Effect of vascular targeting agent in rat tumor model: dynamic contrast-enhanced versus diffusion-weighted MR imaging

PURPOSE: To compare dynamic contrast material-enhanced magnetic resonance (MR) imaging and diffusion-weighted MR imaging for noninvasive evaluation of early and late effects of a vascular targeting agent in a rat tumor model. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee for animal care and use. Thirteen rats with one rhabdomyosarcoma in each flank (26 tumors) underwent dynamic contrast-enhanced imaging and diffusion-weighted echo-planar imaging in a 1.5-T MR unit before intraperitoneal injection of combretastatin A4 phosphate and at early (1 and 6 hours) and later (2 and 9 days) follow-up examinations after the injection. Histopathologic examination was performed at each time point. The apparent diffusion coefficient (ADC) of each tumor was calculated separately on the basis of diffusion-weighted images obtained with low b gradient values (ADC(low); b = 0, 50, and 100 sec/mm(2)) and high b gradient values (ADC(high); b = 500, 750, and 1000 sec/mm(2)). The difference between ADC(low) and ADC(high) was used as a surrogate measure of tissue perfusion (ADC(low) - ADC(high) = ADC(perf)). From the dynamic contrast-enhanced MR images, the volume transfer constant k and the initial slope of the contrast enhancement-time curve were calculated. For statistical analyses, a paired two-tailed Student t test and linear regression analysis were used. RESULTS: Early after administration of combretastatin, all perfusion-related parameters (k, initial slope, and ADC(perf)) decreased significantly (P < .001); at 9 days after combretastatin administration, they increased significantly (P < .001). Changes in ADC(perf) were correlated with changes in k (R(2) = 0.46, P < .001) and the initial slope (R(2) = 0.67, P < .001). CONCLUSION: Both dynamic contrast-enhanced MR imaging and diffusion-weighted MR imaging allow monitoring of perfusion changes induced by vascular targeting agents in tumors. Diffusion-weighted imaging provides additional information about intratumoral cell viability versus necrosis after administration of combretastatin.

Using state variables to model the response of tumour cells to radiation and heat: a novel multi-hit-repair approach

In order to overcome the limitations of the linear-quadratic model and include synergistic effects of heat and radiation, a novel radiobiological model is proposed. The model is based on a chain of cell populations which are characterized by the number of radiation induced damages (hits). Cells can shift downward along the chain by collecting hits and upward by a repair process. The repair process is governed by a repair probability which depends upon state variables used for a simplistic description of the impact of heat and radiation upon repair proteins. Based on the parameters used, populations up to 4-5 hits are relevant for the calculation of the survival. The model describes intuitively the mathematical behaviour of apoptotic and nonapoptotic cell death. Linear-quadratic-linear behaviour of the logarithmic cell survival, fractionation, and (with one exception) the dose rate dependencies are described correctly. The model covers the time gap dependence of the synergistic cell killing due to combined application of heat and radiation, but further validation of the proposed approach based on experimental data is needed. However, the model offers a work bench for testing different biological concepts of damage induction, repair, and statistical approaches for calculating the variables of state.

An Ensemble Kalman Filter multi-tracer assimilation: Determining uncertain ocean model parameters for improved climate-carbon cycle projections

An Ensemble Kalman Filter is applied to assimilate observed tracer fields in various combinations in the Bern3D ocean model. Each tracer combination yields a set of optimal transport parameter values that are used in projections with prescribed CO2 stabilization pathways. The assimilation of temperature and salinity fields yields a too vigorous ventilation of the thermocline and the deep ocean, whereas the inclusion of CFC-11 and radiocarbon improves the representation of physical and biogeochemical tracers and of ventilation time scales. Projected peak uptake rates and cumulative uptake of CO2 by the ocean are around 20% lower for the parameters determined with CFC-11 and radiocarbon as additional target compared to those with salinity and temperature only. Higher surface temperature changes are simulated in the Greenland–Norwegian–Iceland Sea and in the Southern Ocean when CFC-11 is included in the Ensemble Kalman model tuning. These findings highlights the importance of ocean transport calibration for the design of near-term and long-term CO2 emission mitigation strategies and for climate projections.

Oxygen and indicators of stress for marine life in multi-model global warming projections

Decadal-to-century scale trends for a range of marine environmental variables in the upper mesopelagic layer (UML, 100–600 m) are investigated using results from seven Earth System Models forced by a high greenhouse gas emission scenario. The models as a class represent the observation-based distribution of oxygen (O2) and carbon dioxide (CO2), albeit major mismatches between observation-based and simulated values remain for individual models. By year 2100 all models project an increase in SST between 2 °C and 3 °C, and a decrease in the pH and in the saturation state of water with respect to calcium carbonate minerals in the UML. A decrease in the total ocean inventory of dissolved oxygen by 2% to 4% is projected by the range of models. Projected O2 changes in the UML show a complex pattern with both increasing and decreasing trends reflecting the subtle balance of different competing factors such as circulation, production, remineralization, and temperature changes. Projected changes in the total volume of hypoxic and suboxic waters remain relatively small in all models. A widespread increase of CO2 in the UML is projected. The median of the CO2 distribution between 100 and 600m shifts from 0.1–0.2 mol m−3 in year 1990 to 0.2–0.4 mol m−3 in year 2100, primarily as a result of the invasion of anthropogenic carbon from the atmosphere. The co-occurrence of changes in a range of environmental variables indicates the need to further investigate their synergistic impacts on marine ecosystems and Earth System feedbacks.

Carbon dioxide and climate impulse response functions for the computation of greenhouse gas metrics: a multi-model analysis

The responses of carbon dioxide (CO2) and other climate variables to an emission pulse of CO2 into the atmosphere are often used to compute the Global Warming Potential (GWP) and Global Temperature change Potential (GTP), to characterize the response timescales of Earth System models, and to build reduced-form models. In this carbon cycle-climate model intercomparison project, which spans the full model hierarchy, we quantify responses to emission pulses of different magnitudes injected under different conditions. The CO2 response shows the known rapid decline in the first few decades followed by a millennium-scale tail. For a 100 Gt-C emission pulse added to a constant CO2 concentration of 389 ppm, 25 ± 9% is still found in the atmosphere after 1000 yr; the ocean has absorbed 59 ± 12% and the land the remainder (16 ± 14%). The response in global mean surface air temperature is an increase by 0.20 ± 0.12 °C within the first twenty years; thereafter and until year 1000, temperature decreases only slightly, whereas ocean heat content and sea level continue to rise. Our best estimate for the Absolute Global Warming Potential, given by the time-integrated response in CO2 at year 100 multiplied by its radiative efficiency, is 92.5 × 10−15 yr W m−2 per kg-CO2. This value very likely (5 to 95% confidence) lies within the range of (68 to 117) × 10−15 yr W m−2 per kg-CO2. Estimates for time-integrated response in CO2 published in the IPCC First, Second, and Fourth Assessment and our multi-model best estimate all agree within 15% during the first 100 yr. The integrated CO2 response, normalized by the pulse size, is lower for pre-industrial conditions, compared to present day, and lower for smaller pulses than larger pulses. In contrast, the response in temperature, sea level and ocean heat content is less sensitive to these choices. Although, choices in pulse size, background concentration, and model lead to uncertainties, the most important and subjective choice to determine AGWP of CO2 and GWP is the time horizon.

A multi-model comparison of Atlantic multidecadal variability

A multi-model analysis of Atlantic multidecadal variability is performed with the following aims: to investigate the similarities to observations; to assess the strength and relative importance of the different elements of the mechanism proposed by Delworth et al. (J Clim 6:1993–2011, 1993) (hereafter D93) among coupled general circulation models (CGCMs); and to relate model differences to mean systematic error. The analysis is performed with long control simulations from ten CGCMs, with lengths ranging between 500 and 3600 years. In most models the variations of sea surface temperature (SST) averaged over North Atlantic show considerable power on multidecadal time scales, but with different periodicity. The SST variations are largest in the mid-latitude region, consistent with the short instrumental record. Despite large differences in model configurations, we find quite some consistency among the models in terms of processes. In eight of the ten models the mid-latitude SST variations are significantly correlated with fluctuations in the Atlantic meridional overturning circulation (AMOC), suggesting a link to northward heat transport changes. Consistent with this link, the three models with the weakest AMOC have the largest cold SST bias in the North Atlantic. There is no linear relationship on decadal timescales between AMOC and North Atlantic Oscillation in the models. Analysis of the key elements of the D93 mechanisms revealed the following: Most models present strong evidence that high-latitude winter mixing precede AMOC changes. However, the regions of wintertime convection differ among models. In most models salinity-induced density anomalies in the convective region tend to lead AMOC, while temperature-induced density anomalies lead AMOC only in one model. However, analysis shows that salinity may play an overly important role in most models, because of cold temperature biases in their relevant convective regions. In most models subpolar gyre variations tend to lead AMOC changes, and this relation is strong in more than half of the models.