Oxaliplatin induces drug resistance more rapidly than cisplatin in H69 small cell lung cancer cells

Cisplatin produces good responses in solid tumours including small cell lung cancer (SCLC) but this is limited by the development of resistance. Oxaliplatin is reported to show activity against some cisplatin-resistant cancers but there is little known about oxaliplatin in SCLC and there are no reports of oxaliplatin resistant SCLC cell lines. Studies of drug resistance mainly focus on the cellular resistance mechanisms rather than how the cells develop resistance. This study examines the development of cisplatin and oxaliplatin resistance in H69 human SCLC cells in response to repeated treatment with clinically relevant doses of cisplatin or oxaliplatin for either 4 days or 2h. Treatments with 200ng/ml cisplatin or 400ng/ml oxaliplatin for 4 days produced sublines (H69CIS200 and H69OX400 respectively) that showed low level (approximately 2-fold) resistance after 8 treatments. Treatments with 1000ng/ml cisplatin or 2000ng/ml oxaliplatin for 2h also produced sublines, however these were not stably resistant suggesting shorter treatment pulses of drug may be more effective. Cells survived the first five treatments without any increase in resistance, by arresting their growth for a period and then regrowing. The period of growth arrest was reduced after the sixth treatment and the H69CIS200 and H69OX400 sublines showed a reduced growth arrest in response to cisplatin and oxaliplatin treatment suggesting that "regrowth resistance" initially protected against drug treatment and this was further upregulated and became part of the resistance phenotype of these sublines. Oxaliplatin dose escalation produced more surviving sublines than cisplatin dose escalation but neither set of sublines were associated with increased resistance as determined by 5-day cytotoxicity assays, also suggesting the involvement of regrowth resistance. The resistant sublines showed no change in platinum accumulation or glutathione levels even though the H69OX400 subline was more sensitive to buthionine sulfoximine treatment. The H69CIS200 cells were cross-resistant to oxaliplatin demonstrating that oxaliplatin does not have activity against low level cisplatin resistance. Relative to the H69 cells, the H69CIS200 and H69OX400 sublines were more sensitive to paclitaxel and taxotere suggests the taxanes may be useful in the treatment of platinum resistant SCLC. These novel cellular models of cisplatin and oxaliplatin resistant SCLC will be useful in developing strategies to treat platinum-resistant SCLC

Assessment of Minimal Residual Disease in Standard-Risk AML

BACKGROUND: Despite the molecular heterogeneity of standard-risk acute myeloid leukemia (AML), treatment decisions are based on a limited number of molecular genetic markers and morphology-based assessment of remission. Sensitive detection of a leukemia-specific marker (e.g., a mutation in the gene encoding nucleophosmin [NPM1]) could improve prognostication by identifying submicroscopic disease during remission. METHODS: We used a reverse-transcriptase quantitative polymerase-chain-reaction assay to detect minimal residual disease in 2569 samples obtained from 346 patients with NPM1-mutated AML who had undergone intensive treatment in the National Cancer Research Institute AML17 trial. We used a custom 51-gene panel to perform targeted sequencing of 223 samples obtained at the time of diagnosis and 49 samples obtained at the time of relapse. Mutations associated with preleukemic clones were tracked by means of digital polymerase chain reaction. RESULTS: Molecular profiling highlighted the complexity of NPM1-mutated AML, with segregation of patients into more than 150 subgroups, thus precluding reliable outcome prediction. The determination of minimal-residual-disease status was more informative. Persistence of NPM1-mutated transcripts in blood was present in 15% of the patients after the second chemotherapy cycle and was associated with a greater risk of relapse after 3 years of follow-up than was an absence of such transcripts (82% vs. 30%; hazard ratio, 4.80; 95% confidence interval [CI], 2.95 to 7.80; P<0.001) and a lower rate of survival (24% vs. 75%; hazard ratio for death, 4.38; 95% CI, 2.57 to 7.47; P<0.001). The presence of minimal residual disease was the only independent prognostic factor for death in multivariate analysis (hazard ratio, 4.84; 95% CI, 2.57 to 9.15; P<0.001). These results were validated in an independent cohort. On sequential monitoring of minimal residual disease, relapse was reliably predicted by a rising level of NPM1-mutated transcripts. Although mutations associated with preleukemic clones remained detectable during ongoing remission after chemotherapy, NPM1 mutations were detected in 69 of 70 patients at the time of relapse and provided a better marker of disease status. CONCLUSIONS: The presence of minimal residual disease, as determined by quantitation of NPM1-mutated transcripts, provided powerful prognostic information independent of other risk factors. (Funded by Bloodwise and the National Institute for Health Research; Current Controlled Trials number, ISRCTN55675535.)

Evaluative and discriminative properties of the Portuguese MacNew Heart Disease Health‐related Quality of Life Questionnaire.

Qual Life Res. 2005 Dec;14(10):2335-41. Evaluative and discriminative properties of the Portuguese MacNew Heart Disease Health-related Quality of Life Questionnaire. Leal A, Paiva C, Höfer S, Amado J, Gomes L, Oldridge N. Cardiac Rehabilitation Unit, Hospital Sto António Porto, Largo Prof Abel Salazar 400, Portugal. [email protected] Abstract The aim of this study was to validate the Portuguese version of the self-administered MacNew Heart Disease Health-related Quality of Life (MacNew) questionnaire in patients after diagnosis of acute coronary syndrome. The MacNew, with a Global score and physical, emotional and social subscales, the Short Form SF-36 (SF-36) and the Hospital Anxiety and Depression Scale (HADS) were completed at baseline by 150 patients and again by 48 clinically stable patients 2-3 weeks later. A cohort of 50 different patients completed the same questionnaires before and after a cardiac rehabilitation program in order to examine responsiveness. Acceptance of the MacNew by the patients was good and the three factor model was substantiated and explained 52.2% of the variance. Internal consistency, intra-class-correlation, and test-retest reliability each exceeded 0.72. The predicted construct validity hypotheses were partially confirmed. The discriminative validity of the MacNew was confirmed with significantly higher MacNew scores for patients with normal left ventricular function, with improved health status, and who were not anxious or depressed. Even though MacNew scores improved significantly following cardiac rehabilitation, the evaluative validity of the MacNew was less robust with small responsiveness statistics. The Portuguese version of the MacNew HRQL questionnaire appears to be a reliable, valid, and moderately responsive instrument to evaluate health-related quality of life after diagnosis of acute coronary syndrome. PMID: 16328913 [PubMed - indexed for MEDLINE

Mental health and legal representation for asylum seekers in the ‘legacy caseload’

This article examines the legal challenges asylum seekers arriving by boat to Australia experience when seeking assistance with their claims and its impact on their mental health. The authors outline the experiences of asylum seekers in the “legacy caseload” group who have been waiting up to four years to have their protection claims assessed. The complex interplay between legal assistance to support refugee claims and the way those making claims inevitably struggle to understand, engage and participate in the process is analysed. It is argued that provision of legal assistance for this group will be essential to ensuring that the refugee status determination process is fair and allows asylum seekers to understand and participate more fully in the process. Recent changes to the assessment of claims combined with a reduction in funding for legal assistance create significant hurdles and combine to compound existing stress and emotional trauma leading to detrimental outcomes on the mental health of asylum seekers

Crystalline phases involved in the hydration of calcium silicate-based cements: Semi-quantitative Rietveld X-ray diffraction analysis

Chemical comparisons of powder and hydrated forms of calcium silicate cements (CSCs) and calculation of alterations in tricalcium silicate (Ca3SiO5) calcium hydroxide (Ca(OH)2) are essential for understanding their hydration processes. This study aimed to evaluate and compare these changes in ProRoot MTA, Biodentine and CEM cement. Powder and hydrated forms of tooth coloured ProRoot MTA, Biodentine and CEM cement were subjected to X-ray diffraction (XRD) analysis with Rietveld refinement to semi-quantitatively identify and quantify the main phases involved in their hydration process. Data were reported descriptively. Reduction in Ca3SiO5 and formation of Ca(OH)2 were seen after the hydration of ProRoot MTA and Biodentine; however, in the case of CEM cement, no reduction of Ca3SiO5 and no formation of Ca(OH)2 were detected. The highest percentages of amorphous phases were seen in Biodentine samples. Ettringite was detected in the hydrated forms of ProRoot MTA and CEM cement but not in Biodentine

Processing and characterization of chitosan microspheres to be used as templates for layer-by-layer assembly

Chitosan (Ch) microspheres have been developed by precipitation method, cross-linked with glutaraldehyde and used as a template for layer-by-layer (LBL) deposition of two natural polyelectrolytes. Using a LBL methodology, Ch microspheres were alternately coated with hyaluronic acid (HA) and Ch under mild conditions. The roughness of the Ch-based crosslinked microspheres was characterized by atomic force microscopy (AFM). Morphological characterization was performed by environmental scanning electron microscopy (ESEM), scanning electron microscopy (SEM) and stereolight microscopy. The swelling behaviour of the microspheres demonstrated that the ones with more bilayers presented the highest water uptake and the uncoated cross-linked Ch microspheres showed the lowest uptake capability. Microspheres presented spherical shape with sizes ranging from 510 to 840 lm. ESEM demonstrated that a rougher surface with voids is formed in multilayered microspheres caused by the irregular stacking of the layers. A short term mechanical stability assay was also performed, showing that the LBL procedure with more than five bilayers of HA/Ch over Ch cross-linked microspheres provide higher mechanical stability

Towards energy aware cloud computing application construction

The energy consumption of cloud computing continues to be an area of significant concern as data center growth continues to increase. This paper reports on an energy efficient interoperable cloud architecture realised as a cloud toolbox that focuses on reducing the energy consumption of cloud applications holistically across all deployment models. The architecture supports energy efficiency at service construction, deployment and operation. We discuss our practical experience during implementation of an architectural component, the Virtual Machine Image Constructor (VMIC), required to facilitate construction of energy aware cloud applications. We carry out a performance evaluation of the component on a cloud testbed. The results show the performance of Virtual Machine construction, primarily limited by available I/O, to be adequate for agile, energy aware software development. We conclude that the implementation of the VMIC is feasible, incurs minimal performance overhead comparatively to the time taken by other aspects of the cloud application construction life-cycle, and make recommendations on enhancing its performance

A proposed quantitative methodology for the evaluation of the effectiveness of Human Element, Leadership and Management (HELM) training in the UK

In 2006, a review of maritime accidents found that non-technical skills (NTSs) are the single largest contributing factor towards such incidents. NTSs are composed of both interpersonal and cognitive elements. These include things such as situational awareness, teamwork, decision making, leadership, management and communication skills. In a crisis situation, good NTSs allow a deck officer to quickly recognise that a problem exists and then harness the resources that are at their disposal to safely and efficiently bring the situation back under control. This paper has two aims. The first is to develop a methodology which will enable educators to quantitatively assess the impact of Maritime and Coastguard Agency (MCA)-approved Human Element, Leadership and Management (HELM) training on deck officer’s NTSs with a view to identifying further training requirements. The second is to determine whether the HELM training provided to develop the NTSs of trainee deck officers is fit for purpose. To achieve these aims, a three-phase approach was adopted. Initially, a taxonomy for deck officer’s NTSs is established, behavioural markers are identified and the relative importance of each attribute is calculated using the analytical hierarchy process (AHP). Subsequently, a set of scenarios were identified for the assessment of deck officer’s NTSs in a ship bridge simulator environment. A random selection of students that have completed the Chief Mate (CM) programme was performed, and data regarding their NTS-related performance in the scenarios was collected. Finally, the collected data was fed into the evidential reasoning (ER) algorithm, utility values were produced and, having established these values, the effectiveness of the HELM training that the students have received was then evaluated

Experimental investigation on variable speed operation of air conditioning

Paper presented at the 9th International Conference on Heat Transfer, Fluid Mechanics and Thermodynamics, Malta, 16-18 July, 2012.Air conditioning installations are typically designed with enough cooling capacity to satisfy the desired minimum temperature under the heaviest load. Since heat loads tend to be less than the maximum designed loads, the system will most often be working under part-load rather than full-load conditions. Operating at these part-load conditions at fixed capacity will be more expensive than if the capacity were able to match the required load. Varying capacity air conditioning systems, which make use of inverter technology, have been developed in order to track the required cooling load more closely. These high quality air conditioners are advertised as consuming around 30 per cent less energy than conventional systems. This experimental investigation looked into the steady state performance and start-up power requirements of an inverter driven refrigeration unit versus fixed speed operation. A three phase (745 W motor) air conditioning laboratory setup was used in direct-on-line (fixed speed) mode and also with a variable frequency drive (inverter). The results obtained showed that the cooling coefficient of performance increased as the operating frequency was reduced. This means that an improved performance can be achieved at lower operating frequencies. A reduced start-up power was required for the inverter driven system, however the additional power requirements for the inverter resulted in the mains driven system being more efficient at full-load conditions. The improved coefficient of performance at lower frequencies resulted in an improved performance for the inverter driven system when compared to a conventional system at part-load conditions.dc201

The Role of Cardiovascular Magnetic Resonance Imaging in Athletic Individuals-A Narrative Review

Cardiovascular magnetic resonance imaging (MRI) is an advanced cardiac imaging modality that is often required when evaluating athletic individuals. Unrestricted imaging planes, excellent spatial resolution, and a lack of ionising radiation are some of the benefits of this modality. Cardiac MRI has been established as the gold standard imaging modality for morphological assessment, volumetric analysis, and tissue characterisation. Cardiac MRI without any doubt is an excellent diagnostic tool when evaluating athletes with symptoms or those individuals exhibiting equivocal findings at screening. It is also useful for athletes who fall within the grey zone and is especially important among athletes with a suspected or confirmed diagnosis. Cardiac MRI plays a strategic role when adopting a shared decision-making model in athletes with heart disease, tailoring and personalising medical care to the condition and the athlete’s wishes. The aim of this review is to provide a comprehensive yet practical overview of the role of cardiac MRI when evaluating athletes in clinic