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

Molecular modelling of dendrimers for nanoscale applications

Dendrimers are well defined, highly branched macromolecules that radiate from a central core and are synthesized through a stepwise, repetitive reaction sequence that guarantees complete shells for each generation, leading to polymers that are monodisperse. The synthetic procedures developed for dendrimer preparation permit nearly complete control over the critical molecular design parameters, such as size, shape, surface/interior chemistry, flexibility, and topology. Recent results suggest that dendritic polymers may provide the key to developing a reliable and economical fabrication and manufacturing route to functional nanoscale materials that would have unique properties (electronic, optical, opto-electronic, magnetic, chemical, or biological). In turn, these could be used in designing new nanoscale devices. In this paper, we determine the 3D molecular structure of various dendrimers with continuous configurational Boltzmann biased direct Monte Carlo method and study their energetic and structural properties using molecular dynamics after annealing these molecular representations

Resilience: A Literature Review

Resilience has, in the past four decades, been a term increasingly employed throughout a number of sciences: psychology and ecology, most prominently. Increasingly one finds it in political science, business administration, sociology, history, disaster planning, urban planning, and international development. The shared use of the term does not, however, imply unified concepts of resilience nor the theories in which it is embedded. Different uses generate different methods, sometimes different methodologies. Evidential or other empirical support can differ between domains of application, even when concepts are broadly shared. The review centres on three resilience frameworks, of increasing complexity: Engineering Resilience (or ‘Common Sense’ resilience); Systems Resilience, called Robustness in economics; and Resilience in Complex Adaptive Systems. Although each framework has historical roots in particular disciplines, the frameworks themselves can be applied to any domain: Engineering Resilience is utilised in some child development studies; Systems Resilience is often used in governance and management; and the Complex Adaptive Systems approach has been applied to economics, innovation in technology, history, and urban planning. Thus different frameworks along the spectrum offer a choice of perspective; the acceptability of trade-offs between them, and not subject matter, will ultimately determine which perspective is chosen.The Rockerfeller Foundatio

A comparison of broad-spectrum and narrow-spectrum dry cow therapy used alone and in combination with a teat sealant

The dry period is a critical time in the lactation cycle, offering the optimum time for cure of existing intramammary infection (IMI), while also encompassing the periods of highest susceptibility to new intramammary infection. Until recent years, intramammary infection in the dry period has been controlled with the use of antibiotic dry cow therapy. The aim of this study was to investigate 3 different dry cow therapy regimens, in low-somatic cell count (SCC; bulk milk SCC < 250,000 cells/mL) herds in southwest England. A total of 489 cows was recruited to the study and randomly allocated to receive either the broad-spectrum antibiotic cefquinome, a combination treatment comprising the narrow-spectrum antibiotic cloxacillin and an internal teat sealant, or the narrow-spectrum antibiotic cloxacillin alone. All quarters were sampled for bacteriology at drying off and again in the week immediately postcalving; 2 quarters were also sampled 2 wk before the estimated calving date to allow an assessment of infection dynamics during the dry period. Quarters were subsequently monitored for clinical mastitis for the first 100 d of lactation. Conventional multilevel (random effects) models were constructed to assess the efficacy of products in preventing IMI. Survival analysis was used to examine factors that influenced the risk of clinical mastitis using conventional Cox proportional hazards models. No differences were identified between the treatment groups in terms of cure of IMI caused by the major pathogens. Quarters in both the combination and cefquinome-treated groups were more likely to be free of a major pathogen or enterobacterial pathogen postcalving. With respect to clinical mastitis, the cefquinome-treated group was less likely to develop clinical mastitis than was the cloxacillin treated group

Assessing Vancomycin Dosing Per Pharmacy in Elderly Patients Over the Age of 74 Years

Vancomycin has a complex pharmacokinetic profile and carries potential risks for nephrotoxicity and ototoxicity. The pharmacokinetic profile in elderly patients significantly differs from that of younger patients. It is common practice in many institutions for pharmacists to intentionally round serum creatinine levels to 1 mg/dl in elderly patients with levels \u3c1 mg/ dl to avoid overestimating clearance and toxicities. This can potentially lead to underestimation of creatinine clearance, and subsequently lead to vancomycin under dosing. The aim of this study was to evaluate vancomycin target trough attainment and the time to trough attainment with vancomycin dosing per pharmacy in elderly patients

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How to Launch an Interdisciplinary Leadership Program

Building a doctoral program in leadership is never an easy task, and building an interdisciplinary doctoral program is even more difficult. Yet, it is the interdisciplinary approach that differentiates typical leadership programs from others and offers learners an integrated view of leadership theories and practices. This special report presents an example of designing and implementing an interdisciplinary doctoral program that promotes social justice leadership. Drawing from firsthand experiences of program faculty, staff, and administration, we share lessons learned and the logic behind adopting an interdisciplinary approach for those creating programs that seeks to promote social justice. We found that by allowing students and faculty to convene together, rather than disperse into separate, isolated academic disciplines, emerging scholar-practitioners are encouraged to engage in realistic, professional practice investigation and problem-solving techniques. Through this experience, we also found that conscious coursework design involves integrating multiple, often quite divergent, disciplines into a core set of courses. Additionally, we learned that unifying students through a common mission permits distinctive discussions, including personal reflection and ethical decision-making opportunities among the concepts, constructs, and knowledge that extend beyond disciplinary lines (Cherney et al., 2012). We also found that cultivating a diverse student body and faculty base requires everyone to work strategically within the program, recognizing the call for coherence and consistency across disciplinary lines. Finally, we discovered that developing a dissertation in practice allows students to implement an evidence-based solution within their professional practice setting as their pinnacle doctorate work (Herr & Anderson, 2014; Olson & Clark, 2009). We conclude this paper by reiterating our finding that leadership programs that promote social justice are enhanced by adopting an interdisciplinary approach as this allows for the creation of a program that challenges students to learn at a more complex level, faculty to integrate disciplines, and programs to promote socially just ideals. We discuss implications for other schools seeking to develop an interdisciplinary doctoral leadership program

Measuring troublesomeness of chronic pain by location

Background Current measures of pain assess the relative contribution of pain in different body regions to the overall impact of pain. We developed a series of questions to measure the relative 'troublesomeness' of pain in different body regions (the "troublesomeness grid"). The study aimed to determine whether the "troublesomeness grid" is an appropriate measure to assess the severity of pain in different body regions, allowing the comparative severity of pain in different body regions to be assessed. Methods We used data from a pilot for a population survey of pain (N = 205) and from the population survey itself (N = 2504) to assess the 'troublesomeness grid's performance. Specifically, its face and content validity using overall and item non-completion rates; its criterion related validity by exploring the relationship between troublesomeness and standard measures of pain, disability, distress and health utility for the five body regions most commonly affected by chronic pain; and its reliability and reproducibility in a test/re-test study. Results The troublesomeness grid appeared to have good face validity as it had good completion rates. It also appeared to have good content validity as the percentage agreement between the grid and the pain manikin was high (over 90%). In terms of criterion related validity, troublesomeness was most strongly correlated with pain intensity and health related quality of life, but less with disability and distress. The test-retest reliability was between 80% and 90% for the majority of body regions examined. Conclusion The troublesomeness grid is well completed and appears to be an appropriate tool to assess the comparative severity of pain in different body regions

A new automated technique for the reconstitution of hydrophobic proteins into planar bilayer membranes. Studies of human recombinant uncoupling protein 1

AbstractElectrophysiological characterisation of the vast number of annotated channel and transport proteins in the postgenomic era would be greatly facilitated by the introduction of rapid and robust methods for the functional incorporation of membrane proteins into defined lipid bilayers. Here, we describe an automated technique for reconstitution of membrane proteins into lipid bilayer membranes, which substantially reduces both the reconstitution time and the amount of protein required for the membrane formation. The method allows the investigation of single protein channels as well as insertion of multiple copies (∼107) into a single bilayer. Despite a comparatively large membrane area (up to 300 μm diameter), the high stability of the membrane permits the application of transmembrane voltages up to 300 mV. This feature is especially important for studies of inner membrane mitochondrial proteins, since they act at potentials up to ∼200 mV under physiological conditions. It is a combination of these advantages that enables the detailed investigation of the minuscule single protein conductances typical for proton transporters. We have applied the new technique for the reconstitution and electrophysiological characterisation of human recombinant uncoupling protein 1, hUCP1, that has been overexpressed in E. coli and purified from inclusion bodies. We demonstrate that hUCP1 activity in the presence of fatty acids is comparable to the activity of UCP1 isolated from brown adipose tissue