Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Synergy of extreme drought and shrub invasion reduce ecosystem functioning and resilience in water-limited climates

Extreme drought events and plant invasions are major drivers of global change that can critically affect ecosystem functioning and alter ecosystem-atmosphere exchange. Invaders are expanding worldwide and extreme drought events are projected to increase in frequency and intensity. However, very little is known on how these drivers may interact to affect the functioning and resilience of ecosystems to extreme events. Using a manipulative shrub removal experiment and the co-occurrence of an extreme drought event (2011/2012) in a Mediterranean woodland, we show that native shrub invasion and extreme drought synergistically reduced ecosystem transpiration and the resilience of key-stone oak tree species. Ecosystem transpiration was dominated by the water use of the invasive shrub Cistus ladanifer, which further increased after the extreme drought event. Meanwhile, the transpiration of key-stone tree species decreased, indicating a competitive advantage in favour of the invader. Our results suggest that in Mediterranean-type climates the invasion of water spending species and projected recurrent extreme drought events may synergistically cause critical drought tolerance thresholds of key-stone tree species to be surpassed, corroborating observed higher tree mortality in the invaded ecosystems. Ultimately, this may shift seasonally water limited ecosystems into less desirable alternative states dominated by water spending invasive shrubs

Evaluation of the HadGEM3-A simulations in view of detection and attribution of human influence on extreme events in Europe

A detailed analysis is carried out to assess the HadGEM3-A global atmospheric model skill in simulating extreme temperatures, precipitation and storm surges in Europe in the view of their attribution to human influence. The analysis is performed based on an ensemble of 15 atmospheric simulations forced with observed Sea Surface Temperature of the 54 year period 1960-2013. These simulations, together with dual simulations without human influence in the forcing, are intended to be used in weather and climate event attribution. The analysis investigates the main processes leading to extreme events, including atmospheric circulation patterns, their links with temperature extremes, land-atmosphere and troposphere-stratosphere interactions. It also compares observed and simulated variability, trends and generalized extreme value theory parameters for temperature and precipitation. One of the most striking findings is the ability of the model to capture North Atlantic atmospheric weather regimes as obtained from a cluster analysis of sea level pressure fields. The model also reproduces the main observed weather patterns responsible for temperature and precipitation extreme events. However, biases are found in many physical processes. Slightly excessive drying may be the cause of an overestimated summer interannual variability and too intense heat waves, especially in central/northern Europe. However, this does not seem to hinder proper simulation of summer temperature trends. Cold extremes appear well simulated, as well as the underlying blocking frequency and stratosphere-troposphere interactions. Extreme precipitation amounts are overestimated and too variable. The atmospheric conditions leading to storm surges were also examined in the Baltics region. There, simulated weather conditions appear not to be leading to strong enough storm surges, but winds were found in very good agreement with reanalyses. The performance in reproducing atmospheric weather patterns indicates that biases mainly originate from local and regional physical processes. This makes local bias adjustment meaningful for climate change attribution

On the Link between the Subseasonal Evolution of the North Atlantic Oscillation and East Asian Climate

We analyse the impact of the North Atlantic Oscillation (NAO) on the climate of East Asia at subseasonal time scales during both winter and summer. These teleconections have mainly been investigated at seasonal and longer time scales, while higher-frequency links are largely unexplored. The NAO is defined using extended empirical orthogonal functions on pentad-mean observations, which allows to elucidate the oscillation’s spatial and temporal evolution and clearly separate the development and decay phases. The downstream dynamical imprint and associated temperature and precipitation anomalies are quantified by means of a linear regression analysis. It is shown that the NAO generates a significant climate response over East Asia during both the dry and wet seasons, whose spatial pattern is highly dependent on the phase of the NAO’s life cycle. Temperature and precipitation anomalies develop concurrently with the NAO mature phase, and reach maximum amplitude 5–10 days later. These are shown to be systematically related to mid and high-latitude teleconnections across the Eurasian continent via eastward-propagating quasi-stationary Rossby waves instigated over the Atlantic and terminating in the northeastern Pacific. These findings underscore the importance of rapidly evolving dynamical processes in governing the NAO’s downstream impacts and teleconnections with East Asia.</p

Projections of global warming-induced impacts on winter storm losses in the German private household sector

We present projections of winter storm-induced insured losses in the German residential building sector for the 21st century. With this aim, two structurally most independent downscaling methods and one hybrid downscaling method are applied to a 3-member ensemble of ECHAM5/MPI-OM1 A1B scenario simulations. One method uses dynamical downscaling of intense winter storm events in the global model, and a transfer function to relate regional wind speeds to losses. The second method is based on a reshuffling of present day weather situations and sequences taking into account the change of their frequencies according to the linear temperature trends of the global runs. The third method uses statistical-dynamical downscaling, considering frequency changes of the occurrence of storm-prone weather patterns, and translation into loss by using empirical statistical distributions. The A1B scenario ensemble was downscaled by all three methods until 2070, and by the (statistical-) dynamical methods until 2100. Furthermore, all methods assume a constant statistical relationship between meteorology and insured losses and no developments other than climate change, such as in constructions or claims management. The study utilizes data provided by the German Insurance Association encompassing 24 years and with district-scale resolution. Compared to 1971–2000, the downscaling methods indicate an increase of 10-year return values (i.e. loss ratios per return period) of 6–35 % for 2011–2040, of 20–30 % for 2041–2070, and of 40–55 % for 2071–2100, respectively. Convolving various sources of uncertainty in one confidence statement (data-, loss model-, storm realization-, and Pareto fit-uncertainty), the return-level confidence interval for a return period of 15 years expands by more than a factor of two. Finally, we suggest how practitioners can deal with alternative scenarios or possible natural excursions of observed losses

Theory and practice of social norms interventions: eight common pitfalls.

BACKGROUND: Recently, Global Health practitioners, scholars, and donors have expressed increased interest in "changing social norms" as a strategy to promote health and well-being in low and mid-income countries (LMIC). Despite this burgeoning interest, the ability of practitioners to use social norm theory to inform health interventions varies widely. MAIN BODY: Here, we identify eight pitfalls that practitioners must avoid as they plan to integrate a social norms perspective in their interventions, as well as eight learnings. These learnings are: 1) Social norms and attitudes are different; 2) Social norms and attitudes can coincide; 3) Protective norms can offer important resources for achieving effective social improvement in people's health-related practices; 4) Harmful practices are sustained by a matrix of factors that need to be understood in their interactions; 5) The prevalence of a norm is not necessarily a sign of its strength; 6) Social norms can exert both direct and indirect influence; 7) Publicising the prevalence of a harmful practice can make things worse; 8) People-led social norm change is both the right and the smart thing to do. CONCLUSIONS: As the understanding of how norms evolve in LMIC advances, practitioners will develop greater understanding of what works to help people lead change in harmful norms within their contexts. Awareness of these pitfalls has helped several of them increase the effectiveness of their interventions addressing social norms in the field. We are confident that others will benefit from these reflections as well

Patient-reported outcome measures for cancer caregivers: a systematic review

Purpose Informal caregivers provide invaluable help and support to people with cancer. As treatments extend survival and the potential burdens on carers increase, there is a need to assess the impact of the role. This systematic review identified instruments that measure the impact of caregiving, evaluated their psychometric performance specifically in cancer and appraised the content. Methods A 2-stage search strategy was employed to: 1. identify instruments that measure the impact of caregiving, 2. run individual searches on each measure to identify publications evaluating psychometric performance in the target population. Searches were conducted in Medline, Embase, CINAHL and Psychinfo and restricted to English for instrument used and article language. Psychometric performance was evaluated for content and construct validity, internal consistency, test-retest reliability, precision, responsiveness and acceptability. Individual scale items were extracted and systematically categorised into conceptual domains. Results 10 papers were included reporting on the psychometric properties of 8 measures. Although construct validity and internal consistency were most frequently evaluated, no study comprehensively evaluated all relevant properties. Few studies met our inclusion criteria so it was not possible to consider the psychometric performance of the measures across a group of studies. Content analysis resulted in 16 domains with 5 overarching themes: lifestyle disruption; wellbeing; health of the caregiver; managing the situation and relationships. Conclusions Few measures of caregiver impact have been subject to psychometric evaluation in cancer caregivers. Those that have do not capture well changes in roles and responsibilities within the family and career, indicating the need for a new instrument