Resistance to docetaxel is a major clinical problem in advanced prostate cancer. The overexpression of AXL receptor tyrosine kinase (AXL) has been correlated with chemotherapeutic drug resistance. However, the role of AXL expression in docetaxel resistance in prostate cancer is yet unclear. In this study, we demonstrate that AXL is overexpressed and activated independent of Gas6 in docetaxel-resistant prostate cancer cells (PC3-DR and DU145-DR). Moreover, we show that forced overexpression of AXL in PC3 and DU145 cells is sufficient to induce resistance to docetaxel in these cell lines. Notably, genetic or pharmacologic inhibition of AXL in the resistant models suppressed cell proliferation, migration, invasion, and tumor growth, and these effects were significantly augmented when AXL inhibition was combined with docetaxel treatment. Mechanistically, we found that AXL inhibition led to reversion of the epithelial-mesenchymal transition (EMT) phenotype and decreased the expression of ATP-binding cassette B1 (ABCB1). Overall, our results identify AXL as an important mediator of docetaxel resistance in prostate cancer. We propose that AXL-targeted therapy, in combination with docetaxel, has the potential to improve the response to docetaxel therapy and reduce resistance induced by prolonged docetaxel therapy in prostate cancer.

Early decompression may improve neurological outcome after spinal cord injury (SCI), but is often difficult to achieve because of logistical issues. The aims of this study were to 1) determine the time to decompression in cases of isolated cervical SCI in Australia and New Zealand and 2) determine where substantial delays occur as patients move from the accident scene to surgery. Data were extracted from medical records of patients aged 15-70 years with C3-T1 traumatic SCI between 2010 and 2013. A total of 192 patients were included. The median time from accident scene to decompression was 21 h, with the fastest times associated with closed reduction (6 h). A significant decrease in the time to decompression occurred from 2010 (31 h) to 2013 (19 h, p = 0.008). Patients undergoing direct surgical hospital admission had a significantly lower time to decompression, compared with patients undergoing pre-surgical hospital admission (12 h vs. 26 h, p < 0.0001). Medical stabilization and radiological investigation appeared not to influence the timing of surgery. The time taken to organize the operating theater following surgical hospital admission was a further factor delaying decompression (12.5 h). There was a relationship between the timing of decompression and the proportion of patients demonstrating substantial recovery (2-3 American Spinal Injury Association Impairment Scale grades). In conclusion, the time of cervical spine decompression markedly improved over the study period. Neurological recovery appeared to be promoted by rapid decompression. Direct surgical hospital admission, rapid organization of theater, and where possible, use of closed reduction, are likely to be effective strategies to reduce the time to decompression.

Aim This systematic review aimed to determine the effect of aerobic exercise interventions, including high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), on liver fat in adults. A secondary aim was to investigate the interaction between total weekly exercise volume and exercise-related energy expenditure and change in liver fat. Methods Relevant databases were searched to December 2020 for randomised trials, comparing HIIT to control, MICT to control, or HIIT to MICT. Studies were excluded if they did not implement ≥2 weeks intervention or assess liver fat using magnetic resonance-based techniques. Weighted mean differences and 95% confidence intervals (CI) were calculated. Regression analyses were undertaken to determine the interaction between weekly exercise volume in minutes and kcal with change in liver fat %. Results The search returned 28,262 studies of which 19 were included involving 745 participants. Both HIIT and MICT elicited moderate reductions in liver fat % when compared to control (HIIT:-2.85%, 95%CI:-4.86 to -0.84, p=0.005, I 2=0%, n=114, low certainty evidence; MICT:-3.14%, 95%CI:-4.45 to -1.82, p&lt;0.001, I 2=5.2%, n=533, moderate certainty evidence). There was no difference between HIIT or MICT (-0.34%, 95%CI:-2.20 to 1.52, p=0.721, I 2=0%, n=177, moderate certainty evidence). Neither total exercise volume in minutes (β=0.0002, SE=0.0017, Z=0.13, p=0.89) nor exercise-related energy expenditure in kcal (β=0.0001, SE=0.0002, Z=-0.63, p=0.52) were related to changes in liver fat %. Conclusion HIIT elicits comparable improvements in liver fat to MICT despite often requiring less energy and time commitment. Further studies should be undertaken to assess the relative importance of aerobic exercise prescription variables, such as intensity, on liver fat.

Given inaccuracies in the manual ISNCSCI worksheets in this long-term clinical trial setting, continued training and a computerised algorithm are essential to ensure accurate scoring, scaling and classification of the ISNCSCI and confidence in clinical trials.

Summary Excess visceral adiposity contributes to elevated cardiometabolic risk, and waist circumference is commonly used as a surrogate measure of visceral adipose tissue. Although regular aerobic exercise is known to improve abdominal obesity, its effect on waist circumference is unclear. A systematic review and meta‐analysis was performed to determine (1) the effect of aerobic exercise on waist circumference in adults with overweight or obesity; (2) the association between any change in waist circumference and change in visceral adipose tissue and/or bodyweight with aerobic exercise interventions; and (3) if reductions in waist circumference with exercise are moderated by clinical characteristics or components of aerobic exercise prescription. Twenty‐five randomized controlled trials (1686 participants) were included. Regular aerobic exercise significantly reduced waist circumference by 3.2 cm (95% confidence interval [CI] −3.86, −2.51, p ≤ 0.001) versus control. Change in waist circumference was associated with change in visceral adipose tissue (β = 4.02; 95% CI 1.37, 6.66, p = 0.004), and vigorous intensity produced superior reduction (−4.2 cm, 95% CI −4.99, −3.42, p < 0.0001) in waist circumference compared with moderate intensity (−2.50 cm, 95% CI −3.22, −1.79, p = 0.058). These findings suggest regular aerobic exercise results in modest reductions in waist circumference and associated visceral adipose tissue and that higher intensity exercise may offer superior benefit to moderate intensity.