Sounder (TOVS) and Global Aerosol Data Set (GADS). The model surface radiative fluxes were validated against surface measurements from 22 stations of the Baseline Surface Radiation Network (BSRN) covering the years 1992-2000, and from 700 stations of the Global Energy Balance Archive (GEBA), covering the period 1984-2000. The model is in good agreement with BSRN and GEBA, with a negative bias of 14 and 6.5 Wm-2, respectively. The model is able to reproduce interesting features of the seasonal and geographical variation of the surface SW fluxes at global scale. Based on the 17-year average model results, the global mean SW downward surface radiation (DSR) is equal to 171.6 Wm-2, whereas the net downward (or absorbed) surface SW radiation is equal to 149.4 Wm-2, values that correspond to 50.2 and 43.7% of the incoming SW radiation at the top of the Earth's atmosphere. These values involve a long-term surface albedo equal to 12.9%. Significant increasing trends in DSR and net DSR fluxes were found, equal to 4.1 and 3.7 Wm-2, respectively, over the 1984-2000 period (equivalent to 2.4 and 2.2 Wm-2 per decade), indicating an increasing surface solar radiative heating. This surface SW radiative heating is primarily attributed to clouds, especially low-level, and secondarily to other parameters such as total precipitable water. The surface solar heating occurs mainly in the period starting from the early 1990s, in contrast to decreasing trend in DSR through the late 1980s. The computed global mean DSR and net DSR flux anomalies were found to range within ±8 and ±6 Wm-2, respectively, with signals from El Niño and La Niña events, and the Pinatubo eruption, whereas significant positive anomalies have occurred in the period 1992-2000

Analysis of the decrease in the tropical mean outgoing shortwave radiation at the top of atmosphere for the period 1984%ndash;2000

International audienceA decadal-scale trend in the tropical radiative energy budget has been observed recently by satellites, which however is not reproduced by climate models. In the present study, we have computed the outgoing shortwave radiation (OSR) at the top of atmosphere (TOA) at 2.5° longitude-latitude resolution and on a mean monthly basis for the 17-year period 1984?2000, by using a deterministic solar radiative transfer model and cloud climatological data from the International Satellite Cloud Climatology Project (ISCCP) D2 database. Atmospheric temperature and humidity vertical profiles, as well as other supplementary data, were taken from the National Centers for Environmental Prediction ? National Center for Atmospheric Research (NCEP/NCAR) and the European Center for Medium-Range Weather Forecasts (ECMWF) Global Reanalysis Projects, while other global databases, such as the Global Aerosol Data Set (GADS) for aerosol data, were also used. Anomaly time series for the mean monthly pixel-level OSR fluxes, as well as for the key physical parameters, were constructed. A significant decreasing trend in OSR anomalies, starting mainly from the late 1980s, was found in tropical and subtropical regions (30° S?30° N), indicating an increase in solar planetary heating equal to 3.2±0.5 Wm-2 over the 17-year time period from 1984 to 2000 or 1.9±0.3 Wm-2/decade, reproducing well the features recorded by satellite observations, in contrast to climate model results. The model computed trend is in good agreement with the corresponding linear decrease of 3.7±0.5 Wm-2 (or 2.5±0.4 Wm-2/decade) in tropical mean OSR anomalies derived from ERBE S-10N non-scanner data. An attempt was made to identify the physical processes responsible for the decreasing trend in tropical mean OSR. A detailed correlation analysis using pixel-level anomalies of OSR flux and ISCCP cloud cover over the entire tropical and subtropical region (30° S?30° N), gave a correlation coefficient of 0.79, indicating that decreasing cloud cover is the main reason for the tropical OSR trend. According to the ISCCP-D2 data derived from the combined visible/infrared (VIS/IR) analysis, the tropical cloud cover has decreased by 6.6±0.2% per decade, in relative terms. A detailed analysis of the inter-annual and long-term variability of the various parameters determining the OSR at TOA, has shown that the most important contribution to the observed OSR trend comes from a decrease in low-level cloud cover over the period 1984?2000, followed by decreases in middle and high-level cloud cover. Opposite but small trends are introduced by increases in cloud scattering optical depth of low and middle clouds

Modelling the direct effect of aerosols in the solar near-infrared on a planetary scale

International audienceWe used a spectral radiative transfer model to compute the direct radiative effect (DRE) of natural plus anthropogenic aerosols in the solar near-infrared (IR), between 0.85?10 ?m, namely, their effect on the outgoing near-IR radiation at the top of atmosphere (TOA, ?FTOA), on the atmospheric absorption of near-IR radiation (?Fatmab) and on the surface downward and absorbed near-IR radiation (?Fsurf, and ?Fsurfnet, respectively). The computations were performed on a global scale (over land and ocean) under all-sky conditions, using detailed spectral aerosol optical properties taken from the Global Aerosol Data Set (GADS) supplemented by realistic data for the rest of surface and atmospheric parameters. The computed aerosol DRE, averaged over the 12-year period 1984?1995 for January and July, shows that on a global mean basis aerosols produce a planetary cooling by increasing the scattered near-IR radiation back to space by 0.48 W m?2, they warm the atmosphere by 0.37 W m?2 and cool the surface by decreasing the downward and absorbed near-IR radiation at surface by 1.03 and 0.85 W m?2, respectively. The magnitude of the near-IR aerosol DRE is smaller than that of the combined ultraviolet (UV) and visible DRE, but it is still energetically important, since it contributes to the total shortwave (SW) DRE by 22?31%. The aerosol-produced near-IR surface cooling combined with the atmospheric warming, may affect the thermal dynamics of the Earth-atmosphere system, by increasing the atmospheric stability, decreasing thus cloud formation, and precipitation, especially over desertification threatened regions such as the Mediterranean basin. This, together with the fact that the sign of near-IR aerosol DRE is sometimes opposite to that of UV-visible DRE, demonstrates the importance of performing detailed spectral computations to provide estimates of the climatic role of aerosols for the Earth-atmosphere system. This was demonstrated by sensitivity tests revealing very large differences (up to 300%) between aerosol DREs computed using detailed spectral and spectrally-averaged aerosol optical properties. Our model results indicate thus that the aerosol direct radiative effect on the near-IR radiation is very sensitive to the treatment of the spectral dependence of aerosol optical properties and solar radiation

ENSO surface longwave radiation forcing over the tropical Pacific

International audienceWe have studied the spatial and temporal variation of the surface longwave radiation (downwelling and net) over a 21-year period in the tropical and subtropical Pacific Ocean (40 S?40 N, 90 E?75 W). The fluxes were computed using a deterministic model for atmospheric radiation transfer, along with satellite data from the ISCCP-D2 database and reanalysis data from NCEP/NCAR (acronyms explained in main text), for the key atmospheric and surface input parameters. An excellent correlation was found between the downwelling longwave radiation (DLR) anomaly and the Niño-3.4 index time-series, over the Niño-3.4 region located in the central Pacific. A high anti-correlation was also found over the western Pacific (15?0 S, 105?130 E). There is convincing evidence that the time series of the mean downwelling longwave radiation anomaly in the western Pacific precedes that in the Niño-3.4 region by 3?4 months. Thus, the downwelling longwave radiation anomaly is a complementary index to the SST anomaly for the study of ENSO events and can be used to asses whether or not El Niño or La Niña conditions prevail. Over the Niño-3.4 region, the mean DLR anomaly values range from +20 Wm?2 during El Niño episodes to ?20 Wm?2 during La Niña events, while over the western Pacific (15?0 S, 105?130 E) these values range from ?15 Wm?2 to +10 Wm?2, respectively. The long- term average (1984?2004) distribution of the net surface longwave radiation to the surface over the tropical and subtropical Pacific for the three month period November-December-January shows a net thermal cooling of the ocean surface. When El Niño conditions prevail, the thermal radiative cooling in the central and south-eastern tropical Pacific becomes weaker by 10 Wm?2 south of the equator in the central Pacific (7?0 S, 160?120 W) for the three-month period of NDJ, because the DLR increase is larger than the increase in surface thermal emission. In contrast, the thermal radiative cooling over Indonesia is enhanced by 10 Wm?2 during the early (August?September?October) El Niño phase