A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1

A systematic review of cell models of acquired drug resistance not involving genetic manipulation showed that 80% of cell models had an inverse resistance relationship between cisplatin and paclitaxel. Here we systematically review genetically modified cell lines in which the inverse cisplatin/paclitaxel resistance phenotype has resulted. This will form a short list of genes which may play a role in the mechanism of the inverse resistance relationship as well as act as potential markers for monitoring the development of resistance in the clinical treatment of cancer. The literature search revealed 91 genetically modified cell lines which report toxicity or viability/apoptosis data for cisplatin and paclitaxel relative to their parental cell lines. This resulted in 26 genes being associated with the inverse cisplatin/paclitaxel phenotype. The gene with the highest number of genetically modified cell lines associated with the inverse resistance relationship was BRCA1 and this gene is discussed in detail with reference to chemotherapy response in cell lines and in the clinical treatment of breast, ovarian and lung cancer. Other genes associated with the inverse resistance phenotype included dihydrodiol dehydrogenase (DDH) and P-glycoprotein. Genes which caused cross resistance or cross sensitivity between cisplatin and paclitaxel were also examined, the majority of these genes were apoptosis associated genes which may be useful for predicting cross resistance. We propose that BRCA1 should be the first of a panel of cellular markers to predict the inverse cisplatin/paclitaxel resistance phenotype

ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair

Background: The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. Results: A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Conclusion: Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1

A 39 kDa fragment of endogenous ASK1 suggests specific cleavage not degradation by the proteasome

Transfected human apoptosis signal-regulating kinase 1 (ASK1) produces a 150 kDa protein. However, we have detected endogenous ASK1 predominantly as 39 and 50 kDa C-terminal and 75 and 110 kDa N-terminal fragments in a panel of nontransfected cancer cell lines and HUVEC endothelial cells. This suggests that in nonapoptotic cells, endogenous ASK1 protein is normally cleaved at a number of specific sites, some of which are in the kinase domain. Transfected ASK1 protein is known to be degraded by the proteasome. In contrast, the cleavage of endogenous ASK1 is independent of the proteasome as treatment with the proteasome inhibitor, lactacystin did not inhibit cleavage. Cisplatin treatment decreased the amount of 39 kDa C-terminal ASK1 fragments in mutant p53 cell lines suggesting a decrease in cleavage associated with apoptosis. Transfected ASK1 may, therefore, not accurately reflect the role of endogenous ASK1

Platinum resistance needs the mythbusters

Letter to the Edito

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 feasibility study of signed consent for the collection of patient identifiable information for a national paediatric clinical audit database

Objectives: To investigate the feasibility of obtaining signed consent for submission of patient identifiable data to a national clinical audit database and to identify factors influencing the consent process and its success. Design: Feasibility study. Setting: Seven paediatric intensive care units in England. Participants: Parents/guardians of patients, or patients aged 12-16 years old, approached consecutively over three months for signed consent for submission of patient identifiable data to the national clinical audit database the Paediatric Intensive Care Audit Network (PICANet). Main outcome measures: The numbers and proportions of admissions for which signed consent was given, refused, or not obtained (form not returned or form partially completed but not signed), by age, sex, level of deprivation, ethnicity (South Asian or not), paediatric index of mortality score, length of hospital stay (days in paediatric intensive care). Results: One unit did not start and one did not fully implement the protocol, so analysis excluded these two units. Consent was obtained for 182 of 422 admissions (43%) (range by unit 9% to 84%). Most (101/182; 55%) consents were taken by staff nurses. One refusal (0.2%) was received. Consent rates were significantly better for children who were more severely ill on admission and for hospital stays of six days or more, and significantly poorer for children aged 10-14 years. Long hospital stays and children aged 10-14 years remained significant in a stepwise regression model of the factors that were significant in the univariate model. Conclusion: Systematically obtaining individual signed consent for sharing patient identifiable information with an externally located clinical audit database is difficult. Obtaining such consent is unlikely to be successful unless additional resources are specifically allocated to training, staff time, and administrative support

Integrable Generalisations of the 2-dimensional Born Infeld Equation

The Born-Infeld equation in two dimensions is generalised to higher dimensions whilst retaining Lorentz Invariance and complete integrability. This generalisation retains homogeneity in second derivatives of the field.Comment: 11 pages, Latex, DTP/93/3

Factors related to discontinued clinic attendance by patients with podoconiosis in southern Ethiopia: a qualitative study

Background Podoconiosis is a lymphoedema of non-infectious cause which results in long-term ill health in affected individuals. Simple, effective treatment is available in certain parts of Ethiopia, but evidence indicates that not all patients continue collecting treatment supplies from clinic sites once started. We used qualitative techniques to explore factors related to discontinued attendance at outreach clinics of a non-government organization in southern Ethiopia. Methods A cross-sectional qualitative study was conducted in four clinic sites through unstructured in-depth interviews, key informant interviews and focus group discussions with the involvement of 88 study subjects. Results Discontinuation of clinic visits is common among podoconiosis patients. The reasons were: remoteness from the clinic sites, unrealistic expectation of ‘special’ aid, worry about increasing stigma, illness and misconceptions about treatment. Conclusions Several of these factors are remediable through community and individual information and education. Appropriate routes to deliver this information must be identified. Certain factors (such as distance to clinic sites and stigma) require substantial expansion of services or liaison with village-level government health services

Numerical Simulation of an EUV Coronal Wave Based on the February 13, 2009 CME Event Observed by STEREO

On 13 February 2009, a coronal wave -- CME -- dimming event was observed in quadrature by the STEREO spacecraft. We analyze this event using a three-dimensional, global magnetohydrodynamic (MHD) model for the solar corona. The numerical simulation is driven and constrained by the observations, and indicates where magnetic reconnection occurs between the expanding CME core and surrounding environment. We focus primarily on the lower corona, extending out to $3R_{\odot}$; this range allows simultaneous comparison with both EUVI and COR1 data. Our simulation produces a diffuse coronal bright front remarkably similar to that observed by STEREO/EUVI at 195 \AA. It is made up of \emph{two} components, and is the result of a combination of both wave and non-wave mechanisms. The CME becomes large-scale quite low ($<$ 200 Mm) in the corona. It is not, however, an inherently large-scale event; rather, the expansion is facilitated by magnetic reconnection between the expanding CME core and the surrounding magnetic environment. In support of this, we also find numerous secondary dimmings, many far from the initial CME source region. Relating such dimmings to reconnecting field lines within the simulation provides further evidence that CME expansion leads to the "opening" of coronal field lines on a global scale. Throughout the CME expansion, the coronal wave maps directly to the CME footprint. Our results suggest that the ongoing debate over the "true" nature of diffuse coronal waves may be mischaracterized. It appears that \emph{both} wave and non-wave models are required to explain the observations and understand the complex nature of these events

Quantum causal histories

Quantum causal histories are defined to be causal sets with Hilbert spaces attached to each event and local unitary evolution operators. The reflexivity, antisymmetry, and transitivity properties of a causal set are preserved in the quantum history as conditions on the evolution operators. A quantum causal history in which transitivity holds can be treated as ``directed'' topological quantum field theory. Two examples of such histories are described.Comment: 16 pages, epsfig latex. Some clarifications, minor corrections and references added. Version to appear in Classical and Quantum Gravit