Search

Research suggests that the addition of dexmedetomidine to local anesthetics can prolong peripheral nerve blocks; however, it is not known whether dexmedetomidine can reduce the quantity of local anesthetic needed. We hypothesized that adding dexmedetomidine as an adjuvant to an obturator nerve block could reduce the median effective concentration of lidocaine. In this double-blinded randomized trial, 60 patients scheduled for elective transurethral resection of bladder tumors on the lateral wall were randomly divided into two groups: the control group (C group, n = 30) and the dexmedetomidine group (D group, n = 30). Two main branches of the obturator nerve (i.e., anterior and posterior) were identified using neural stimulation at the inguinal level, with only lidocaine used for the C group and 1 μg/kg dexmedetomidine combined with lidocaine used for the D group. The median effective concentration was determined by an up-and-down sequential trial. The ratio of two consecutive concentrations was 1.2. The median effective concentration (95% confidence interval) of lidocaine was 0.57% (0.54%-0.62%) in the C group and 0.29% (0.28%-0.38%) in the D group. The median effective concentration of lidocaine was significantly lower in the D group than in the C group (p < 0.05). These results indicate that dexmedetomidine (1 μg/kg) in combination with lidocaine for obturator nerve block decreases the median effective concentration of lidocaine. Trial Registration: ClinicalTrials.gov [ABSTRACT FROM AUTHOR]

The ability to predict the response of a cancer patient to a therapeutic agent is a major goal in modern oncology that should ultimately lead to personalized treatment. Existing approaches to predicting drug sensitivity rely primarily on profiling of cancer cell line panels that have been treated with different drugs and selecting genomic or functional genomic features to regress or classify the drug response. Here, we propose a dual-layer integrated cell line-drug network model, which uses both cell line similarity network (CSN) data and drug similarity network (DSN) data to predict the drug response of a given cell line using a weighted model. Using the Cancer Cell Line Encyclopedia (CCLE) and Cancer Genome Project (CGP) studies as benchmark datasets, our single-layer model with CSN or DSN and only a single parameter achieved a prediction performance comparable to the previously generated elastic net model. When using the dual-layer model integrating both CSN and DSN, our predicted response reached a 0.6 Pearson correlation coefficient with observed responses for most drugs, which is significantly better than the previous results using the elastic net model. We have also applied the dual-layer cell line-drug integrated network model to fill in the missing drug response values in the CGP dataset. Even though the dual-layer integrated cell line-drug network model does not specifically model mutation information, it correctly predicted that BRAF mutant cell lines would be more sensitive than BRAF wild-type cell lines to three MEK1/2 inhibitors tested. [ABSTRACT FROM AUTHOR]

Predicting anticancer drug sensitivity can enhance the ability to individualize patient treatment, thus making development of cancer therapies more effective and safe. In this paper, we present a new network flow-based method, which utilizes the topological structure of pathways, for predicting anticancer drug sensitivities. Mutations and copy number alterations of cancer-related genes are assumed to change the pathway activity, and pathway activity difference before and after drug treatment is used as a measure of drug response. In our model, Contributions from different genetic alterations are considered as free parameters, which are optimized by the drug response data from the Cancer Genome Project (CGP). 10-fold cross validation on CGP data set showed that our model achieved comparable prediction results with existing elastic net model using much less input features. [ABSTRACT FROM AUTHOR]

The objective of this article is to evaluate the effect of dexmedetomidine on emergence agitation (EA) and recovery profiles in children after sevoflurane anesthesia and its pharmacological mechanisms. Standard bibliographic databases, including MEDLINE, EMBASE, PsycINFP, Springer and ISI Web of Knowledge, were artificially searched to identify all randomized controlled trials (RCTs) comparing the impact of dexmedetomidine with placebo, fentanyl and midazolam on EA and recovery profiles after sevoflurane anesthesia in post-anesthesia care unit (PACU). Two authors assessed the quality of each study independently in accordance with strict inclusion criteria and extracted data. RevMan 5.0 software was applied for performing statistic analysis. The outcomes analyzed included: 1) incidence of EA, 2) emergence time, 3) time to extubation, 4) incidence of post-operation nausea and vomiting, 5) number of patients requiring an analgesic, and 6) time to discharge from PACU. A total of 1364 patients (696 in the dexmedetomidine group and 668 in the placebo, fentanyl and midazolam group) from 20 prospective RCTs were included in the meta-analysis. Compared with placebo, dexmedetomidine decreased the incidence of EA (risk ratio [RR] 0.37; 95% CI 0.30 to 0.46), incidence of nausea and vomiting (RR 0.57; 95% CI 0.38 to 0.85) and number of patients requiring an analgesic (RR 0.43; 95% CI 0.31 to 0.59). However, dexmedetomidine had a significantly delayed effect on the emergence time (weighted mean differences [WMD] 1.16; 95% CI 0.72 to 1.60), time to extubation (WMD 0.61; 95% CI 0.27 to 0.95), and time to discharge from recovery room (WMD 2.67; 95% CI 0.95 to 4.39). Compared with fentanyl (RR 1.39; 95% CI 0.78 to 2.48) and midazolam (RR 1.12; 95% CI 0.54 to 2.35), dexmedetomidine has no significantly difference on the incidence of EA. However, the analgesia effect of dexmedetomidine on postoperation pain has no significantly statistical differences compared with fentanyl (RR 1.12; 95% CI 0.66 to 1.91), which implied that its analgesia effect might play an important role in decreasing the incident of EA. No evidence of publication bias was observed. [ABSTRACT FROM AUTHOR]

Prediction of drug response based on genomic alterations is an important task in the research of personalized medicine. Current elastic net model utilized a sure independence screening to select relevant genomic features with drug response, but it may neglect the combination effect of some marginally weak features. In this work, we applied an iterative sure independence screening scheme to select drug response relevant features from the Cancer Cell Line Encyclopedia (CCLE) dataset. For each drug in CCLE, we selected up to 40 features including gene expressions, mutation and copy number alterations of cancer-related genes, and some of them are significantly strong features but showing weak marginal correlation with drug response vector. Lasso regression based on the selected features showed that our prediction accuracies are higher than those by elastic net regression for most drugs. [ABSTRACT FROM AUTHOR]

Previously, we have shown that the phosphoinositide-3-kinase (PI3K) mediated acute (24 h) post-conditioning neuroprotection induced by propofol. We also found that propofol post-conditioning produced long term neuroprotection and inhibited the internalization of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR2 subunit up to 28 days post middle cerebral artery occlusion (MCAO). However, the relationship between PI3K with AMPA receptor GluR2 subunit trafficking in propofol post-conditioning has never been explored. Here we showed that propofol post-conditioning promoted the binding of PI3K to the C-terminal of AMPA receptor GluR2 subunit and formed a complex within 1 day after transient MCAO. Interestingly, the enhanced activity of PI3K was observed in the hippocampus of post-conditioning rats at day 1 post ischemia, whereas the decrease of AMPA receptor GluR2 subunit internalization was found up to 28 days in the same group. Administration of PI3K selective antagonist wortmannin inhibited the improvement of spatial learning memory and the increase of neurogenesis in the dentate gyrus up to 28 days post ischemia. It also reversed the inhibition of AMPA receptor GluR2 internalization induced by propofol post-conditioning. Together, our data indicated the critical role of PI3K in regulating the long term neuroprotection induced by propofol post-conditioning. Moreover, this role was established by first day activation of PI3K and formation of PI3K-AMPA receptor GluR2 complex, thus stabilized the structure of postsnaptic AMPA receptor and inhibited the internalization of GluR2 subunit during the early stage of propofol post-conditioning. [ABSTRACT FROM AUTHOR]

A large number of experimental and clinical studies have confirmed that brief remifentanil exposure can enhance pain sensitivity presenting as opioid-induced hyperalgesia (OIH). N-methyl-D-aspartate (NMDA) receptor antagonists have been reported to inhibit morphine analgesic tolerance in many studies. Recently, we found that glycogen synthase kinase-3β (GSK-3β) modulated NMDA receptor trafficking in a rat model of remifentanil-induced postoperative hyperalgesia. In the current study, it was demonstrated that GSK-3β inhibition prevented remifentanil-induced hyperalgesia via regulating the expression and function of spinal NMDA receptors in vivo and in vitro. We firstly investigated the effects of TDZD-8, a selective GSK-3β inhibitor, on thermal and mechanical hyperalgesia using a rat model of remifentanil-induced hyperalgesia. GSK-3β activity as well as NMDA receptor subunits (NR1, NR2A and NR2B) expression and trafficking in spinal cord L4-L5 segments were measured by Western blot analysis. Furthermore, the effects of GSK-3β inhibition on NMDA-induced current amplitude and frequency were studied in spinal cord slices by whole-cell patch-clamp recording. We found that remifentanil infusion at 1 μg·kg-1·min-1 and 2 μg·kg-1·min-1 caused mechanical and thermal hyperalgesia, up-regulated NMDA receptor subunits NR1 and NR2B expression in both membrane fraction and total lysate of the spinal cord dorsal horn and increased GSK-3β activity in spinal cord dorsal horn. GSK-3β inhibitor TDZD-8 significantly attenuated remifentanil-induced mechanical and thermal hyperalgesia from 2 h to 48 h after infusion, and this was associated with reversal of up-regulated NR1 and NR2B subunits in both membrane fraction and total lysate. Furthermore, remifentanil incubation increased amplitude and frequency of NMDA receptor-induced current in dorsal horn neurons, which was prevented with the application of TDZD-8. These results suggest that inhibition of GSK-3β can significantly ameliorate remifentanil-induced hyperalgesia via modulating the expression and function of NMDA receptors, which present useful insights into the mechanistic action of GSK-3β inhibitor as potential anti-hyperalgesic agents for treating OIH. [ABSTRACT FROM AUTHOR]