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From an evolutive perspective, tumor cells endure successive turnover upon stress conditions and pressure to adapt to new environments. These cells use exceptional communication skills to share biological information to “survive upon every metabolic cost”. The tumor microenvironment (TME) is a miscellaneous collection of cells, factors, and extracellular vesicles (EVs). EVs are small lipid bilayer-delimited particles derived from cells with sizes ranging from 100 to 1000 nm. Exosomes (

The recovery of a new Antarctic ice core spanning the past ∼ 1.5 million years will advance our understanding of climate system dynamics during the Quaternary. Recently, glaciological field surveys have been conducted to select the most suitable core location near Dome Fuji (DF), Antarctica. Specifically, ground-based radar-echo soundings have been used to acquire highly detailed images of bedrock topography and internal ice layers. In this study, we use a one-dimensional (1-D) ice-flow model to compute the temporal evolutions of age and temperature, in which the ice flow is linked with not only transient climate forcing associated with past glacial–interglacial cycles but also transient basal melting diagnosed along the evolving temperature profile. We investigated the influence of ice thickness, accumulation rate, and geothermal heat flux on the age and temperature profiles. The model was constrained by the observed temperature and age profiles reconstructed from the DF ice-core analysis. The results of sensitivity experiments indicate that ice thickness is the most crucial parameter influencing the computed age of the ice because it is critical to the history of basal temperature and basal melting, which can eliminate old ice. The 1-D model was applied to a 54 km long transect in the vicinity of DF and compared with radargram data. We found that the basal age of the ice is mostly controlled by the local ice thickness, demonstrating the importance of high-spatial-resolution surveys of bedrock topography for selecting ice-core drilling sites.

We reconstructed surface mass balance (SMB) around Dome Fuji, Antarctica, over the last 5000 years using the data from 15 shallow ice cores and seven snow pits. The depth–age relationships for the ice cores were determined by synchronizing them with a layer-counted ice core from West Antarctica (WAIS Divide ice core) using volcanic signals. The reconstructed SMB records for the last 4000 years show spatial patterns that may be affected by their locations relative to the ice divides around Dome Fuji, proximity to the ocean, and wind direction. The SMB records from the individual ice cores and snow pits were stacked to reconstruct the SMB history in the Dome Fuji area. The stacked record exhibits a long-term decreasing trend at -0.037±0.005 kg m−2 per century over the last 5000 years in the preindustrial period. The decreasing trend may be the result of long-term surface cooling over East Antarctica and the Southern Ocean and sea ice expansion in the water vapor source areas. The multidecadal to centennial variations of the Dome Fuji SMB after detrending the record shows four distinct periods during the last millennium: a mostly negative period before 1300 CE, a slightly positive period from 1300 to 1450 CE, a slightly negative period from 1450 to 1850 CE with a weak maximum around 1600 CE, and a strong increase after 1850 CE. These variations are consistent with those of previously reconstructed SMB records in the East Antarctic plateau. The low accumulation rate periods tend to coincide with the combination of strong volcanic forcings and solar minima for the last 1000 years, but the correspondence is not clear for the older periods, possibly because of the lack of coincidence of volcanic and solar forcings or the deterioration of the SMB record due to a smaller number of stacked cores.

The retrieval of continuous ice core records of more than 1 Myr is an important challenge in palaeo-climatology. For identifying suitable sites for drilling such ice, knowledge of the subglacial topography and englacial layering is crucial. For this purpose, extensive ground-based ice radar surveys were carried out over Dome Fuji in the East Antarctic plateau during the 2017/18 and 2018/19 austral summers by the Japanese Antarctic Research Expedition, on the basis of ground-based radar surveys conducted over the previous ∼ 30 years. High-gain Yagi antennae were used to improve the antenna beam directivity, thereby significantly decreasing hyperbolic features of unfocused along-track diffraction hyperbolae in the echoes from mountainous ice–bedrock interfaces. We combined the new ice thickness data with the previous ground-based data, recorded since the 1980s, to generate an accurate high-spatial-resolution (up to 0.5 km between survey lines) ice thickness map. This map revealed a complex landscape composed of networks of subglacial valleys and highlands. Based on the new map, we examined the roughness of the ice–bed interface, the bed surface slope, the driving stress of ice and the subglacial hydrological condition. These new products and analyses set substantial constraints on identifying possible locations for new drilling. In addition, our map was compared with a few bed maps compiled by earlier independent efforts based on airborne radar data to examine the difference in features between datasets. Our analysis suggests that widely available bed topography products should be validated with in situ observations where possible.

Glacial periods undergo frequent climate shifts between warm interstadials and cold stadials on a millennial timescale. Recent studies show that the duration of these climate modes varies with the background climate; a colder background climate and lower CO2 generally result in a shorter interstadial and a longer stadial through its impact on the Atlantic Meridional Overturning Circulation (AMOC). However, the duration of stadials is shorter during Marine Isotope Stage 3 (MIS3) than during MIS5, despite the colder climate in MIS3, suggesting potential control from other climate factors on the duration of stadials. In this study, we investigate the role of glacial ice sheets. For this purpose, freshwater hosing experiments are conducted with an atmosphere–ocean general circulation model under MIS5a and MIS3 boundary conditions, as well as MIS3 boundary conditions with MIS5a ice sheets. The impact of ice sheet differences on the duration of the stadials is evaluated by comparing recovery times of the AMOC after the freshwater forcing is stopped. These experiments show a slightly shorter recovery time of the AMOC during MIS3 compared with MIS5a, which is consistent with ice core data. We find that larger glacial ice sheets in MIS3 shorten the recovery time. Sensitivity experiments show that stronger surface winds over the North Atlantic shorten the recovery time by increasing the surface salinity and decreasing the sea ice amount in the deepwater formation region, which sets favorable conditions for oceanic convection. In contrast, we also find that surface cooling by larger ice sheets tends to increase the recovery time of the AMOC by increasing the sea ice thickness over the deepwater formation region. Thus, this study suggests that the larger ice sheet during MIS3 compared with MIS5a could have contributed to the shortening of stadials in MIS3, despite the climate being colder than that of MIS5a, because surface wind plays a larger role.

Ice-sheet age computations are formulated using an Eulerian advection equation, and there are many schemes that can be used to solve them numerically. Typically, these differ in numerical characteristics such as stability, accuracy, and diffusivity. Furthermore, although various methods have been presented for ice-sheet age computations, the constrained interpolation profile method and its variants have not been examined in this context. The present study introduces one of its variants, a rational function-based constrained interpolation profile (RCIP) scheme, to one-dimensional ice age computation and demonstrates its performance levels via comparisons with those obtained from first- and second-order upwind schemes. Our results show that the RCIP scheme preserves the pattern of input surface mass balance histories in terms of the vertical profile of internal annual layer thickness better than the other schemes.

The sea level contribution of the Antarctic ice sheet constitutes a large uncertainty in future sea level projections. Here we apply a linear response theory approach to 16 state-of-the-art ice sheet models to estimate the Antarctic ice sheet contribution from basal ice shelf melting within the 21st century. The purpose of this computation is to estimate the uncertainty of Antarctica's future contribution to global sea level rise that arises from large uncertainty in the oceanic forcing and the associated ice shelf melting. Ice shelf melting is considered to be a major if not the largest perturbation of the ice sheet's flow into the ocean. However, by computing only the sea level contribution in response to ice shelf melting, our study is neglecting a number of processes such as surface-mass-balance-related contributions. In assuming linear response theory, we are able to capture complex temporal responses of the ice sheets, but we neglect any self-dampening or self-amplifying processes. This is particularly relevant in situations in which an instability is dominating the ice loss. The results obtained here are thus relevant, in particular wherever the ice loss is dominated by the forcing as opposed to an internal instability, for example in strong ocean warming scenarios. In order to allow for comparison the methodology was chosen to be exactly the same as in an earlier study (Levermann et al., 2014) but with 16 instead of 5 ice sheet models. We include uncertainty in the atmospheric warming response to carbon emissions (full range of CMIP5 climate model sensitivities), uncertainty in the oceanic transport to the Southern Ocean (obtained from the time-delayed and scaled oceanic subsurface warming in CMIP5 models in relation to the global mean surface warming), and the observed range of responses of basal ice shelf melting to oceanic warming outside the ice shelf cavity. This uncertainty in basal ice shelf melting is then convoluted with the linear response functions of each of the 16 ice sheet models to obtain the ice flow response to the individual global warming path. The model median for the observational period from 1992 to 2017 of the ice loss due to basal ice shelf melting is 10.2 mm, with a likely range between 5.2 and 21.3 mm. For the same period the Antarctic ice sheet lost mass equivalent to 7.4 mm of global sea level rise, with a standard deviation of 3.7 mm (Shepherd et al., 2018) including all processes, especially surface-mass-balance changes. For the unabated warming path, Representative Concentration Pathway 8.5 (RCP8.5), we obtain a median contribution of the Antarctic ice sheet to global mean sea level rise from basal ice shelf melting within the 21st century of 17 cm, with a likely range (66th percentile around the mean) between 9 and 36 cm and a very likely range (90th percentile around the mean) between 6 and 58 cm. For the RCP2.6 warming path, which will keep the global mean temperature below 2 ∘C of global warming and is thus consistent with the Paris Climate Agreement, the procedure yields a median of 13 cm of global mean sea level contribution. The likely range for the RCP2.6 scenario is between 7 and 24 cm, and the very likely range is between 4 and 37 cm. The structural uncertainties in the method do not allow for an interpretation of any higher uncertainty percentiles. We provide projections for the five Antarctic regions and for each model and each scenario separately. The rate of sea level contribution is highest under the RCP8.5 scenario. The maximum within the 21st century of the median value is 4 cm per decade, with a likely range between 2 and 9 cm per decade and a very likely range between 1 and 14 cm per decade.

The sixth version of the Model for Interdisciplinary Research on Climate (MIROC), called MIROC6, was cooperatively developed by a Japanese modeling community. In the present paper, simulated mean climate, internal climate variability, and climate sensitivity in MIROC6 are evaluated and briefly summarized in comparison with the previous version of our climate model (MIROC5) and observations. The results show that the overall reproducibility of mean climate and internal climate variability in MIROC6 is better than that in MIROC5. The tropical climate systems (e.g., summertime precipitation in the western Pacific and the eastward-propagating Madden–Julian oscillation) and the midlatitude atmospheric circulation (e.g., the westerlies, the polar night jet, and troposphere–stratosphere interactions) are significantly improved in MIROC6. These improvements can be attributed to the newly implemented parameterization for shallow convective processes and to the inclusion of the stratosphere. While there are significant differences in climates and variabilities between the two models, the effective climate sensitivity of 2.6 K remains the same because the differences in radiative forcing and climate feedback tend to offset each other. With an aim towards contributing to the sixth phase of the Coupled Model Intercomparison Project, designated simulations tackling a wide range of climate science issues, as well as seasonal to decadal climate predictions and future climate projections, are currently ongoing using MIROC6.

Earlier large-scale Greenland ice sheet sea-level projections (e.g. those run during the ice2sea and SeaRISE initiatives) have shown that ice sheet initial conditions have a large effect on the projections and give rise to important uncertainties. The goal of this initMIP-Greenland intercomparison exercise is to compare, evaluate, and improve the initialisation techniques used in the ice sheet modelling community and to estimate the associated uncertainties in modelled mass changes. initMIP-Greenland is the first in a series of ice sheet model intercomparison activities within ISMIP6 (the Ice Sheet Model Intercomparison Project for CMIP6), which is the primary activity within the Coupled Model Intercomparison Project Phase 6 (CMIP6) focusing on the ice sheets. Two experiments for the large-scale Greenland ice sheet have been designed to allow intercomparison between participating models of (1) the initial present-day state of the ice sheet and (2) the response in two idealised forward experiments. The forward experiments serve to evaluate the initialisation in terms of model drift (forward run without additional forcing) and in response to a large perturbation (prescribed surface mass balance anomaly); they should not be interpreted as sea-level projections. We present and discuss results that highlight the diversity of data sets, boundary conditions, and initialisation techniques used in the community to generate initial states of the Greenland ice sheet. We find good agreement across the ensemble for the dynamic response to surface mass balance changes in areas where the simulated ice sheets overlap but differences arising from the initial size of the ice sheet. The model drift in the control experiment is reduced for models that participated in earlier intercomparison exercises.

Documenting past changes in the East Antarctic surface mass balance is important to improve ice core chronologies and to constrain the ice-sheet contribution to global mean sea-level change. Here we reconstruct past changes in the ratio of surface mass balance (SMB ratio) between the EPICA Dome C (EDC) and Dome Fuji (DF) East Antarctica ice core sites, based on a precise volcanic synchronization of the two ice cores and on corrections for the vertical thinning of layers. During the past 216 000 a, this SMB ratio, denoted SMBEDC/SMBDF, varied between 0.7 and 1.1, being small during cold periods and large during warm periods. Our results therefore reveal larger amplitudes of changes in SMB at EDC compared with DF, consistent with previous results showing larger amplitudes of changes in water stable isotopes and estimated surface temperature at EDC compared with DF. Within the last glacial inception (Marine Isotope Stages, MIS-5c and MIS-5d), the SMB ratio deviates by up to 0.2 from what is expected based on differences in water stable isotope records. Moreover, the SMB ratio is constant throughout the late parts of the current and last interglacial periods, despite contrasting isotopic trends.

The present paper revisits the future surface-climate experiments on the Greenland ice sheet proposed by the Sea-level Response to Ice Sheet Evolution (SeaRISE; Bindschadler et al., 2013) study. The projections of the different SeaRISE participants show dispersion, which has not been examined in detail to date. A series of sensitivity experiments are conducted and analyzed using the ice-sheet model for integrated Earth-system studies (IcIES) by replacing one or more formulations of the model parameters with those adopted in other model(s). The results show that large potential sources of the dispersion among the projections of the different SeaRISE participants are differences in the initialization methods and in the surface mass balance methods, and both aspects have almost equal impact on the results. The treatment of ice-sheet margins in the simulation has a secondary impact on the dispersion. We conclude that spinning up the model using fixed topography through the spin-up period while the temperature is allowed to evolve according to the surface temperature history is the preferred representation, at least for the experiment configuration examined in the present paper. A benchmark model experimental setup that most of the numerical models can perform is proposed for future intercomparison projects, in order to evaluate the uncertainties relating to pure ice-sheet model flow characteristics.

Skin melanoma is one of the most aggressive and difficult-to-treat human malignancies, characterized by poor survival rates, thus requiring urgent novel therapeutic approaches. Although metabolic reprogramming has represented so far, a cancer hallmark, accumulating data indicate a high plasticity of cancer cells in modulating cellular metabolism to adapt to a heterogeneous and continuously changing microenvironment, suggesting a novel therapeutic approach for dietary manipulation in cancer therapy. To this aim, we exposed melanoma cells to combined nutrient-restriction/sorafenib. Results indicate that cell death was efficiently induced, with apoptosis representing the prominent feature. In contrast, autophagy was blocked in the final stage by this treatment, similarly to chloroquine, which also enhanced melanoma cell sensitization to combined treatment. Energy stress was evidenced by associated treatment with mitochondrial dysfunction and glycolysis impairment, suggesting metabolic stress determining melanoma cell death. A reduction of tumor growth after cycles of intermittent fasting together with sorafenib treatment was also observed in vivo, reinforcing that the nutrient shortage can potentiate anti-melanoma therapy. Our findings showed that the restriction of nutrients by intermittent fasting potentiates the effects of sorafenib due to the modulation of cellular metabolism, suggesting that it is possible to harness the energy of cancer cells for the treatment of melanoma.

Slime mold species in the genus Dictyostelium are considered to have a close relationship with non-parasitic nematodes; they are sympatric in soils and can exhibit interspecific competition for food. We investigated whether this relationship extends to a plant-parasitic nematode that is active in the rhizosphere and has broad host specificity, damaging crops worldwide. Using a novel assay to examine the interaction between the cellular slime mold, Dictyostelium discoideum, and the plant-parasitic nematodes, Meloidogyne spp., we found that cellular slime molds can repel plant parasitic nematodes. Specifically, the repulsion activity was in response to chemical compounds released by cellular slime mold fruiting bodies. Under laboratory conditions, these soluble chemical extracts from fruiting bodies of D. discoideum showed repulsion activity strong enough to protect plant roots. The fruiting body cell extracts repelled but were not toxic to the plant-parasitic nematodes.

We describe the creation of a data set describing changes related to the presence of ice sheets, including ice-sheet extent and height, ice-shelf extent, and the distribution and elevation of ice-free land at the Last Glacial Maximum (LGM), which were used in LGM experiments conducted as part of the fifth phase of the Coupled Modelling Intercomparison Project (CMIP5) and the third phase of the Palaeoclimate Modelling Intercomparison Project (PMIP3). The CMIP5/PMIP3 data sets were created from reconstructions made by three different groups, which were all obtained using a model-inversion approach but differ in the assumptions used in the modelling and in the type of data used as constraints. The ice-sheet extent in the Northern Hemisphere (NH) does not vary substantially between the three individual data sources. The difference in the topography of the NH ice sheets is also moderate, and smaller than the differences between these reconstructions (and the resultant composite reconstruction) and ice-sheet reconstructions used in previous generations of PMIP. Only two of the individual reconstructions provide information for Antarctica. The discrepancy between these two reconstructions is larger than the difference for the NH ice sheets, although still less than the difference between the composite reconstruction and previous PMIP ice-sheet reconstructions. Although largely confined to the ice-covered regions, differences between the climate response to the individual LGM reconstructions extend over the North Atlantic Ocean and Northern Hemisphere continents, partly through atmospheric stationary waves. Differences between the climate response to the CMIP5/PMIP3 composite and any individual ice-sheet reconstruction are smaller than those between the CMIP5/PMIP3 composite and the ice sheet used in the last phase of PMIP (PMIP2).

In the context of future climate change, understanding the nature and behaviour of ice sheets during warm intervals in Earth history is of fundamental importance. The late Pliocene warm period (also known as the PRISM interval: 3.264 to 3.025 million years before present) can serve as a potential analogue for projected future climates. Although Pliocene ice locations and extents are still poorly constrained, a significant contribution to sea-level rise should be expected from both the Greenland ice sheet and the West and East Antarctic ice sheets based on palaeo sea-level reconstructions. Here, we present results from simulations of the Antarctic ice sheet by means of an international Pliocene Ice Sheet Modeling Intercomparison Project (PLISMIP-ANT). For the experiments, ice-sheet models including the shallow ice and shelf approximations have been used to simulate the complete Antarctic domain (including grounded and floating ice). We compare the performance of six existing numerical ice-sheet models in simulating modern control and Pliocene ice sheets by a suite of five sensitivity experiments. We include an overview of the different ice-sheet models used and how specific model configurations influence the resulting Pliocene Antarctic ice sheet. The six ice-sheet models simulate a comparable present-day ice sheet, considering the models are set up with their own parameter settings. For the Pliocene, the results demonstrate the difficulty of all six models used here to simulate a significant retreat or re-advance of the East Antarctic ice grounding line, which is thought to have happened during the Pliocene for the Wilkes and Aurora basins. The specific sea-level contribution of the Antarctic ice sheet at this point cannot be conclusively determined, whereas improved grounding line physics could be essential for a correct representation of the migration of the grounding-line of the Antarctic ice sheet during the Pliocene.

The understanding of the nature and behavior of ice sheets in past warm periods is important for constraining the potential impacts of future climate change. The Pliocene warm period (between 3.264 and 3.025 Ma) saw global temperatures similar to those projected for future climates; nevertheless, Pliocene ice locations and extents are still poorly constrained. We present results from the efforts to simulate mid-Pliocene Greenland Ice Sheets by means of the international Pliocene Ice Sheet Modeling Intercomparison Project (PLISMIP). We compare the performance of existing numerical ice sheet models in simulating modern control and mid-Pliocene ice sheets with a suite of sensitivity experiments guided by available proxy records. We quantify equilibrated ice sheet volume on Greenland, identifying a potential range in sea level contributions from warm Pliocene scenarios. A series of statistical measures are performed to quantify the confidence of simulations with focus on inter-model and inter-scenario differences. We find that Pliocene Greenland Ice Sheets are less sensitive to differences in ice sheet model configurations and internal physical quantities than to changes in imposed climate forcing. We conclude that Pliocene ice was most likely to be limited to the highest elevations in eastern and southern Greenland as simulated with the highest confidence and by synthesizing available regional proxies; however, the extent of those ice caps needs to be further constrained by using a range of general circulation model (GCM) climate forcings.

One hundred thousand years of ice sheet buildup came to a rapid end ∼25–10 thousand years before present (ka BP), when ice sheets receded quickly and multi-proxy reconstructed global mean surface temperatures rose by ∼3–5 °C. It still remains unresolved whether insolation changes due to variations of earth's tilt and orbit were sufficient to terminate glacial conditions. Using a coupled three-dimensional climate–ice sheet model, we simulate the climate and Northern Hemisphere ice sheet evolution from 78 ka BP to 0 ka BP in good agreement with sea level and ice topography reconstructions. Based on this simulation and a series of deglacial sensitivity experiments with individually varying orbital parameters and prescribed CO2, we find that enhanced calving led to a slowdown of ice sheet growth as early as ∼8 ka prior to the Last Glacial Maximum (LGM). The glacial termination was then initiated by enhanced ablation due to increasing obliquity and precession, in agreement with the Milankovitch theory. However, our results also support the notion that the ∼100 ppmv rise of atmospheric CO2 after ∼18 ka BP was a key contributor to the deglaciation. Without it, the present-day ice volume would be comparable to that of the LGM and global mean temperatures would be about 3 °C lower than today. We further demonstrate that neither orbital forcing nor rising CO2 concentrations alone were sufficient to complete the deglaciation.

Paleoclimate experiments using contemporary climate models are an effective measure to evaluate climate models. In recent years, Earth system models (ESMs) were developed to investigate carbon cycle climate feedbacks, as well as to project the future climate. Paleoclimate events can be suitable benchmarks to evaluate ESMs. The variation in aerosols associated with the volcanic eruptions provide a clear signal in forcing, which can be a good test to check the response of a climate model to the radiation changes. The variations in atmospheric CO2 level or changes in ice sheet extent can be used for evaluation as well. Here we present implementations of the paleoclimate experiments proposed by the Coupled Model Intercomparison Project phase 5/Paleoclimate Modelling Intercomparison Project phase 3 (CMIP5/PMIP3) using MIROC-ESM, an ESM based on the global climate model MIROC (Model for Interdisciplinary Research on Climate). In this paper, experimental settings and spin-up procedures of the mid-Holocene, the Last Glacial Maximum, and the Last Millennium experiments are explained. The first two experiments are time slice experiments and the last one is a transient experiment. The complexity of the model requires various steps to correctly configure the experiments. Several basic outputs are also shown.

Predictions of marine ice-sheet behaviour require models that are able to robustly simulate grounding line migration. We present results of an intercomparison exercise for marine ice-sheet models. Verification is effected by comparison with approximate analytical solutions for flux across the grounding line using simplified geometrical configurations (no lateral variations, no effects of lateral buttressing). Unique steady state grounding line positions exist for ice sheets on a downward sloping bed, while hysteresis occurs across an overdeepened bed, and stable steady state grounding line positions only occur on the downward-sloping sections. Models based on the shallow ice approximation, which does not resolve extensional stresses, do not reproduce the approximate analytical results unless appropriate parameterizations for ice flux are imposed at the grounding line. For extensional-stress resolving "shelfy stream" models, differences between model results were mainly due to the choice of spatial discretization. Moving grid methods were found to be the most accurate at capturing grounding line evolution, since they track the grounding line explicitly. Adaptive mesh refinement can further improve accuracy, including fixed grid models that generally perform poorly at coarse resolution. Fixed grid models, with nested grid representations of the grounding line, are able to generate accurate steady state positions, but can be inaccurate over transients. Only one full-Stokes model was included in the intercomparison, and consequently the accuracy of shelfy stream models as approximations of full-Stokes models remains to be determined in detail, especially during transients.

We present the results of the first ice sheet model intercomparison project for higher-order and full-Stokes ice sheet models. These models are compared and verified in a series of six experiments of which one has an analytical solution obtained from a perturbation analysis. The experiments are applied to both 2-D and 3-D geometries; five experiments are steady-state diagnostic, and one has a time-dependent prognostic solution. All participating models give results that are in close agreement. A clear distinction can be made between higher-order models and those that solve the full system of equations. The full-Stokes models show a much smaller spread, hence are in better agreement with one another and with the analytical solution.

The ice sheet-climate interaction as well as the climatic response to orbital parameters and atmospheric CO2 concentration are examined in order to drive an ice sheet model throughout an ice age cycle. Feedback processes between ice sheet and atmosphere are analyzed by numerical experiments using a high resolution General Circulation Model (GCM) under different conditions at the Last Glacial Maximum. Among the proposed processes, the ice albedo feedback, the elevation-mass balance feedback and the desertification effect over the ice sheet were found to be the dominant processes for the ice-sheet mass balance. For the elevation-mass balance feedback, the temperature lapse rate over the ice sheet is proposed to be weaker than assumed in previous studies. Within the plausible range of parameters related to these processes, the ice sheet response to the orbital parameters and atmospheric CO2 concentration for the last glacial/interglacial cycle was simulated in terms of both ice volume and geographical distribution, using a three-dimensional ice-sheet model. Careful treatment of climate-ice sheet feedback is essential for a reliable simulation of the ice sheet changes during ice age cycles.

Melanoma cells express the platelet-activating factor receptor (PAFR) and, thus, respond to PAF, a bioactive lipid produced by both tumour cells and those in the tumour microenvironment such as macrophages. Here, we show that treatment of a human melanoma SKmel37 cell line with cisplatin led to increased expression of PAFR and its accumulation. In the presence of exogenous PAF, melanoma cells were significantly more resistant to cisplatin-induced cell death. Inhibition of PAFR-dependent signalling pathways by a PAFR antagonist (WEB2086) showed chemosensitisation of melanoma cells in vitro. Nude mice were inoculated with SKmel37 cells and treated with cisplatin and WEB2086. Animals treated with both agents showed significantly decreased tumour growth compared to the control group and groups treated with only one agent. PAFR accumulation and signalling are part of a prosurvival program of melanoma cells, therefore constituting a promising target for combination therapy for melanomas.