Molecular mechanisms of cisplatin resistance in lung cancer

Cisplatin is one of the most potent anticancer agents, displaying significant clinical activity against a variety of solid tumours. To date, cisplatin-based combination treatment remains the most effective systemic chemotherapy for non-small cell lung cancer (NSCLC) patients. Unfortunately, the outcome of cisplatin therapy in NSCLC has reached a plateau due to the development of both intrinsic and acquired resistance that have become a major obstacle in the use of cisplatin in the clinical setting. The molecular mechanisms that underlie chemoresistance are largely unknown. Mechanisms of acquired resistance to cisplatin include reduced intracellular accumulation of the drug, enhanced drug inactivation by metallothionine and glutathione, increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. Cisplatin-induced cytotoxicity is mediated through the induction of apoptosis and cell cycle arrest as a result of cisplatin-DNA adduct formation, which in turn, activates multiple signaling pathways and mediators. These include p53, Bcl-2 family, caspases, cyclins, CDKs, MAPK and PI3K/Akt. Increased expression of anti-apoptotic genes and mutations in the intrinsic apoptotic pathway may also contribute to the inability of cells to detect DNA damage or to induce apoptosis. This chapter will provide an insight into the mechanisms involved in cisplatin resistance and a better understanding of the molecular basis of the cellular response to cisplatin-based chemotherapy in lung cancer.

Targeting nuclear factor-kappa B to overcome resistance to chemotherapy

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge in the treatment of cancer patients. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation, and evasion of apoptosis. Pre-clinical models have demonstrated that many chemotherapy drugs, such as platinum-based agents, antracyclines, and taxanes, promote the activation of the NF-κB pathway. NF-κB is a key transcription factor, playing a role in the development and progression of cancer and chemoresistance through the activation of a multitude of mediators including anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anti-cancer target. Here, we describe the role of NF-κB in cancer and in the development of resistance, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signaling by pharmacological intervention will be addressed.

'Too high in human terms' : the costs of high security imprisonment. Review of Imprisoning Resistance by Bree Carlton and Intractable by Bernie Matthews.

The article discusses the issues of resistance; that is resistance by prisoners to the various manifestations of power operating in high security prisons, as well as that of attempted shifts in the regime from physical to psychological control. Other topics highlighted include legitimacy and 'official discourse', mourning and the construction of 'ungrievable lives' and the importance of finding a way out of the cycle of violence, which high security regimes perpetuate.

Small acts of resistance : the role of intergenerational collaborative drawing in early childhood teaching and learning

This chapter focuses on ‘intergenerational collaborative drawing’, a particular process of drawing whereby adults and children draw at the same time on a blank paper space. Such drawings can be produced for a range of purposes, and based on different curriculum or stimulus subjects. Children of all ages, and with a range of physical and intellectual abilities are able to draw with parents, carers and teachers. Intergenerational collaborative drawing is a highly potent method for drawing in early childhood contexts because it brings adults and children together in the process of thinking and theorizing in order to create visual imagery and this exposes in deep ways to adults and children, the ideas and concepts being learned about. For adults, this exposure to a child’s thinking is a far more effective assessment tool than when they are presented with a finished drawing they know little about. This chapter focuses on drawings to examine wider issues of learning independence and how in drawing, preferred schema in the form of hand-out worksheets, the suggestive drawings provided by adults, and visual material seen in everyday life all serve to co-opt a young child into making particular schematic choices. I suggest that intergenerational collaborative drawing therefore serves to work as a small act of resistance to that co-opting, in that it helps adults and children to collectively challenge popular creativity and learning discourses.

The resistance of PRESENT-80 against related-key differential attacks

We examine the security of the 64-bit lightweight block cipher PRESENT-80 against related-key differential attacks. With a computer search we are able to prove that for any related-key differential characteristic on full-round PRESENT-80, the probability of the characteristic only in the 64-bit state is not higher than 2−64. To overcome the exponential (in the state and key sizes) computational complexity of the search we use truncated differences, however as the key schedule is not nibble oriented, we switch to actual differences and apply early abort techniques to prune the tree-based search. With a new method called extended split approach we are able to make the whole search feasible and we implement and run it in real time. Our approach targets the PRESENT-80 cipher however,with small modifications can be reused for other lightweight ciphers as well.

Heat transfer measurements on the first experimental layer of the FIRE II reentry vehicle in expansion tubes

The present study focused on simulating a trajectory point towards the end of the first experimental heatshield of the FIRE II vehicle, at a total flight time of 1639.53s. Scale replicas were sized according to binary scaling and instrumented with thermocouples for testing in the X1 expansion tube, located at The University of Queensland. Correlation of flight to experimental data was achieved through the separation, and independent treatment of the heat modes. Preliminary investigation indicates that the absolute value of radiant surface flux is conserved between two binary scaled models, whereas convective heat transfer increases with the length scale. This difference in the scaling techniques result in the overall contribution of radiative heat transfer diminishing to less than 1% in expansion tubes from a flight value of approximately 9-17%. From empirical correlation's it has been shown that the St √Re number decreases, under special circumstances, in expansion tubes by the percentage radiation present on the flight vehicle. Results obtained in this study give a strong indication that the relative radiative heat transfer contribution in the expansion tube tests is less than that in flight, supporting the analysis that the absolute value remains constant with binary scaling.

Perceived obstacles to multi-storey timber-frame construction : an Australian study

The contemporary default materials for multi-storey buildings – namely concrete and steel – are all significant generators of carbon and the use of timber products provides a technically, economically and environmentally viable alternative. In particular, timber’s sustainability can drive increased use and subsequent evolution of the Blue economy as a new economic model. National research to date, however, indicates a resistance to the uptake of timber technologies in Australia. To investigate this further, a preliminary study involving a convenience sample of 15 experts was conducted to identify the main barriers involved in the use of timber frames in multi-storey buildings. A closed-ended questionnaire survey involving 74 experienced construction industry participants was then undertaken to rate the relative importance of the barriers. The survey confirmed the most significant barriers to be a perceived increase in maintenance costs and fire risk, together with a limited awareness of the emerging timber technologies available. It is expected that the results will benefit government and the timber industry, contributing to environmental improvement by developing strategies to increase the use of timber technologies in multi-storey buildings by countering perceived barriers in the Australian context.

Synthetic rating procedures for railway bridges

One of the most important parts of any Bridge Management System (BMS) is the condition assessment and rating of bridges. This paper, introduces a procedure for condition assessment, based on criticality and vulnerability analysis. According to this procedure, new rating equations are developed. The inventory data is used to determine the contribution of different critical factors such as environmental effects, flood, earthquake, wind, and vehicle impacts. The criticality of the components to live load and vulnerability of the components to the above critical factors are identified. Based on the criticality and the vulnerability of the components and criticality of factors, and by using the new rating equations, the condition assessment and the rating of the railway bridges and their components at the network level will be conducted. This method for the first time incorporates structural analysis, available knowledge of risk assessment in structural engineering standards, and the experience of structural engineers in a practical way to enhance the reliability of the condition assessment and rating a network of bridges.

Performance-based structural fire design and testing of structures

Fire incident in buildings is common in Hong Kong and this could lead to heavy casualties due to its high population density, so the fire safety design of the framed structure is an important research topic. This paper describes a computer tool for determination of capacity of structural safety against various fire scenarios and the well-accepted second-order direct plastic analysis is adopted for simulation of material yielding and buckling. A computer method is developed to predict structural behaviour of bare steel framed structures at elevated temperatures but the work can be applied to structures made of other materials. These effects of thermal expansion and material degradation due to heating are required to be considered in order to capture the actual behavior of the structure under fire. Degradation of material strength with increasing temperature is included by a set of temperature-stress-strain curves according to BS5950 Part 8 mainly, which implicitly allows for creep deformation. Several numerical and experimental verifications of framed structures are presented and compared against solutions by other researchers. The proposed method allows us to adopt the truly performance-based structural fire analysis and design with significant saving in cost and time.

Environmental indicators for sustainable road development and operation

Road construction, maintenance and operation are activities that impact the environment by way of energy use, resource consumption and emission. Components such as construction material, transportation, street lighting, rolling resistance, traffic congestion during works, albedo and end-of-life processing impact the environment at different phases of the life of a road. With a view to promote sustainable development, a few sustainability rating schemes, e.g. Infrastructure Sustainability and Invest (Australia), Envision and Greenroads (USA), and CEEQUAL (UK) have been developed, that can assess road projects. These schemes address environmental areas such as: energy and emission, land, water, materials, discharges into surroundings, waste and ecology as factors for sustainable development. This paper assesses different rating schemes based on a defined comprehensive life cycle assessment (LCA) system boundary for road projects to identify different environmental indicators that address sustainable road development and operation. The findings indicate that new indicators are required to address different environmental components during the operation phase of roads.

Indexes of insulin resistance and secretion in obese children and adolescents : a validation study

OBJECTIVE To assess the concurrent validity of fasting indexes of insulin sensitivity and secretion in - obese prepubertal (Tanner stage 1) children and pubertal (Tanner stages 2-5) glucose tolerance test (FSIVGTT) as a criterion measure. RESEARCH DESIGN AND METHODS Eighteen obese children and adolescents (11 girls and 7 boys, mean age 12.2 +/- 2.4 years, mean BMI 35.4 +/- 6.2 kg/m(2), mean BMI-SDS 3.5 +/- 0.5, 7 prepubertal and I I pubertal) participated in the study. All participants underwent an insulin-modified FSIVGTT on two occasions, and 15 repeated this test a third time (mean 12.9 and 12.0 weeks apart). S-i measured by the FSIVGTT was compared with homeostasis model assessment (HOMA) of insulin resistance (HOMA-IR), quantitative insulin-sensitivity check index (QUICKI), fasting glucose-to-insulin ratio (FGIR), and fasting insulin (estimates of insulin sensitivity derived from fasting samples). The acute insulin response (AIR) measured by the FSIVGTT was compared with HOMA of percent beta-cell function (HOMA-beta%), FGIR, and fasting insulin (estimates of insulin secretion derived from fasting samples). RESULTS There was a significant negative correlation between HOMA-IR and S-i (r = -0.89, r = -0.90, and r = -0.81, P < 0.01) and a significant positive correlation between QUICKI and S-i (r = 0.89, r = 0.90, and r = 0.81, P < 0.01) at each time point. There was a significant positive correlation between FGIR and S-i (r = 0.91, r = 0.91, and r = 0.82, P < 0.01) and a significant negative correlation between fasting insulin and S-i (r = -90, r = -0.90, and r = -0.88, P < 0.01). HOMA-beta% was not as strongly correlated with AIR (r = 0.60, r = 0.54, and r = 0.61, P < 0.05). CONCLUSIONS HOMA-IR, QUICKI, FGIR, and fasting insulin correlate strongly with S-i assessed by the FSIVGTT in obese children and adolescents. Correlations between HOMA-β% FGIR and fasting insulin, and AIR were not as strong. Indexes derived from fasting samples are a valid tool for assessing insulin sensitivity in prepubertal and pubertal obese children.

Dispositional resistance to change : measurement equivalence and the link to personal values across 17 nations

The concept of dispositional resistance to change has been introduced in a series of exploratory and confirmatory analyses through which the validity of the Resistance to Change (RTC) Scale has been established (S. Oreg, 2003). However, the vast majority of participants with whom the scale was validated were from the United States. The purpose of the present work was to examine the meaningfulness of the construct and the validity of the scale across nations. Measurement equivalence analyses of data from 17 countries, representing 13 languages and 4 continents, confirmed the cross-national validity of the scale. Equivalent patterns of relationships between personal values and RTC across samples extend the nomological net of the construct and provide further evidence that dispositional resistance to change holds equivalent meanings across nations.

Trait and behavioural motor control is associated with resistance to overconsumption

While overall obesity rates are rising, a minority of individuals appear to resist overconsumption and remain lean in spite of an ‘obesogenic’ environment. Studying the factors hypothesised to underpin behaviours associated with resistance to overconsumption may inform weight management strategies in an adverse environment. Trait (BIS-11) and behavioural (response inhibition, GoStop) self control were assessed in the laboratory. Snack food consumption was measured covertly via a sham taste test. Lack of motor control was positively correlated (r = .32, p <. 05) and successful response inhibition was negatively correlated (r = −.35, p <. 05) with snack food intake. Low motor control was also associated with further food intake when satiated (r = .39, p < .01). These relationships were independent of self-reported palatability and perceived reward value of the food. Motor control may be an important factor implicated in ‘mindless’ eating in an environment abundant in palatable, energy-dense snack foods.