Development of taxane resistance in a panel of human lung cancer cell lines

Using a selection process designed to reflect clinically relevant conditions, a panel of taxane-selected variants were developed to study further the mechanisms of resistance in lung cancer. Unlike continuous or pulse exposure to high concentrations of chemotherapeutic drugs which yield high resistance and often cross resistance, most variants developed here displayed low level resistance to the selecting drug with slight cross-resistance. Pulsing with taxol resulted in more highly resistant clones (up to 51.4-fold). Analysis of taxol and taxotere in the four major lung cancer cell types showed the taxanes to be more effective against NSCLC (with the exception of SKMES-taxane selected variants) than against the SCLC. Comparison of taxol and taxotere shows that taxol induces higher levels of resistance than taxotere. Further, in taxotere-selected cell lines, the cells are more resistant to taxol than taxotere, suggesting that taxotere may be a superior taxane from a clinical view. Taxol treatment resulted in increased cross-resistance to 5-FU in all classes of lung cancer except DMS-53. The high levels of Pgp in the DMS-53 and selected variant suggests this mechanism is not related to Pgp expression. Analysis of the Pgp and MRP-1 status by combination inhibitory assays and Western blotting showed no consistent relationship between expression of the membrane pumps Pgp or MRP-1 and resistance. However, where high level resistance was seen, the parent cell line expressed Pgp or MRP-1 and was accompanied by increased levels in the variants. Overall we found that the clinically relevant models used here are useful for investigating mechanisms of taxane resistance

Coordinating International Standards: The Formation of the ISO

In the article on “Standardization” in the 14th edition of the Encyclopædia Britannica, Paul Gough Agnew, the long-time Secretary of the American Standards Association (ASA), argued: In the flow of products from farm, forest, mine, and sea through processing and fabricating plants, and through wholesale and retail markets to the ultimate consumer, most difficulties are met at the transition points––points at which the product passes from department to department within a company, or is sold by one company to another or to an individual. The main function of standards is to facilitate the flow of products through these transition points. Standards are thus both facilitators and integrators. In smoothing out points of difficulty, or “bottlenecks,” they provide the evolutionary adjustments which are necessary for industry to keep pace with technical advances. They do this in the individual plant, in particular industries, and in industry at large. They are all the more effective as integrators in that they proceed by simple evolutionary steps, albeit inconspicuously.2 Albeit inconspicuous, standard setting has been among the nuts and bolts of globalizing industrial capitalism since its beginning, assuring that things needing to work together fit from product to product, industry to industry, and country to country. The foci of the first two of the now 229 “technical committees” of the non-specialized international standards organizations that emerged after the two world wars—the interwar International Standards Association [ISA] and the post-World War II International Organization for Standardization [ISO]—are iconic: “Screw Threads” and “Bolts, Nuts and Accessories.” Over the past two decades, voluntary standardization processes, invented by turn-of-the-twentieth-century engineers working in national and international technical committees, have increasingly been 1 We would like to thank Madame Beatrice Frey at ISO for her help in providing us access to original documents from UNSCC and ISO, and Stacy Leistner at ANSI for his help in providing access to the minutes from AESC and ASA meetings. 2 Quoted as epigraph of Dickson Reck, ed., National Standards in a Modern Economy, (New York, 1956), v. 3 applied to issues that have little in common with those of fitting one mechanical part to another, such as work processes (ISO 9000), environmental pollution (ISO 14,000), and human rights (SA 8000 and the planned ISO 26000)

The Use of Wearable Technology to Measure Energy Expenditure, Physical Activity and Sleep Patterns in Dementia.

Project Description Unexplained weight loss is frequently observed in dementia leading to further cognitive decline, frailty and disability. Apparent mechanisms that could lead to weight loss (lower energy intake and/or higher expenditure) remain unresolved and may be different in the various stages and types of dementia. During the progression of the illness, the extent to which altered sleep duration and variable physical activity patterns (intermittent or constant pacing/lying down) could affect weight loss is unknown. We have used an innovative light weight physical activity monitor (Sensewear TM Armband, Body Media, Pittsburgh, PA) to objectively determine total energy expenditure (TEE), sleep duration, physical activity and number of steps in people with dementia living in care homes. The armband was placed around the left upper triceps for up to 7 days. The device measures tri-axial acceleration, skin temperature, galvanic skin response and heat flux and has been shown to be valid in resting, exercise and free-living conditions in older people. The mean age of the residents (n=20) was 78.5 (58-99) years, 50% were women with confirmed diagnosis of a range of dementia types. Body Mass Index (BMI) was 23.0 (range 13.7-30.0) kg/m2 with 40% classified as underweight, 50% normal range, 10% overweight. Duration of sleeping ranged from 0.4-12.5 (mean 5.9) hrs/d and time spent lying down was 1.0-16.0 (8.1) hrs/d. On average residents spent 17.4 (6.0-23.7) hrs/d undertaking sedentary activity. Sleeping duration was inversely related to body weight (r= -0.46, p<0.05) and TEE (r= -0.59, P<0.01). There was an inverse association between time lying down for both body weight (r= -0.45, p<0.05) and TEE (r= -0.62, p<0.01).TEE was positively correlated with number of steps per day (r= 0.45, p<0.05). There was no relationship between TEE or BMI and the amount of physical activity. Variable patterns of physical activity and sleep duration demonstrates the need to recognise the influence of these factors on meeting energy requirements and the challenge of providing appropriate food and nutrition within the care home environment. Thus wearable technology has the potential to offer real-time feedback to support better nutritional management and improve efforts to prevent weight loss in dementia

Understanding the strategies required to meet hydration needs of people living with dementia.

BackgroundDementia can increase the risk of dehydration as cognitive impairment and old age reduce the ability to recognise thirst. Dehydration can cause further deterioration in cognitive function and other health problems. There is no consensus on recommended fluid intakes for dementia but generally 1500 ml per day is regarded as sufficient. However the challenges of meeting appropriate hydration continue to be reported. The aim of this study, using quantitative and qualitative methods was to gain a deeper understanding of the strategies required to understand hydration needs of people living with dementia.MethodsQuantitative measures of fluid intake were recorded over a period of five days in residents (n=18) who were living in care homes. The mean age of the residents was 79 (104-58) years, 50% were women with a diagnosis of a range of dementia types. Qualitative research using a blend of nine focus groups and five semi structured interviews were conducted with all those involved in the care of people with dementia, including nurses, managers, chefs, care workers, family members, dietitians and speech and language therapists. Thematic analysis of transcripts enabled core themes to be explored.ResultsThe daily intake of fluid was 1065 ± 836 ml (mean ± 2 standard deviations). Fifteen (83%) residents did not meet the recommended fluid intake. The qualitative themes highlighted ways to overcome poor fluid intake and included alternative ways to improve hydration; a person centred approach to delivering fluid with a recognition of psychosocial and cultural influences; communication between front-line staff and key healthcare professionals.ConclusionsUsing this combined methodological approach, the results show that new strategies are needed to meet the hydration needs, with a person centred approach to care for people living with dementia. It is important to ensure all staff are well trained and competent to encourage sufficient fluid intake