MicroRNAs (miRNAs) have been shown to play critical roles in regulating the progress of leukemia. We performed miRNA expression profile in six Chinese patients with chronic lymphocytic leukemia (CLL), and in peripheral B cells from pooled 30 healthy donors, using a platform containing 866 human miRNAs. The most frequent changes in miRNAs in CLL cells included downregulation of miR-126, miR-572, miR-494, miR-923, miR-638, miR-130a, miR-181a and miR-181b and up-regulation of miR-29a, miR-660, miR-20a, miR-106b, miR-142-5p, miR-101, miR-30b, miR-34a, miR-let-7f, miR-21 and miR-155. Among the miRNAs down-regulated in CLL cells, we showed that miR-181a/b expression levels were significantly lower in poor prognostic subgroups defined by unmutated immunoglobulin heavy chain variable status and p53 aberrations. Furthermore, under-expression of miR-181a and miR-181b was associated with shorter overall survival and treatment-free survival in CLL patients. We further evaluated fludarabine-induced apoptosis after transfection of primary CLL cells from 40 patients with miR-15a, miR-16-1, miR-34a, miR-181a and miR-181b mimics. Transfection of miR-34a, miR-181a and miR-181b mimics into CLL cells from p53 wild-type patients led to significant increase in apoptosis compared with miRNA control. However, enforced expression of these miRNAs had no effect on B-CLL cells from p53-attenuated patients. We further demonstrated that miR-181a and miR-181b inhibiting BCL-2, MCL-1 and X-linked inhibitor of apoptosis protein by direct binding to 3'UTR. Thus, these results suggest that miR-181a/b may play important roles in the pathogenesis of CLL and may provide a possible therapeutic avenue and a sensitive indicator of the activity of the p53 axis in CLL.

Intensive care unit-acquired weakness (ICUAW) occurs frequently in the context of critical illness without alternative plausible cause and specific treatment options, and it is important to identify and summarize the independent risk factors for ICUAW. PubMed, Embase, Central, China Biological Medicine, China National Knowledge Infrastructure, VIP and Wanfang databases were searched from database inception until 10 July 2017. Prospective cohort studies on adult ICU patients who were diagnosed with ICUAW using either clinical or electrophysiological criteria were selected. Meta-analysis was performed using Stata version 12.0. The results were analysed using odds ratios (OR) and 95% confidence intervals (CI). Data were pooled using a random-effects model, and heterogeneity was assessed using the I statistic. Qualitative analysis and systematic review were used for risk factors that were deemed inappropriate to combine. Fourteen prospective cohort studies were included in this review. The meta-analysis showed that Acute Physiology and Chronic Health Evaluation II score (OR, 1.05; 95%CI, 1.01-1.10), neuromuscular blocking agents (OR, 2.03; 95%CI, 1.22-3.40) and aminoglycosides (OR, 2.27; 95%CI, 1.07-4.81) were found to be significantly associated with ICUAW. Other risk factors, including female, multiple organ failure, systemic inflammatory response syndrome, sepsis, electrolyte disturbances, hyperglycaemia, hyperosmolarity, high lactate level, duration of mechanical ventilation, parenteral nutrition and use of norepinephrine, were statistically significant on multivariable analysis in each single studies. This review provides a number of independent risk factors for ICUAW, which should be guided for early prediction and prevention of the disorder.

MicroRNAs (miRNAs) are regulatory RNA molecules that are deregulated in many disease types, including cancer. Recently, miRNAs have shown promise as markers for cancer diagnosis. The aim of this study was to investigate whether serum miRNAs can be used as biomarkers for the detection of diffuse large B cell lymphoma (DLBCL). We measured the levels of miRNAs (miR-15a, miR-16-1, miR-21, miR-29c, miR-34a, miR-155, and miR-223) in serum samples from patients with DLBCL and healthy controls using real-time quantitative reverse-transcription polymerase chain reaction (qRT-PCR). We show here that miRNAs are present in human serum in a remarkably stable form. Four of miRNAs (miR-15a, miR-16-1, miR-29c, and miR-155) were significantly elevated in DLBCL serum when compared with normal controls (P < 0.05), while miR-34a was downregulated in DLBCL serum when compared with controls (P < 0.05). Receiver operating characteristic analyses reflects strong discriminating DLBCL from controls, with area under the curves of 0.7722, 0.7002, 0.6672, 0.8538, and 0.7157 for miR-15a, miR-16-1, miR-29c, miR-34a, and miR-155, respectively. At the cut-off value of 0.0006 for miR-15a, the sensitivity was 80% and the specificity was 76%; at the cut-off value of 0.0886 for miR-16-1, the sensitivity was 94% and the specificity was 51%; at the cut-off value of 1.395 for miR-34a, the sensitivity was 100% and the specificity was 70%; at the cut-off value of 0.0022 for miR-155, the sensitivity was 83% and the specificity was 65%. In conclusion, these data suggest that serum miRNAs are potentially useful tools as novel noninvasive biomarker for the diagnosis of DLBCL.

Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations derive clinical benefit from treatment with EGFR-tyrosine kinase inhibitors ((EGFR-TKIs)-namely gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. Despite the fact that this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as T790M or amplification of the MET proto-oncogene, there are other mechanisms which need to be explored. MicroRNAs (miRs) are a class of small non-coding RNAs that play pivotal roles in tumorigenesis, tumor progression and chemo-resistance. In this study, we firstly successfully established a gefitinib resistant cell line-HCC827/GR, by exposing normal HCC827 cells (an NSCLC cell line with a 746E-750A in-frame deletion of EGFR gene) to increasing concentrations of gefitinib. Then, we found that miR-214 was significantly up-regulated in HCC827/ GR. We also showed that miR-214 and PTEN were inversely expressed in HCC827/GR. Knockdown of miR-214 altered the expression of PTEN and p-AKT and re-sensitized HCC827/GR to gefitinib. Taken together, miR-214 may regulate the acquired resistance to gefitinib in HCC827 via PTEN/AKT signaling pathway. Suppression of miR-214 may thus reverse the acquired resistance to EGFR-TKIs therapy.

The phenotypic effect of mutations can depend on their genetic background, a phenomenon known as epistasis. Many experimental studies have found that epistasis is pervasive, and some indicate that it may follow a general pattern dependent on the fitness effect of the interacting mutations. These studies have, however, typically examined the effect of interactions between a small number of focal mutations in a single genetic background. Here, we extend this approach by considering how the interaction between two beneficial mutations that were isolated from a population of laboratory evolved Escherichia coli changes when they are added to divergent natural isolate strains of E. coli. We find that interactions between the focal mutations and the different genetic backgrounds are common. Moreover, the pairwise interaction between the focal mutations also depended on their genetic background, being more negative in backgrounds with higher absolute fitness. Together, our results indicate the presence of interactions between focal mutations, but also caution that these interactions depend quantitatively on the wider genetic background.

The effect of a mutation depends on its interaction with the genetic background in which it is assessed. Studies in experimental systems have demonstrated that such interactions are common among beneficial mutations and often follow a pattern consistent with declining evolvability of more fit genotypes. However, these studies generally examine the consequences of interactions between a small number of focal mutations. It is not clear, therefore, that findings can be extrapolated to natural populations, where new mutations may be transferred between genetically divergent backgrounds. We build on work that examined interactions between four beneficial mutations selected in a laboratory-evolved population of Escherichia coli to test how they interact with the genomes of diverse natural isolates of the same species. We find that the fitness effect of transferred mutations depends weakly on the genetic and ecological similarity of recipient strains relative to the donor strain in which the mutations were selected. By contrast, mutation effects were strongly inversely correlated to the initial fitness of the recipient strain. That is, there was a pattern of diminishing returns whereby fit strains benefited proportionally less from an added mutation. Our results strengthen the view that the fitness of a strain can be a major determinant of its ability to adapt. They also support a role for barriers of transmission, rather than differential selection of transferred DNA, as an explanation of observed phylogenetically determined patterns of restricted recombination among E. coli strains.

Recently, epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have revolutionized non-small cell lung cancer (NSCLC) treatment. However, resistance remains a major obstacle. Anexelekto (AXL) is a member of receptor tyrosine kinases (RTKs) and shares the same downstream signaling pathways with EGFR, such as PI3K/AKT and MAPK/ERK. AXL overexpression in resistant tumors has been implicated in many previous studies in vitro and in vivo. In this study, we further examined whether expression of AXL and its downstream targets increased in gefitinib-resistant PC9 cells (PC9GR). In addition, we hypothesize that knocking down AXL in PC9GR and overexpressing AXL in PC9 using genetic tools can restore and decrease the sensitivity to gefitinib, respectively. We found that silencing AXL could sensitize the resistance to gefitinib, and the downstream pathways were significantly inhibited. Interestingly, we also discovered that increased AXL expression did promote the resistance, and its downstream targets were activated accordingly. Then 69 NSCLC patients who harbored EGFR mutation were recruited to analyze the expression of AXL and the association between AXL expression and clinical characteristics. We found that 5 of the 69 patients were AXL positive (about 7%), and AXL was related to tumor differentiation and tumor size. In this study, we concluded that the molecular mechanisms of AXL mediated resistance involved in the increased activity of the PI3K/AKT and MAPK/ERK1/2 pathways, and AXL overexpression could promote resistance, but it can be weakened when AXL expression is silenced.

BackgroundSedation and analgesia are commonly required to relieve anxiety and pain in mechanically ventilated patients. Fentanyl and morphine are the most frequently used opioids. Remifentanil is a selective μ-opioid receptor that is metabolized by unspecific esterases and eliminated independently of liver or renal function. Remifentanil has a rapid onset and offset and a short context-sensitive half-life regardless of the duration of infusion, which may lead to reductions in weaning and extubation. We aimed to compare the efficacy and safety of remifentanil to that of other opioids in mechanically ventilated patients.MethodsWe conducted a search to identify relevant randomized controlled studies (RCTs) in the PubMed, Embase, Cochrane Library and SinoMed databases that had been published up to 31 December 2016. The results were analysed using weighted mean differences (WMDs) and 95% confidence intervals (CIs).ResultsTwenty-three RCTs with 1905 patients were included. Remifentanil was associated with reductions in the duration of mechanical ventilation (mean difference -1.46; 95% CI -2.44 to -0.49), time to extubation after sedation cessation (mean difference -1.02; 95% CI -1.59 to -0.46), and ICU-LOS (mean difference -0.10; 95% CI -0.16 to -0.03). No significant differences were identified in hospital-LOS (mean difference -0.05; 95% CI -0.25 to 0.15), costs (mean difference -709.71; 95% CI -1590.98 to 171.55; I2 88%), mortality (mean difference -0.64; 95% CI -1.33 to 0.06; I2 87%) or agitation (mean difference -0.71; 95% CI -1.80 to 0.37; I2 93%).ConclusionsRemifentanil seems to be associated with reductions in the duration of mechanical ventilation, time to extubation after cessation of sedation, and ICU-LOS. No significant differences were identified between remifentanil and other opioids in terms of hospital-LOS, costs, mortality or agitation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13054-017-1789-8) contains supplementary material, which is available to authorized users.