Long non‐coding RNAs in melanoma Yu, Xin; Zheng, Heyi; Tse, Gary ...
Cell proliferation,
August 2018, Letnik:
51, Številka:
4
Journal Article
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Melanoma is the most lethal cutaneous cancer with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have shed new insights into the mechanism of melanoma ...development, the involvement of regulatory non‐coding RNAs remain unclear. Long non‐coding RNAs (lncRNAs) are a group of endogenous non‐protein‐coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidences have shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration and invasion. In the melanoma, deregulation of a number of lncRNAs, such as HOTAIR, MALAT1, BANCR, ANRIL, SPRY‐IT1 and SAMMSON, have been reported. Our review summarizes the functional role of lncRNAs in melanoma and their potential clinical application for diagnosis, prognostication and treatment.
Osteosarcoma is the most common primary bone tumour. Increasing evidence has demonstrated the pathogenic role of microRNA (miRNAs) dysregulation in tumour development. miR‐379 was previously reported ...to function as an oncogenic or tumour‐suppressing miRNA in a tissue‐dependent manner. However, its function in osteosarcoma remains unknown. In this study, we found that the expression of miR‐379 was downregulated in osteosarcoma tissues and cell lines. Further functional characterization revealed that miR‐379 suppressed osteosarcoma cell proliferation and invasion in vitro and retarded the growth of osteosarcoma xenografts in vivo. Mechanistically, PDK1 was identified as the direct target of miR‐379 in osteosarcoma, in which PDK1 expression was up‐regulated and showed inverse correlation with miR‐379. Enforced expression of PDK1 promoted osteosarcoma cell proliferation and rescued the anti‐proliferative effect of miR‐379. These data suggest that miR‐379 could function as a tumour‐suppressing miRNA via targeting PDK1 in osteosarcoma.
BACKGROUND AND PURPOSE—Experimental evidence has indicated the benefits of simvastatin for the treatment of subarachnoid hemorrhage. Two randomized placebo-controlled pilot trials that used the ...highest clinically approved dose of simvastatin (80 mg daily) gave positive results despite the fact that a lower dose of simvastatin (40 mg daily) did not improve clinical outcomes. We hypothesized that a high dose of 80 mg of simvastatin daily for 3 weeks would reduce the incidence of delayed ischemic deficits after subarachnoid hemorrhage compared with a lower dose (40 mg of simvastatin daily) and lead to improved clinical outcomes.
METHODS—The study design was a randomized controlled double-blinded clinical trial. Patients with aneurysmal subarachnoid hemorrhage (presenting within 96 hours of the ictus) from 6 neurosurgical centers were recruited for 3 years. The primary outcome measure was the presence of delayed ischemic deficits, and secondary outcome measures included a modified Rankin disability score at 3 months and an analysis of cost-effectiveness.
RESULTS—No difference was observed between the groups treated with the higher dose or the lower dose of simvastatin in the incidence of delayed ischemic deficits (27% versus 24%; odds ratio, 1.2; 95% confidence interval, 0.7–2.0; P=0.586) or in the rate of favorable outcomes (modified Rankin Scale score, 0–2) at 3 months (73% versus 72%; odds ratio, 1.1; 95% confidence interval, 0.6–1.9; P=0.770).
CONCLUSIONS—High-dose simvastatin treatment should not be prescribed routinely for aneurysmal subarachnoid hemorrhage.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01077206.
Exposure to air pollution is known to increase the risks for cardiovascular, pulmonary and metabolic diseases. Growing evidences also indicated that air pollution exposure during pregnancy could ...negatively impact on early embryonic development and children’s health. We performed RNA sequencing to identify deregulated mRNAs in air pollution-exposed rat embryos. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to analyse the potential cellular functions of deregulated mRNAs. Our analysis indicated that a total of 1678 mRNAs were differentially expressed on gestation day 9 upon in utero exposure to fine particulate matter of > 200 μg/m
3
, among which 1098 mRNAs were downregulated and 580 mRNAs were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed gap junction, cell adhesion, axon guidance and the neurotrophin signalling pathway as key biological processes perturbed by air pollution exposure. Furthermore, reconstruction of the mRNA regulatory network highlighted the central roles of Tbx4, Bmp4, Sox10, Wnt9b, Bmp7 and Foxc2. These data suggested that embryonic mRNA deregulation may underlie the formation of air pollution-associated congenital defects.
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•Molecular dynamics simulations provide atomistic resolution of protein dynamics.•Advancements in computation resources enable simulations of large system like membrane ...transporters.•Markov state models statistically quantify thermodynamics and kinetics.
The flux of ions and molecules in and out of the cell is vital for maintaining the basis of various biological processes. The permeation of substrates across the cellular membrane is mediated through the function of specialized integral membrane proteins commonly known as membrane transporters. These proteins undergo a series of structural rearrangements that allow a primary substrate binding site to be accessed from either side of the membrane at a given time. Structural insights provided by experimentally resolved structures of membrane transporters have aided in the biophysical characterization of these important molecular drug targets. However, characterizing the transitions between conformational states remains challenging to achieve both experimentally and computationally. Though molecular dynamics simulations are a powerful approach to provide atomistic resolution of protein dynamics, a recurring challenge is its ability to efficiently obtain relevant timescales of large conformational transitions as exhibited in transporters. One approach to overcome this difficulty is to adaptively guide the simulation to favor exploration of the conformational landscape, otherwise known as adaptive sampling. Furthermore, such sampling is greatly benefited by the statistical analysis of Markov state models. Historically, the use of Markov state models has been effective in quantifying slow dynamics or long timescale behaviors such as protein folding. Here, we review recent implementations of adaptive sampling and Markov state models to not only address current limitations of molecular dynamics simulations, but to also highlight how Markov state modeling can be applied to investigate the structure–function mechanisms of large, complex membrane transporters.
OBJECTIVE:To determine the prognostic relevance, clinical characteristics, and 30-day outcomes associated with myocardial injury after noncardiac surgery (MINS) in vascular surgical patients.
...BACKGROUND:MINS has been independently associated with 30-day mortality after noncardiac surgery. The characteristics and prognostic importance of MINS in vascular surgery patients are poorly described.
METHODS:This was an international prospective cohort study of 15,102 noncardiac surgery patients 45 years or older, of whom 502 patients underwent vascular surgery. All patients had fourth-generation plasma troponin T (TnT) concentrations measured during the first 3 postoperative days. MINS was defined as a TnT of 0.03 ng/mL of higher secondary to ischemia. The objectives of the present study were to determine (i) if MINS is prognostically important in vascular surgical patients, (ii) the clinical characteristics of vascular surgery patients with and without MINS, (iii) the 30-day outcomes for vascular surgery patients with and without MINS, and (iv) the proportion of MINS that probably would have gone undetected without routine troponin monitoring.
RESULTS:The incidence of MINS in the vascular surgery patients was 19.1% (95% confidence interval (CI), 15.7%–22.6%). 30-day all-cause mortality in the vascular cohort was 12.5% (95% CI 7.3%–20.6%) in patients with MINS compared with 1.5% (95% CI 0.7%–3.2%) in patients without MINS (P < 0.001). MINS was independently associated with 30-day mortality in vascular patients (odds ratio, 9.48; 95% CI, 3.46–25.96). The 30-day mortality was similar in MINS patients with (15.0%; 95% CI, 7.1–29.1) and without an ischemic feature (12.2%; 95% CI, 5.3–25.5, P = 0.76). The proportion of vascular surgery patients who suffered MINS without overt evidence of myocardial ischemia was 74.1% (95% CI, 63.6–82.4).
CONCLUSIONS:Approximately 1 in 5 patients experienced MINS after vascular surgery. MINS was independently associated with 30-day mortality. The majority of patients with MINS were asymptomatic and would have gone undetected without routine postoperative troponin measurement.
CONTEXT Of the 200 million adults worldwide who undergo noncardiac surgery each year, more than 1 million will die within 30 days. OBJECTIVE To determine the relationship between the peak ...fourth-generation troponin T (TnT) measurement in the first 3 days after noncardiac surgery and 30-day mortality. DESIGN, SETTING, AND PARTICIPANTS A prospective, international cohort study that enrolled patients from August 6, 2007, to January 11, 2011. Eligible patients were aged 45 years and older and required at least an overnight hospital admission after having noncardiac surgery. MAIN OUTCOME MEASURES Patients' TnT levels were measured 6 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We undertook Cox regression analysis in which the dependent variable was mortality until 30 days after surgery, and the independent variables included 24 preoperative variables. We repeated this analysis, adding the peak TnT measurement during the first 3 postoperative days as an independent variable and used a minimum P value approach to determine if there were TnT thresholds that independently altered patients' risk of death. RESULTS A total of 15 133 patients were included in this study. The 30-day mortality rate was 1.9% (95% CI, 1.7%-2.1%). Multivariable analysis demonstrated that peak TnT values of at least 0.02 ng/mL, occurring in 11.6% of patients, were associated with higher 30-day mortality compared with the reference group (peak TnT ≤ 0.01 ng/mL): peak TnT of 0.02 ng/mL (adjusted hazard ratio aHR, 2.41; 95% CI, 1.33-3.77); 0.03 to 0.29 ng/mL (aHR, 5.00; 95% CI, 3.72-6.76); and 0.30 ng/mL or greater (aHR, 10.48; 95% CI, 6.25-16.62). Patients with a peak TnT value of 0.01 ng/mL or less, 0.02, 0.03-0.29, and 0.30 or greater had 30-day mortality rates of 1.0%, 4.0%, 9.3%, and 16.9%, respectively. Peak TnT measurement added incremental prognostic value to discriminate those likely to die within 30 days for the model with peak TnT measurement vs without (C index = 0.85 vs 0.81; difference, 0.4; 95% CI, 0.2-0.5; P < .001 for difference between C index values). The net reclassification improvement with TnT was 25.0% (P < .001). CONCLUSION Among patients undergoing noncardiac surgery, the peak postoperative TnT measurement during the first 3 days after surgery was significantly associated with 30-day mortality.
A potential therapeutic strategy for neutralizing SARS-CoV-2 infection is engineering high-affinity soluble ACE2 decoy proteins to compete for binding to the viral spike (S) protein. Previously, a ...deep mutational scan of ACE2 was performed and has led to the identification of a triple mutant variant, named sACE22.v.2.4, that exhibits subnanomolar affinity to the receptor-binding domain (RBD) of S. Using a recently developed transfer learning algorithm, TLmutation, we sought to identify other ACE2 variants that may exhibit similar binding affinity with decreased mutational load. Upon training a TLmutation model on the effects of single mutations, we identified multiple ACE2 double mutants that bind SARS-CoV-2 S with tighter affinity as compared to the wild type, most notably L79V;N90D that binds RBD similarly to ACE22.v.2.4. The experimental validation of the double mutants successfully demonstrates the use of machine learning approaches for engineering protein–protein interactions and identifying high-affinity ACE2 peptides for targeting SARS-CoV-2.
Circular RNAs (circRNAs) are an important class of non-coding RNAs partly by acting as microRNA sponges. Growing evidence indicates that air pollution exposure during pregnancy could lead to ...congenital defects in the offspring. In this study, using circRNAs sequencing, we profiled differentially expressed circRNAs in rat embryos exposed to a high concentration (> 200 μg/m
3
) of fine particulate matter (PM
2.5
)
in utero
. Compared with the control embryos whose mothers were reared in clean air, 25 and 55 circRNAs were found to be downregulated and upregulated, respectively, in the air pollution–exposed group. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses of circRNA-coexpressed genes indicated that segmentation, brain development, and system development together with lysine degradation, Rap1 signaling pathway, and adrenergic signaling were deregulated by
in utero
air pollution exposure. We also identified the central role of three circRNAs, namely circ_015003, circ_030724, and circ_127215 in the circRNA-microRNA interaction network. These data suggested that circRNA deregulation might play a crucial role in the development of air pollution–associated congenital malformations.
...awareness of, and compliance with, appropriate infection control measures—which varied considerably between studies—might have significantly mitigated nosocomial infection. ...no data were ...provided in the included studies on how aerosols were generated and dispersed, suggesting that aerosol transmission was not fully considered at the time. ...classifications of AGPs vary between professional guidelines, especially in the context of covid-199 (appendix 1). High flow rate, coughing, and NIV increase dispersion in an exponential fashion, whereas a tight-fitting mask, exhalation filter, suction, or expired gas scavenging minimise dispersion. ...understanding dispersion characteristics may reduce exposure to respiratory particles.
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