Aminoacyl-tRNA synthetases use a variety of mechanisms to ensure fidelity of the genetic code and ultimately select the correct amino acids to be used in protein synthesis. The physiological necessity of these quality control mechanisms in different environments remains unclear, as the cost vs benefit of accurate protein synthesis is difficult to predict. We show that in Escherichia coli, a non-coded amino acid produced through oxidative damage is a significant threat to the accuracy of protein synthesis and must be cleared by phenylalanine-tRNA synthetase in order to prevent cellular toxicity caused by mis-synthesized proteins. These findings demonstrate how stress can lead to the accumulation of non-canonical amino acids that must be excluded from the proteome in order to maintain cellular viability.DOI: http://dx.doi.org/10.7554/eLife.02501.001

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BackgroundWe aimed to investigate the diagnostic utility of osteocalcin (OC), undercarboxylated osteocalcin (ucOC), and alkaline phosphatase (ALP) in pre- and postmenopausal women for femoral neck, L1-4, and L2-4 bone mineral density (BMD) values by taking into consideration their age, body mass index (BMI), and menopausal status.MethodsPremenopausal (N=40) and postmenopausal cases (N=42) were classified as 25-34 or 35-45 yr of age and within the first 5 yr or 5 yr or more after the onset of menopause, respectively.ResultsAmong the groups, statistical differences were found for age, BMI, OC, ucOC, ALP, femoral neck BMD, L1-4 BMD, and L2-4 BMD. The highest serum OC, ucOC, and ALP levels were observed in cases within the first 5 yr after the onset of menopause, probably due to a more rapid bone turnover rate. The best predictors for the femoral neck osteoporosis were ALP, OC, and calcium (areas under the ROC curve [AUC]=0.882, 0.829, and 0.761, respectively), and those for L1-4 and L2-4 osteoporosis were OC, ALP, and ucOC (AUC=0.949, 0.873, and 0.845; and 0.866, 0.819, and 0.814, respectively). Multiple logistic regression analysis revealed that the most discriminative parameter for osteoporosis was OC.ConclusionsThese results indicate that serum OC levels, with or without ucOC and ALP, may be useful to monitor follow-up changes that currently cannot be assessed with BMD and to diagnose femoral neck, L1-4 spine, and L2-4 spine osteoporosis.

Determination of the liver histological lesions with noninvasive tests is an important part of the diagnostic work-up of patients with non-alcoholic fatty liver disease (NAFLD). We aimed to determine the predictive value of noninvasive biochemical markers, serum prolidase enzyme activity (SPEA), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and AST/ALT ratio for the liver histological lesions. Fifty-four liver biopsy-proven patients with NAFLD and 37 healthy controls were enrolled to the study. The diagnostic accuracies of biochemical markers were evaluated by receiver operating characteristic (ROC) curves and multiple linear regression analysis to predict the degree of fatty infiltration, lobular inflammation, NAFLD activity score, and stage of fibrosis. The SPEA of patients with steatohepatitis is significantly increased compared with the patients with simple steatosis and controls (1,338 [1,138-1,624] U/l; 974 [768-1,160] U/l; 972 [862-1,122] U/l, shown as median [25th-75th interquartile range], respectively, P < 0.0001). SPEA was positively correlated with the grade of liver fatty infiltration, lobular inflammation and NAFLD activity score, and stage of fibrosis, (r = 0.377, P < 0.005; r = 0.443, P < 0.001; r = 0.457, P < 0.001; r = 0.321, P < 0.018, respectively). SPEA was the best predictor for distinguishing steatohepatitis from simple steatosis according to the ROC analysis (area under the curve [AUC]: 0.85). Multivariate analysis revealed that the most useful single test for predicting lobular inflammation, NAFLD activity score, and fibrosis was SPEA, and for predicting the fatty infiltration, it was ALT (P < 0.00001, P < 0.001, P < 0.0001, P < 0.0001, respectively). This study demonstrated that SPEA can accurately predict the degree and stage of all histological lesions in NAFLD. It could be helpful for distinguishing steatohepatitis from simple steatosis and reducing the need for liver biopsy in the majority of patients with NAFLD.

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Prior in vitro work demonstrated that PARP inhibition induces cell death in PTEN-null endometrial cancer cell lines, but the in vivo therapeutic efficacy of these agents against endometrial cancer remains unknown. Here we test the efficacy of AZD2281 (Olaparib), an oral PARP inhibitor, in therapy of PTEN-null endometrial tumors in a pre-clinical endometrial cancer mouse model. Primary endometrial tumors were generated by epithelial loss of PTEN using an in vivo model. This model recapitulates epithelial specific loss of PTEN seen in human tumors and histologically resembles endometrioid carcinomas, the predominant sub-type of human endometrial cancers. Olaparib was administered orally to tumor bearing mice in two hormonal extremes: high or low estrogen. Olaparib treatment achieved a significant reduction in tumor size in a low estrogenic milieu. In striking contrast, no response to Olaparib was seen in tumors exposed to high levels of estrogen. Two key observations were made when estrogen levels were dropped. Serum concentration of Olaparib was significantly increased resulting in sustained PARP inhibition at the tumor bed. The homologous recombination pathway was compromised evidenced by decreased Rad51 protein and function. These two mechanisms may account for the sensitization of PTEN-null tumors to Olaparib with estrogen deprivation. Results of this pre-clinical trial suggest that orally administered PARP inhibitors in a low estrogenic hormonal milieu can effectively target PTEN-null endometrial tumors. Extension of this work to clinical trials could personalize the therapy of women afflicted with advanced endometrial cancer using well tolerated orally administered therapeutic agents.

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There is increasing evidence that neutrophil-lymphocyte ratio (NLR) may play a role in predicting recurrence in patients with hepatitis B virus-related hepatocellular carcinoma (HCC) after liver transplantation. In the original study by Yan et al , it was aimed to determine whether an elevated NLR is associated with tumor recurrence. Total tumor size (> 9 cm) and macro-vascular invasion were found to be more significant than NLR according to the multivariate logistic regression analysis. Therefore, substantive significance should be emphasized rather than NLR because total tumor size and macro-vascular invasion are easier and more expressive than NLR in assessing HCC recurrence. NLR and platelet-lymphocyte ratio (PLR) are markers which are easy to obtain and can be used as inflammation indicators. Moreover, assessment of both NLR and PLR may add some value as a good predictor of risk for post-liver transplantation HCC recurrence. However, while the study was constructed on whole blood analysis, further details about the features and performance characteristics of the whole-blood analyzer, and preanalytical/analytical variables should also be mentioned.© 2014 Baishideng Publishing Group Inc. All rights reserved.Key words: Hepatocellular carcinoma; Liver transplantation; Neutrophil-lymphocyte ratio; Platelet-tolymphocyte ratio; Prognosis Core tip: Neutrophil-lymphocyte ratio (NLR), total tumor size (> 9 cm) and macro-vascular invasion may play a role in the prediction of recurrence in patients with hepatitis B virus-related hepatocellular carcinoma after liver transplantation. Assessment of both NLR and platelet-lymphocyte ratio, as inflammation markers, may increase the prediction rate for these patients. Factors affecting the laboratory results should also be evaluated, in such a study. TO THE EDITORWe read with great interest the recently published article by Xiao et al [1] regarding the value of neutrophil-lymphocyte ratio (NLR) for predicting recurrence in patients with hepatocellular carcinoma after liver transplantation. In the original study, it was aimed to determine whether an elevated NLR is associated with tumor recurrence in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) after liver transplantation (LT), and to determine the optimal predictive NLR cut-off value. They concluded that preoperative elevated NLR