Continued development and validation of the AER two-dimensional interactive model

Results from two-dimensional chemistry-transport models have been used to predict the future behavior of ozone in the stratosphere. Since the transport circulation, temperature, and aerosol surface area are fixed in these models, they cannot account for the effects of changes in these quantities, which could be modified because of ozone redistribution and/or other changes in the troposphere associated with climate changes. Interactive two-dimensional models, which calculate the transport circulation and temperature along with concentrations of the chemical species, could provide answers to complement the results from three-dimension model calculations. In this project, we performed the following tasks in pursuit of the respective goals: (1) We continued to refine the 2-D chemistry-transport model; (2) We developed a microphysics model to calculate the aerosol loading and its size distribution; (3) The treatment of physics in the AER 2-D interactive model were refined in the following areas--the heating rate in the troposphere, and wave-forcing from propagation of planetary waves

Stratospheric aircraft exhaust plume and wake chemistry studies

This report documents progress to date in an ongoing study to analyze and model emissions leaving a proposed High Speed Civil Transport (HSCT) from when the exhaust gases leave the engine until they are deposited at atmospheric scales in the stratosphere. Estimates are given for the emissions, summarizing relevant earlier work (CIAP) and reviewing current propulsion research efforts. The chemical evolution and the mixing and vortical motion of the exhaust are analyzed to track the exhaust and its speciation as the emissions are mixed to atmospheric scales. The species tracked include those that could be heterogeneously reactive on the surfaces of the condensed solid water (ice) particles and on exhaust soot particle surfaces. Dispersion and reaction of chemical constituents in the far wake are studied with a Lagrangian air parcel model, in conjunction with a radiation code to calculate the net heating/cooling. Laboratory measurements of heterogeneous chemistry of aqueous sulfuric acid and nitric acid hydrates are also described. Results include the solubility of HCl in sulfuric acid which is a key parameter for modeling stratospheric processing. We also report initial results for condensation of nitric acid trihydrate from gas phase H2O and HNO3

The Risk of Recurrence in Breast Cancer Patients Treated with Tamoxifen: Polymorphisms of CYP2D6 and ABCB1

CYP2D6 plays a major role in the metabolism of tamoxifen, and polymorphism of Pglycoprotein has been associated with resistance of many drug therapies. This study investigates the clinical impact of genetic variants of CYP2D6 and ABCB1 in breast cancer patients treated with tamoxifen. Blood samples from 95 breast cancer patients treated with tamoxifen were collected and genotyped for CYP2D6 and ABCB1 variants using allele-specific PCR method. Recurrence risks were calculated using Kaplan–Meier analysis and compared using the log-rank test. Patients carrying CYP2D6*10/*10 and heterozygous null allele (IM) showed higher risks of developing recurrence and metastasis (OR 13.14; 95% CI 1.57–109.94; P=0.004) than patients with CYP2D6*1/*1 and *1/*10 genotypes. Patients with homozygous CC genotypes of ABCB1 C3435T showed a shorter time to recurrence. Patients who were CYP2D6 IM and homozygous CC genotype of C3435T have statistically significant higher risks of recurrence (P=0.002). Similarly, median time to recurrence in these patients was only 12 months (95% CI=0.79–23.2) compared to those without this combination which was 48 months (95% CI=14.7–81.2). Patients with CYP2D6 IM and homozygous CC genotype of ABCB1 C3435T have shorter times to recurrence. The results confirmed the findings of previous studies and support FDA recommendation to perform pre-genotyping in patients before the choice of therapy is determined in breast cancer patients

Profiling tropospheric CO_2 using Aura TES and TCCON instruments

Monitoring the global distribution and long-term variations of CO_2 sources and sinks is required for characterizing the global carbon budget. Total column measurements are useful for estimating regional-scale fluxes; however, model transport remains a significant error source, particularly for quantifying local sources and sinks. To improve the capability of estimating regional fluxes, we estimate lower tropospheric CO_2 concentrations from ground-based near-infrared (NIR) measurements with space-based thermal infrared (TIR) measurements. The NIR measurements are obtained from the Total Carbon Column Observing Network (TCCON) of solar measurements, which provide an estimate of the total CO_2 column amount. Estimates of tropospheric CO_2 that are co-located with TCCON are obtained by assimilating Tropospheric Emission Spectrometer (TES) free tropospheric CO_2 estimates into the GEOS-Chem model. We find that quantifying lower tropospheric CO_2 by subtracting free tropospheric CO_2 estimates from total column estimates is a linear problem, because the calculated random uncertainties in total column and lower tropospheric estimates are consistent with actual uncertainties as compared to aircraft data. For the total column estimates, the random uncertainty is about 0.55 ppm with a bias of −5.66 ppm, consistent with previously published results. After accounting for the total column bias, the bias in the lower tropospheric CO_2 estimates is 0.26 ppm with a precision (one standard deviation) of 1.02 ppm. This precision is sufficient for capturing the winter to summer variability of approximately 12 ppm in the lower troposphere; double the variability of the total column. This work shows that a combination of NIR and TIR measurements can profile CO_2 with the precision and accuracy needed to quantify lower tropospheric CO_2 variability

Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

Stratospheric aircraft exhaust plume and wake chemistry

Progress to date in an ongoing study to analyze and model emissions leaving a proposed High Speed Civil Transport (HSCT) from when the exhaust gases leave the engine until they are deposited at atmospheric scales in the stratosphere is documented. A kinetic condensation model was implemented to predict heterogeneous condensation in the plume regime behind an HSCT flying in the lower stratosphere. Simulations were performed to illustrate the parametric dependence of contrail droplet growth on the exhaust condensation nuclei number density and size distribution. Model results indicate that the condensation of water vapor is strongly dependent on the number density of activated CN. Incorporation of estimates for dilution factors into a Lagrangian box model of the far-wake regime with scale-dependent diffusion indicates negligible decrease in ozone and enhancement of water concentrations of 6-13 times background, which decrease rapidly over 1-3 days. Radiative calculations indicate a net differential cooling rate of the plume about 3K/day at the beginning of the wake regime, with a total subsidence ranging between 0.4 and 1 km. Results from the Lagrangian plume model were used to estimate the effect of repeated superposition of aircraft plumes on the concentrations of water and NO(y) along a flight corridor. Results of laboratory studies of heterogeneous chemistry are also described. Kinetics of HCl, N2O5 and ClONO2 uptake on liquid sulfuric acid were measured as a function of composition and temperature. Refined measurements of the thermodynamics of nitric acid hydrates indicate that metastable dihydrate may play a role in the nucleation of more stable trihydrates PSC's

KRAS-mutation status in relation to colorectal cancer survival: the joint impact of correlated tumour markers.

Background:Mutations in the Kirsten Ras (KRAS) oncogene are common in colorectal cancer (CRC). The role of KRAS-mutation status as a prognostic factor, however, is unclear. We evaluated the relationship between KRAS-mutation status and CRC survival, considering heterogeneity in this association by tumour and patient characteristics.Methods:The population-based study included individuals diagnosed with CRC between 1998-2007 in Western Washington State. Tumour specimens were tested for KRAS exon 2 mutations, the BRAF p.V600E mutation, and microsatellite instability (MSI). We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between KRAS-mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumour site, stage, and MSI. We conducted additional analyses combining KRAS-mutation, BRAF-mutation, and MSI status.Results:Among 1989 cases, 31% had KRAS-mutated CRC. Kirsten Ras (KRAS)-mutated CRC was associated with poorer disease-specific survival (HR=1.37, 95% CI: 1.13-1.66). This association was not evident in cases who presented with distant-stage CRC. Cases with KRAS-wild-type/BRAF-wild-type/MSI-high CRC had the most favourable prognosis; those with CRC exhibiting a KRAS- or BRAF-mutation and no MSI had the poorest prognosis. Patterns were similar for overall survival.Conclusion:Kirsten Ras (KRAS)-mutated CRC was associated with statistically significantly poorer survival after diagnosis than KRAS-wild-type CRC

A polymorphism of EGFR extracellular domain is associated with progression free-survival in metastatic colorectal cancer patients receiving cetuximab-based treatment

International audienceBackground: Cetuximab, a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR), is currently used in metastatic colorectal cancer (mCRC), but predictive factors for therapeutic response are lacking. Mutational status of KRAS and EGFR, and EGFR copy number are potential determinants of cetuximab activity.Methods: We analyzed tumor tissues from 32 EGFR-positive mCRC patients receiving cetuximab/irinotecan combination and evaluable for treatment response. EGFR copy number was quantified by fluorescence in situ hybridization (FISH). KRAS exon 1 and EGFR exons coding for extracellular regions were sequenced.Results: Nine patients experienced an objective response (partial response) and 23 were considered as nonresponders (12 with stable disease and 11 with progressive disease). There was no EGFR amplification found, but high polysomy was noted in 2 patients, both of which were cetuximab responders. No EGFR mutations were found but a variant of exon 13 (R521K) was observed in 12 patients, 11 of which achieved objective response or stable disease. Progression-free and overall survivals were significantly better in patients with this EGFR exon 13 variant. KRAS mutations were found in 14 cases. While there was a trend for an increased KRAS mutation frequency in nonresponder patients (12 mutations out of 23, 52%) as compared to responder patients (2 out of 9, 22%), authentic tumor response or long-term disease stabilization was found in KRAS mutated patients.Conclusion: This preliminary study suggests that: an increase in EGFR copy number may be associated with cetuximab response but is a rare event in CRC, KRAS mutations are associated with low response rate but do not preclude any cetuximab-based combination efficacy and EGFR exon 13 variant (R521K) may predict for cetuximab benefit