The stress-responsive kinase DYRK2 activates heat shock factor 1 promoting resistance to proteotoxic stress.

To survive proteotoxic stress, cancer cells activate the proteotoxic-stress response pathway, which is controlled by the transcription factor heat shock factor 1 (HSF1). This pathway supports cancer initiation, cancer progression and chemoresistance and thus is an attractive therapeutic target. As developing inhibitors against transcriptional regulators, such as HSF1 is challenging, the identification and targeting of upstream regulators of HSF1 present a tractable alternative strategy. Here we demonstrate that in triple-negative breast cancer (TNBC) cells, the dual specificity tyrosine-regulated kinase 2 (DYRK2) phosphorylates HSF1, promoting its nuclear stability and transcriptional activity. DYRK2 depletion reduces HSF1 activity and sensitises TNBC cells to proteotoxic stress. Importantly, in tumours from TNBC patients, DYRK2 levels positively correlate with active HSF1 and associates with poor prognosis, suggesting that DYRK2 could be promoting TNBC. These findings identify DYRK2 as a key modulator of the HSF1 transcriptional programme and a potential therapeutic target.

High NRF2 Levels Correlate with Poor Prognosis in Colorectal Cancer Patients and with Sensitivity to the Kinase Inhibitor AT9283 In Vitro.

Aberrant hyperactivation of nuclear factor erythroid 2 (NF-E2) p45-related factor 2 (NRF2) is a common event in many tumour types and associates with resistance to therapy and poor patient prognosis; however, its relevance in colorectal tumours is not well-established. Measuring the expression of surrogate genes for NRF2 activity in silico, in combination with validation in patients' samples, we show that the NRF2 pathway is upregulated in colorectal tumours and that high levels of nuclear NRF2 correlate with a poor patient prognosis. These results highlight the need to overcome the protection provided by NRF2 and present an opportunity to selectively kill cancer cells with hyperactive NRF2. Exploiting the CRISPR/Cas9 technology, we generated colorectal cancer cell lines with hyperactive NRF2 and used them to perform a drug screen. We identified AT9283, an Aurora kinase inhibitor, for its selectivity towards killing cancer cells with hyperactive NRF2 as a consequence to either genetic or pharmacological activation. Our results show that hyperactivation of NRF2 in colorectal cancer cells might present a vulnerability that could potentially be therapeutically exploited by using the Aurora kinase inhibitor AT9283.

Hibernation Patterns of the European Hedgehog, Erinaceus europaeus, at a Cornish Rescue Centre.

The European hedgehog, Erinaceus europaeus, is frequently admitted to rescue centres in the UK. With many overwintering in captivity, there is cause to investigate hibernation patterns in order to inform and improve husbandry and monitoring protocols. Thirty-five hedgehogs were studied over two winters. Weight change during hibernation for the first winter was used to test for effects of disturbance on different aspects of hibernation, including total duration, frequency and duration of spontaneous arousals. There was no significant difference between the two winters for any of the four aspects studied. Significant positive correlations demonstrated that weight-loss increased with the duration of the hibernation period and with percent of nights spent asleep, but not with the number of arousal events. Thus, weight-loss appears more strongly associated with the proportion of time spent asleep than with the number of arousal events. This was surprising given the assumed energetic expense of repeated arousal and was potentially due to availability of food during arousals. In contrast with previous studies, larger hedgehogs lost less weight per day than did smaller hedgehogs. They also woke up more often (i.e., had more opportunities to feed), which may explain the unexpected pattern of weight-loss. Hibernatory behaviour in captivity differs from that in the wild, likely because of non-natural conditions in hutches and the immediate availability of food. This study provides a basis for further research into the monitoring and husbandry of hedgehogs such that it can be adapted for each individual according to pre-hibernation weight and behaviour during hibernation.

Diagnosis of hypothermia in the European hedgehog, Erinaceus europaeus, using infrared thermography.

The European hedgehog (Erinaceus europaeus) is the most common mammal species admitted to rescue centres in the UK. The temperature of a new admission is useful in assessing health status, hypothermia can indicate shock or impaired health, assessing this can be challenging due to their ability to curl tightly. Measuring body temperature using conventional rectal thermometers is not possible. In order to improve welfare and to maximise successful rehabilitation, it is important to incorporate new technology and understanding into husbandry, assessment and diagnostic protocols and practices used within these rescue centres. This study assessed and diagnosed hypothermia, a common condition of new arrivals as a result of shock, using corneal temperature as recorded by a FLIR E60bx infrared camera, at Prickles and Paws Hedgehog Rescue Centre, Cubert, Cornwall. Corneal temperatures were recorded ranging from 14.3 to 37.4 °C. The thermal camera provided greater accuracy over observational diagnosis made by rescue centre staff, with a significant difference between diagnostic categories, demonstrating misdiagnosis by observation alone of 42% of individuals.. There was a higher mortality within those diagnosed by IRT to be 'mildly hypothermic' or 'hypothermic', with death occurring within 72 h of diagnosis. These findings provide a basis for further research into the treatment of hypothermia in E. europaeus now that temperature can be more accurately assessed by non-invasive methods.

Positive and negative effects of habitat-forming algae on survival, growth and intra-specific competition of limpets.

Understanding the effects of environmental change on the distribution and abundance of strongly interacting organisms, such as intertidal macroalgae and their grazers, needs a thorough knowledge of their underpinning ecological relationships. Control of grazer-plant interactions is bi-directional on northwestern European coasts: grazing by limpets structures populations of macroalgae, while macroalgae provide habitat and food for limpets. Scottish shores dominated by the macroalga Fucus vesiculosus support lower densities and larger sizes of limpets Patella vulgata than shores with less Fucus. These patterns may be due to differences in inter-size-class competitive interactions of limpets among shores with different covers of Fucus. To examine this model, densities of small and large limpets were manipulated in plots with and without Fucus. Amounts of biofilm were measured in each plot. The presence of Fucus increased survival but hindered growth of small (15 mm TL) limpets, which were negatively affected by the presence of large limpets (31 mm TL). In contrast, large limpets were not affected by the presence of Fucus or of small limpets. This suggests the occurrence of asymmetric inter-size-class competition, which was influenced by the presence of macroalgae. Macroalgae and increased densities of limpets did not influence amounts of biofilm. Our findings highlight the role of interactions among organisms in generating ecological responses to environmental change.