331 research outputs found
Understanding cisplatin resistance using cellular models
No full textMany mechanisms of cisplatin resistance have been proposed from studies of cellular models of resistance including changes in cellular drug accumulation, detoxification of the drug, inhibition of apoptosis and repair of the DNA adducts. A series of resistant models were developed from CCRF-CEM leukaemia cells with increasing doses of cisplatin from 100 ng/ml. This produced increasing resistance up to 7-fold with a treatment dose of 1.6 μg/ml. Cisplatin resistance in these cells correlated with increases in the antioxidant glutathione, yet treatment with buthionine sulphoximine, an inhibitor of glutathione synthesis, had no effect on resistance, suggesting that the increase in glutathione was not directly involved in cisplatin resistance. Two models were developed from H69 SCLC cells, H69-CP and H69CIS200 using 100 ng/ml or 200 ng/ml cisplatin respectively. Both cell models were 2-4 fold resistant to cisplatin, and have decreased expression of p21 which may increase the cell’s ability to progress through the cell cycle in the presence of DNA damage. Both the H69-CP and H69CIS200 cells showed no decrease in cellular cisplatin accumulation. However, the H69-CP cells have increased levels of cellular glutathione and are cross resistant to radiation whereas the H69CIS200 cells have neither of these changes. This suggests that increases in glutathione may contribute to cross-resistance to other drugs and radiation, but not directly to cisplatin resistance. There are multiple resistance mechanisms induced by cisplatin treatment, even in the same cell type. How then should cisplatin-resistant cancers be treated? Cisplatin-resistant cell lines are often more sensitive to another chemotherapeutic drug paclitaxel (H69CIS200), or are able to be sensitised to cisplatin with paclitaxel pre-treatment (H69-CP). The understanding of this sensitisation by paclitaxel using cell models of cisplatin resistance will lead to improvements in the clinical treatment of cisplatin resistant tumours
Accelerated Iterative Adaptive Gaussian Mixture Smoother (IAGS) with Optimal Bandwidth h
No full textAccelerate the iterative adaptive Gaussian mixture smoother by introducing a new measure of model nonlinearity, a adaptive way to generate the optimal bandwidth h.Risk and Environmental ModellingApplied mathematicsElectrical Engineering, Mathematics and Computer Scienc
Oxaliplatin for the treatment of cisplatin-resistant cancer: a systematic review
No full textOxaliplatin is widely regarded as being active in cisplatin-resistant cancer. We undertook a systematic review of the literature to identify, describe and critique the clinical and pre-clinical evidence for the use of oxaliplatin in patients with “cisplatin-resistant” cancer. We identified 25 pre-clinical cell models of platinum resistance and 24 clinical trials reporting oxaliplatin based salvage therapy for cisplatin-resistant cancer. The pre-clinical data suggests that there is cross-resistance between cisplatin and oxaliplatin in low-level resistance models. In models with high level resistance (>10 fold) there is less cross resistance between cisplatin and oxaliplatin, which may be a reason why oxaliplatin is thought to be active in cisplatin-resistant cancer. In clinical trials where oxaliplatin has been used as part of salvage therapy for patients who have failed cisplatin or carboplatin combination chemotherapy, there was a much lower response rate in patients with platinum-refractory or resistant cancers compared to platinum-sensitive cancers. This suggests that there may be cross-resistance between cisplatin and oxaliplatin in the clinic. Oxaliplatin as a single agent had a poor response rate in cisplatin refractory and resistant cancer. Oxaliplatin performed better in combination with other agents for the treatment of platinum resistant/refractory cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer
Treating cisplatin-resistant cancer: a systematic analysis of oxaliplatin or paclitaxel salvage chemotherapy
No full textObjective: To examine the pre-clinical and clinical evidence for the use of oxaliplatin or paclitaxel salvage chemotherapy in patients with cisplatin-resistant cancer.
Methods: Medline was searched for 1) Cell models of acquired resistance reporting cisplatin, oxaliplatin and paclitaxel sensitivities and 2) Clinical trials of single agent oxaliplatin or paclitaxel salvage therapy for cisplatin/carboplatin-resistant ovarian cancer. Results: Oxaliplatin - Oxaliplatin is widely regarded as being active in cisplatin-resistant cancer. In contrast, data in cell models suggests that there is cross-resistance between cisplatin and oxaliplatin in cellular models with resistance levels which reflect clinical resistance (<10 fold). Oxaliplatin as a single agent had a poor response rate in patients with cisplatin-resistant ovarian cancer (8%, n=91). Oxaliplatin performed better in combination with other agents for the treatment of platinum-resistant cancer suggesting that the benefit of oxaliplatin may lie in its more favourable toxicity and ability to be combined with other drugs rather than an underlying activity in cisplatin resistance. Oxaliplatin therefore should not be considered broadly active in cisplatin-resistant cancer. Paclitaxel – Cellular data suggests that paclitaxel is active in cisplatin-resistant cancer. 68.1% of cisplatin-resistant cells were sensitive to paclitaxel. Paclitaxel as a single agent had a response rate of 22% in patients with platinum-resistant ovarian cancer (n = 1918), a significant increase from the response of oxaliplatin (p<0.01). Paclitaxel-resistant cells were also sensitive to cisplatin, suggesting that alternating between agents may be beneficial. Studies of single agent paclitaxel in platinum-resistant ovarian cancer where patients had previously received paclitaxel had an improved response rate of 35.3% n=232 (p<0.01), suggesting that pre-treatment with paclitaxel improves the response of salvage paclitaxel therapy.
Conclusions: Cellular models reflect the resistance observed in the clinic as the cross resistant agent oxaliplatin has a lower response rate compared to the non-cross resistant agent paclitaxel in cisplatin-resistant ovarian cancer. Alternating therapy with cisplatin and paclitaxel may therefore lead to an improved response rate in ovarian cancer
Regrowth resistance: low-level platinum resistance mediated by rapid recovery from platinum-induced cell-cycle arrest
No full textThe H69CIS200 and H69OX400 cell lines are novel models of low-level platinum drug resistance developed from H69 human small cell lung cancer cells with eight 4-day treatments of 200 ng/ml cisplatin or 400 ng/ml oxaliplatin respectively. A recovery period was given between treatments to emulate the cycles of chemotherapy given in the clinic. The resistant cell lines were approximately 2-fold resistant to cisplatin and oxaliplatin and were cross resistant to both drugs. Platinum resistance was not associated with increased cellular glutathione, decreased accumulation of platinum or increased DNA repair capacity. The H69 platinum sensitive cells entered a lengthy 3 week growth arrest in response to low-level cisplatin or oxaliplatin treatment. This is an example of the coordinated response between the cell cycle and DNA repair. In contrast the H69CIS200 and H69OX400 cells have an alteration in the cell cycle allowing them to rapidly proliferate post drug treatment. The resistant cell lines also have many chromosomal rearrangements most of which are not associated with the resistant phenotype, suggesting an increase in genomic instability in the resistant cell lines. We hypothesised that there was a lack of coordination between the cell cycle and DNA repair in the resistant cell lines allowing proliferation in the presence of DNA damage which has created an increase in genomic instability. The H69 cells and resistant cell lines have mutant p53 and consequently decrease the expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed with the platinum induced cell cycle arrest and did not correlate with resistance or altered DNA repair capacity. These changes may in part be mediating and maintaining the cell cycle arrest in place of p21.The rapidly proliferating resistant cells have restored the levels of both these proteins to their levels in untreated cells. We use the term ‘regrowth resistance’ to describe this low-level platinum resistance where cells survive treatment through increased proliferation. Regrowth resistance may play a role in the onset of clinical resistance
Evaluating stomatal ozone fluxes in WRF-Chem: Comparing ozone uptake in Mediterranean ecosystems
No full textThe development of modelling tools for estimating stomatal uptake of surface ozone in vegetation is important for the assessment of potential damage induced due to both current and future near surface ozone concentrations. In this study, we investigate the skill in estimating ozone uptake in plants by the Weather Research and Forecasting model coupled with chemistry (WRF-Chem) V3.6.1, with the Wesely dry deposition scheme. To validate the stomatal uptake of ozone, the model simulations were compared with field measurements of three types of Mediterranean vegetation, over seven different periods representing various meteorological conditions. Some systematic biases in modelled ozone fluxes are revealed; the lack of an explicit and time varying dependency on plants’ water availability results in overestimated daytime ozone stomatal fluxes particularly in dry periods. The optimal temperature in the temperature response function is likely too low for the woody species tested here. Also, too low nighttime stomatal conductance leads to underestimation of ozone uptake during night. We demonstrate that modelled stomatal ozone flux is improved by accounting for vapor pressure deficit in the ambient air. Based on the results of the overall comparison to measured fluxes, we propose that additional improvements to the stomatal conductance parameterization should be implemented before applying the modelling system for estimating ozone doses and potential damage to vegetation
A study of four-year HCFC-22 and HCFC-142b in-situ measurements at the Shangdianzi regional background station in China
No full textAtmospheric HCFC-22 (CHClF2) and HCFC-142b (CH3CClF2) in-situ measurements have been recorded by an automated gas chromatograph-electron capture detectors (GC-ECDs) system and a gas chromatography/mass spectrometry (Medusa-GC/MS) system at the Global Atmosphere Watch (GAW) regional background station Shangdianzi (SDZ), China. The mixing ratios of the two HCFCs at SDZ show frequent events with elevated concentrations due to polluted air from urban or industrialized areas. The mean background mixing ratios for HCFC-22 and HCFC-142b were 205.3 ppt (parts per trillion, 1012, molar) and 20.7 ppt, respectively, for the study period (March 2007eFebruary 2011). The yearly background mixing ratios for the two HCFCs at SDZ are similar to those measured at Trinidad Head and Mace Head located in the Northern Hemisphere (NH), but larger than Cape Grim and Cape Matatula (located in the Southern Hemisphere) due to inter-hemispheric differences caused by predominantly NH emissions.
During the study period, background mixing ratios exhibited positive growth rates of 8.7 ppt yr1 for HCFC-22 and 0.95 ppt yr1 for HCFC-142b. HCFC’s seasonality exhibits a summer/autumn maximum and a winter minimum. 4-year averaged background seasonal amplitudes (maximumeminimum) are 6.0 ppt for HCFC-22 and 0.9 ppt for HCFC-142b. The seasonal fluctuations (maximumeminimum) in polluted events are 105.4 ppt for HCFC-22 and 29.1 ppt for HCFC-142b, which are much stronger than the fluctuations under background conditions. However, both HCFC-22 and HCFC-142b show summer minima in 2008, which is most likely due to emission control regulations when the Olympic Games were held in Beijing
Emotional distress in cancer patients: the Edinburgh Cancer Centre symptom study
No full textTo: (1) estimate the prevalence of clinically significant emotional distress in patients attending a cancer outpatient department and (2) determine the associations between distress and demographic and clinical variables, we conducted a survey of outpatients attending selected clinics of a regional cancer centre in Edinburgh, UK. Patients completed the Hospital Anxiety and Depression Scale (HADS) on touch-screen computers and the scores were linked to clinical variables on the hospital database. Nearly one quarter of the cancer outpatients 674 out of 3071 (22%; 95% confidence interval (CI) 20-23%) met our criterion for clinically significant emotional distress (total HADS score 15 or more). Univariate analysis identified the following statistically significant associations: age < 65, female gender, cancer type and extent of disease. Multivariate analysis indicated that age < 65 (odds ratio 1.41; 95% CI 1.18-1.69), female gender (odds ratio 1.58; 95% CI 1.31-1.92) and active disease (odds ratio 1.72; 95% CI 1.43-2.05) but not cancer diagnosis, were the independent predictors of clinically significant emotional distress. Services to treat distress in cancer patients should be organised to target patients by characteristics other than their cancer diagnosis.</p
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