Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer

BACKGROUND: Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression. METHODS: Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis. RESULTS: ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival. CONCLUSIONS: Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.British Journal of Cancer advance online publication, 22 December 2016; doi:10.1038/bjc.2016.402 www.bjcancer.com

Evolutionary History of the Odd-Nosed Monkeys and the Phylogenetic Position of the Newly Described Myanmar Snub-Nosed Monkey Rhinopithecus strykeri

Odd-nosed monkeys represent one of the two major groups of Asian colobines. Our knowledge about this primate group is still limited as it is highlighted by the recent discovery of a new species in Northern Myanmar. Although a common origin of the group is now widely accepted, the phylogenetic relationships among its genera and species, and the biogeographic processes leading to their current distribution are largely unknown. To address these issues, we have analyzed complete mitochondrial genomes and 12 nuclear loci, including one X chromosomal, six Y chromosomal and five autosomal loci, from all ten odd-nosed monkey species. The gene tree topologies and divergence age estimates derived from different markers were highly similar, but differed in placing various species or haplogroups within the genera Rhinopithecus and Pygathrix. Based on our data, Rhinopithecus represent the most basal lineage, and Nasalis and Simias form closely related sister taxa, suggesting a Northern origin of odd-nosed monkeys and a later invasion into Indochina and Sundaland. According to our divergence age estimates, the lineages leading to the genera Rhinopithecus, Pygathrix and Nasalis+Simias originated in the late Miocene, while differentiation events within these genera and also the split between Nasalis and Simias occurred in the Pleistocene. Observed gene tree discordances between mitochondrial and nuclear datasets, and paraphylies in the mitochondrial dataset for some species of the genera Rhinopithecus and Pygathrix suggest secondary gene flow after the taxa initially diverged. Most likely such events were triggered by dramatic changes in geology and climate within the region. Overall, our study provides the most comprehensive view on odd-nosed monkey evolution and emphasizes that data from differentially inherited markers are crucial to better understand evolutionary relationships and to trace secondary gene flow

Safety of Nonsteroidal Anti-inflammatory Drugs in Major Gastrointestinal Surgery: A Prospective, Multicenter Cohort Study

Background Significant safety concerns remain surrounding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) following gastrointestinal surgery, leading to wide variation in their use. This study aimed to determine the safety profile of NSAIDs after major gastrointestinal surgery. Methods Consecutive patients undergoing elective or emergency abdominal surgery with a minimum one-night stay during a 3-month study period were eligible for inclusion. The administration of any NSAID within 3 days following surgery was the main independent variable. The primary outcome measure was the 30-day postoperative major complication rate, as defined by the Clavien–Dindo classification (Clavien–Dindo III–V). Propensity matching with multivariable logistic regression was used to produce odds ratios (OR) and 95 % confidence intervals. Results From 9264 patients, 23.9 % (n = 2212) received postoperative NSAIDs. The overall major complication rate was 11.5 % (n = 1067). Following propensity matching and adjustment, use of NSAIDs were not significantly associated with any increase in major complications (OR 0.90, 0.60–1.34, p = 0.560). Conclusions Early use of postoperative NSAIDs was not associated with an increase in major complications following gastrointestinal surgery