TDP1/TOP1 ratio as a promising indicator for the response of small cell lung cancer to topotecan

BACKGROUND AND OBJECTIVE Small cell lung cancer (SCLC) is one of the most challenging tumors to treat due to high proliferation rate, early metastatic dissemination and rapid development of chemotherapy resistance. The current treatment protocols involve the use of topoisomerase 1 (TOP1) poisons such as irinotecan and topotecan in combination with platinum-based compounds. TOP1 poisons kill cancer cells by trapping TOP1 on DNA, generating lethal DNA double-strand breaks. A potential mechanism employed by cancer cells to resist killing by TOP1 poisons is to overexpress enzymes involved in the repair of TOP1-DNA breaks. Tyrosyl DNA phosphodiesterase 1 (TDP1) is a key player in this process and despite its importance, no data is currently available to correlate TDP1 protein and mRNA levels with catalytic activity in SCLC. In addition, it is not known if TDP1 and TOP1 protein levels correlate with the cellular response of SCLC to TOP1 based therapies. METHODS AND RESULTS We report a remarkable variation in TDP1 and TOP1 protein levels in a panel of SCLC cell lines. TDP1 protein level correlates well with TDP1 mRNA and TDP1 catalytic activity, as measured by two newly developed independent activity assays, suggesting the potential utility of immunohistochemistry in assessing TDP1 levels in SCLC tissues. We further demonstrate that whilst TDP1 protein level alone does not correlate with topotecan sensitivity, TDP1/TOP1 ratio correlates well with sensitivity in 8 out of 10 cell lines examined. CONCLUSION This study provides the first cellular analyses of TDP1 and TOP1 in SCLC and suggests the potential utility of TDP1/TOP1 ratio to assess the response of SCLC to topotecan. The establishment and validation of an easy-to-use TDP1 enzymatic assay in cell extracts could be exploited as a diagnostic tool in the clinic. These findings may help in stratifying patients that are likely to benefit from TOP1 poisons and TDP1 inhibitors currently under development

Identifying innovative and effective practice in e-assessment: findings from seventeen UK case studies

The aim of this JISC funded project was to extend the understanding of what e-assessment meant to users and producers in the HE and FE sectors. A case study methodology was employed to identify and report upon best and current practice within this field of inquiry. This approach facilitated the identification of both the enabling factors and barriers associated with e-assessment. The variety of applications of e-assessment studied and their innovation and general effectiveness indicate the potential of e-assessment to significantly enhance the learning environment and the outcomes for students, in a wide range of disciplines and applications

'Keeping your body and mind active': an ethnographic study of aspirations for healthy ageing.

OBJECTIVE: To describe and explore perceptions, practices and motivations for active living in later life. DESIGN: Qualitative study with semistructured interviews and 'semistructured' participant observations of participant-selected activities, such as exercise classes, private or organised walks, shopping and gardening. PARTICIPANTS: 27 participants (65-80 years) from the European Prospective Investigation into Cancer Norfolk study, purposefully selected by gender, age, occupational class, living status and residential location; 19 of the participants agreed to be accompanied for observed activities. SETTING: Participants' homes, neighbourhoods, places of leisure activities and workplaces in Norfolk, England. RESULTS: All participants regarded a positive attitude as important for healthy ageing; this included staying active, both physically and mentally through sedentary activities such as reading and crosswords. 'Getting out of the house', being busy, or following a variety of interests were regarded as both important motivators and descriptions of their 'activeness'. Purposeful activities formed an important part of this, for example, still being engaged in paid or voluntary work, having caring responsibilities, or smaller incidental activities such as helping neighbours or walking for transport. Many also reported adapting previous, often lifelong, activity preferences and habits to their ageing body, or replacing them altogether with lower impact activities such as walking. This included adapting to the physical limitations of partners and friends which dictated the intensity and frequency of shared activities. The social context of activities could thus form a barrier to active living, but could also encourage it through companionship, social responsibilities and social pressures. CONCLUSIONS: Promoting and maintaining physical activity among older people may require more attention to activeness as an attitude and way of life as well as to its social context, and initiatives encouraging broader activity habits rather than discrete activities.This work was supported by the UK Research Councils’ Lifelong Health and Wellbeing (LLHW) Initiative in partnership with the Department of Health [grant number MR/K025147/1]; LLHW is led by the Medical Research Council. The work was undertaken under the auspices of the Centre for Diet and Activity Research (CEDAR), a UKCRC Public Health Research Centre of Excellence which is funded by the British Heart Foundation, Cancer Research UK, Economic and Social Research Council, Medical Research Council, the National Institute for Health Research, and the Wellcome Trust. SG and DO are also supported by the Medical Research Council [Unit programme numbers MC_UU_12015/4 and MC_UU_12015/6].This is the final version of the article. It was first available from BMJ via http://dx.doi.org/10.1136/bmjopen-2015-00997

From the concrete to the intangible: understanding the diverse experiences and impacts of new transport infrastructure.

BACKGROUND: Changes to the environment that support active travel have the potential to increase population physical activity. The Cambridgeshire Guided Busway is an example of such an intervention that provides new traffic-free infrastructure for walking, cycling and public transport. This qualitative investigation explored the diverse experiences of new transport infrastructure and its impacts on active travel behaviours. METHODS: Thirty-eight adult participants from the Commuting and Health in Cambridge natural experimental study were purposively selected according to their demographic and travel behaviour change characteristics and invited to participate in semi-structured interviews between February and June 2013. A mixed-method, following-a-thread approach was used to construct two contrasting vignettes (stories) to which the participants were asked to respond as part of the interviews. Inductive thematic qualitative analysis of the interview data was performed with the aid of QSR NVivo8. RESULTS: Perceptions of the busway's attributes were important in shaping responses to it. Some participants rarely considered the new transport infrastructure or described it as unappealing because of its inaccessibility or inconvenient routing. Others located more conveniently for access points experienced the new infrastructure as an attractive travel option. Likewise, the guided buses and adjacent path presented ambiguous spaces which were received in different ways, depending on travel preferences. While new features such as on board internet access or off-road cycling were appreciated, shortcomings such as overcrowded buses or a lack of path lighting were barriers to use. The process of adapting to the environmental change was discussed in terms of planning and trialling new behaviours. The establishment of the busway in commuting patterns appeared to be influenced by whether the anticipated benefits of change were realised. CONCLUSIONS: This study examined the diverse responses to an environmental intervention that may help to explain small or conflicting aggregate effects in quantitative outcome evaluation studies. Place and space features, including accessibility, convenience, pleasantness and safety relative to the alternative options were important for the acceptance of the busway. Our findings show how environmental change supporting active travel and public transport can encourage behaviour change for some people in certain circumstances

The transcription factor Glass links eye field specification with photoreceptor differentiation in Drosophila

Eye development requires an evolutionarily conserved group of transcription factors, termed the retinal determination network (RDN). However, little is known about the molecular mechanism by which the RDN instructs cells to differentiate into photoreceptors. We show that photoreceptor cell identity in Drosophila is critically regulated by the transcription factor Glass, which is primarily expressed in photoreceptors and whose role in this process was previously unknown. Glass is both required and sufficient for the expression of phototransduction proteins. Our results demonstrate that the RDN member Sine oculis directly activates glass expression, and that Glass activates the expression of the transcription factors Hazy and Otd. We identified hazy as a direct target of Glass. Induced expression of Hazy in the retina partially rescues the glass mutant phenotype. Together, our results provide a transcriptional link between eye field specification and photoreceptor differentiation in Drosophila, placing Glass at a central position in this developmental process

Did Immigrants Perceive More Job Insecurity during the SARS-CoV-2 Pandemic? : Evidence from German Panel Data

Immigrants have been affected more than native-born ethnic majority populations by the negative economic consequences of the SARS-CoV-2 pandemic. This contribution examines whether they have also experienced higher levels of perceived job insecurity, reflected in a differential increase in financial concerns and the fear of job loss during the SARS-CoV-2 pandemic. This empirical study employs the SOEP-CoV survey, which assesses the socio-economic consequences of SARS-CoV-2. It is embedded in the ongoing German Socio-Economic Panel (SOEP). We present OLS models to compare perceptions of job insecurity across groups, capturing the situation before and during the pandemic. The analyses reveal that first-generation immigrants reported more financial worries, and they perceived a higher chance of job loss than second-generation immigrants and the native-born ethnic majority. This difference in economic concerns emerged only in the pandemic. Despite covering a wide range of conditions signaling objective risk of job loss, as well as individuals’ means and resources for dealing with looming job loss, these disparities persisted in the empirical study. Considering group-membership-related feelings of acceptance and inclusion could provide a promising route for future inquiry that may allow the remaining gap in subjective job insecurity to be accounted for

Hay preferences in horses versus selection by their owners

The objective of the present study was to evaluate the differences in the selection behaviour by horses and by their owners given a choice of three hay types differing in chemical and nutritional composition. Horse groups included 12 French mountain (FM) stallions, 12 Icelandic (IS) and 12 warmblood horses (WB), with the latter groups consisting of mares and geldings. Hays were offered in a free choice experiment over a period of six consecutive days (baseline choice on day 1, adaption period from day 2-5 and a final preference test on day 6). Additionally, the owners of the horses selected among the three hay types, the one which they assumed would best meet their horse’s assumed nutritional requirements. Hay types (A, B and C) showed distinct characteristics based on colour, texture morphology and odour and nutrient contents. The latter were analysed with near-infrared spectroscopy. Most horses (69%) preferred hay type B and 31% preferred hay type C, while horses completely avoided hay type A. The group of FM horses exclusively preferred hay B on both test days, the groups of IS and WB horses also showed a preference for hay B, but less pronounced than FM horses choosing both between hay B and C, respectively. Horses did not choose randomly among the hays offered (P < 0.05). In addition, the horses hay preference was influenced by their group assignment (P < 0.05) which, however, cannot be generalized to breed or gender (mares, stallions or geldings). The content of crude protein (r=0.68), and leaves (r=0.48) of the hay was positively correlated with the preference of the horses for that particular hay type, although correlations were moderate. Among the owners, 42% chose hay type A, which was completely avoided by the horses, while approximately 30 % of the owners chose either hay type B or C, which were richer in energy and protein as the best hay quality for their horses assumed nutritional requirements. Therefore, no significant correlation could be observed between the choice preference of the horses and the selection by the owners. The distinct preference for energy- and protein-rich hay of horses underlines the importance for owners to carefully adjust the hay quality to the horse’s activity level and requirements. For horses with lower energy requirements, omission of concentrate feeds, while providing roughage only diets by mixing different hays qualities, appears suitable

Antimicrobial Brushes on Titanium via “Grafting to” Using Phosphonic Acid/Pyridinium Containing Block Copolymers

Coating medical implants with antibacterial polymers may prevent postoperative infections which are a common issue for conventional titanium implants and can even lead to implant failure. Easily applicable diblock copolymers are presented that form polymer brushes via “grafting to” mechanism on titanium and equip the modified material with antibacterial properties. The polymers carry quaternized pyridinium units to combat bacteria and phosphonic acid groups which allow the linear chains to be anchored to metal surfaces in a convenient coating process. The polymers are synthesized via reversible-addition-fragmentation-chain-transfer (RAFT) polymerization and postmodifications and are characterized using NMR spectroscopy and SEC. Low grafting densities are a major drawback of the “grafting to” approach compared to “grafting from”. Thus, the number of phosphonic acid groups in the anchor block are varied to investigate and optimize the surface binding. Modified titanium surfaces are examined regarding their composition, wetting behavior, streaming potential, and coating stability. Evaluation of the antimicrobial properties revealed reduced bacterial adhesion and biofilm formation for certain polymers, albeit the cell biocompatibility against human gingival fibroblasts is also impaired. The presented findings show the potential of easy-to-apply polymer coatings and aid in designing next-generation implant surface modifications

Successive requirement of Glass and Hazy for photoreceptor specification and maintenance in Drosophila

Development of the insect compound eye requires a highly controlled interplay between transcription factors. However, the genetic mechanisms that link early eye field specification to photoreceptor terminal differentiation and fate maintenance remain largely unknown. Here, we decipher the function of 2 transcription factors, Glass and Hazy, which play a central role during photoreceptor development. The regulatory interactions between Glass and Hazy suggest that they function together in a coherent feed-forward loop in all types of Drosophila photoreceptors. While the glass mutant eye lacks the expression of virtually all photoreceptor genes, young hazy mutants correctly express most phototransduction genes. Interestingly, the expression of these genes is drastically reduced in old hazy mutants. This age-dependent loss of the phototransduction cascade correlates with a loss of phototaxis in old hazy mutant flies. We conclude that Glass can either directly or indirectly initiate the expression of most phototransduction proteins in a Hazy-independent manner, and that Hazy is mainly required for the maintenance of functional photoreceptors in adult flies