As it emerged actor Stephen Fry’s prostate cancer diagnosis sparked a 15% rise in services in England earlier this year, international experts have advised against routine screening for the disease. Photograph: Simon Annand

Fulurija, A., Ashman, R. B. & Papadimitriou, J. M. Neutrophil depletion increases susceptibility to systemic and vaginal candidiasis in mice, and reveals differences between brain and kidney in mechanisms of host resistance. Microbiology 142 (Pt 12), 3487–3496 (1996).

Li, W. et al. Hyperglycemia regulates TXNIP/TRX/ROS axis via p38 MAPK and ERK pathways in pancreatic cancer. Curr Cancer Drug Targets. 14, 348–356 (2014).

‘It was a tough call to leave Bradford but I felt I wanted a fresh challenge. I feel Bolton is a club ready to move forward again,’ said Parkinson, who famously led his former side to the 2013 Capital One Cup final.

Venn diagram depicting identification overlap between methods. Each case and control sample was tested by all three methods. The top number in each sector represents the number of positive cases and controls identified by each method, and the lower percentage is the number of cases identified divided by the total number of samples (cases and controls) positive by each method. The size of the circle and overlap between circles are proportional to the categorical n values. (A) Shigella spp. (n = 1,197). In 709 samples, no Shigella sp. was detected. (B) EPEC (n = 1,028). In 591 samples, no method detected EPEC.

The aim of this study was to test the impact of RST on biomarkers of acute myocardial necrosis by comparing results to those of traditional MCT. Myocardial dimensions and functions were assessed by transthoracal echocardiograpic (TTE) and electrocardiographic (ECG) investigations following each exercise session. We hypothesized, that despite its short total duration, RST training would significantly increase cTnT and CK-MB, compared to MCT of longer duration. Hypothesis confirming results would elucidate the prevalence of an exercise-induced release of myocardial necrosis biochemical markers complemented by additional information on the dose – response relationship between exercise, biomarker release and myocardial adaptations to high intensity training.

Airway inflammation is allergic aspergillosis (ABPA) is typically characterised by increased eosinophils. We have recently reported increased sputum neutrophils in ABPA that correlates with the extent of bronchiectasis on HRCT. In this study we sought to evaluate the role of the neutrophil chemoattractant IL-8 in ABPA. 29 adults with ABPA (20 with central bronchiectasis, ABPA-CB; 9 with serological ABPA, ABPA-S) were compared with 21 normal controls, and 9 asthmatics without Af sensitisation. Induced sputum was examined for cellular differential, IL-8 protein by ELISA and immunocytocheraistry, and IL-8 gene expression by semi-quantitative RTPCR. Sputum supernatant IL-8 was 66ng/mL in ABPA-CB, 65 in ABPA-S, 3.5ng/mL in controls and 3.6ng/mL in asthma (p<0.001 ). Sputum IL-8 correlated with sputum neutrophils (r=0.63) and FEV| % predicted (r=-0.7). IL-8 containing cells were predominantly neutrophils. IL-8mRNA levels were 108 and 24ag/mL in the ABPA groups, compared to 1.2 and 2.4ag/mL in asthma and controls (p<0.05). Conclusion: In ABPA there is elevated IL-8 gene expression and protein release, that correlates with the degree of airflow obstruction and neutrophil influx. IL-8 may be an important cytokine mediating inflammation and lung damage in ABPA.

Taken together, it appears that LMP7 inhibition leads to reduced Th1 and Th17 cell differentiation in response to C. albicans but also affects the innate immunity resulting in higher susceptibility of ONX 0914 treated mice to systemic candidiasis. Hence, the question arises whether immunoproteasome inhibitors can in general be applied in the therapy of autoimmunity if they interfere with host defence against pathogens like fungi. Proteasome inhibitors are already used in humans e.g. for the treatment of multiple myeloma and, importantly, except for an increased incidence of varicella herpes zoster in bortezomib treated patients, there is no evidence for higher susceptibility to fungal infections52,53. Moreover, during infection with WT vaccinia virus (VV-WR) or lymphocytic choriomeningitis virus (LCMV-WE), we observed no influence on the immune system’s capability to clear the virus in mice treated with ONX 09149. Nevertheless, it would be worthwhile to investigate the influence of LMP7 inhibition for example on oropharyngeal candidiasis (OPC) where host resistance is strictly dependent on T helper cells23. However, since even systemic candidiasis can be easily controlled with standard fungicide therapy (Supplementary Fig. S3), our data do not discourage the development and testing of LMP7-selective inhibitors as therapeutics against autoimmune diseases and inflammatory disorders.

Breslauer, D. N., Maamari, R. N., Switz, N. A., Lam, W. A. & Fletcher, D. A. Mobile phone based clinical microscopy for global health applications. PLoS ONE 4, e6320 (2009).

Basler, M., Dajee, M., Moll, C., Groettrup, M. & Kirk, C. J. Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J. Immunol. 185, 634–641 (2010).

Our results obtained with splenocytes and PBMCs stimulated with C. albicans in vitro (Fig. 1) and previous reports suggest a role of LMP7 inhibition in T helper cell differentiation9,11,13. Thus, we intended to investigate whether the immunoproteasome has an influence on the generation or activation of IL-17A- and IFN-γ-producing cells in response to systemic C. albicans infection in vivo. Analyzing cytokine production of splenocytes upon ex vivo restimulation with heat-killed C. albicans on day 7 postinfection revealed a marked reduction of IL-17A and IFN-γ production upon LMP7 inhibition in vivo (Fig. 2). While immunoproteasome-deficient mice showed no altered susceptibility to invasive candidiasis (Fig. 3A), ONX 0914 treated mice suffered from accelerated and more pronounced weight loss as well as higher mortality compared to vehicle treated mice already on day 2 of infection (Fig. 3B,C). Moreover, in some experiments, we observed that LMP7 inhibition led to movement disorders and neurological abnormalities of mice as manifested by a slight tilting of the head and uncontrolled twisting/rotation when handled (data not shown).

‘The embargo issue was a key part of my conversation with Ken,’ said Parkinson after completing his switch from Bradford City.