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  • 1
    Publication Date: 2013-12-01
    Description: Lung cancer is the leading cause of cancer deaths worldwide and current therapies fail to treat this disease in majority of cases. Antrodia camphorata is a medicinal mushroom being widely used as food dietary supplement for cancer prevention. The sesquiterpene lactone antrocin is the most potent among 〉100 secondary metabolites isolated from A. camphorata . However, the molecular mechanisms of antrocin-mediated anticancer effects remain unclear. In this study, we found that antrocin inhibited cell proliferation in two non-small-cell lung cancer cells, namely H441 (wild-type epidermal growth factor receptor, IC 50 = 0.75 μM) and H1975 (gefitnib-resistant mutant T790M, IC 50 = 0.83 μM). Antrocin dose dependently suppressed colony formation and induced apoptosis as evidenced by activated caspase-3 and increased Bax/Bcl2 ratio. Gene profiling studies indicated that antrocin downregulated Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway. We further demonstrated that antrocin suppressed both constitutively activated and interleukin 6-induced STAT3 phosphorylation and its subsequent nuclear translocation. Such inhibition is found to be achieved through the suppression of JAK2 and interaction between STAT3 and extracellular signal-regulated kinase. Additionally, antrocin increased microRNA let-7c expression and suppressed STAT signaling. The combination of antrocin and JAK2/STAT3 gene silencing significantly increased apoptosis in H441 cells. Such dual interruption of JAK2 and STAT3 pathways also induced downregulation of antiapoptotic protein mcl-1 and increased caspase-3 expression. In vivo intraperitoneal administration of antrocin significantly suppressed the growth of lung cancer tumor xenografts. Our results indicate that antrocin may be a potential therapeutic agent for human lung cancer cells through constitutive inhibition of JAK2/STAT3 pathway.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
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  • 2
    Publication Date: 2013-06-19
    Description: DIVERGE is a software system for phylogeny-based analyses of protein family evolution and functional divergence. It provides a suite of statistical tools for selection and prioritization of the amino acid sites that are responsible for the functional divergence of a gene family. The synergistic efforts of DIVERGE and other methods have convincingly demonstrated that the pattern of rate change at a particular amino acid site may contain insightful information about the underlying functional divergence following gene duplication. These predicted sites may be used as candidates for further experiments. We are now releasing an updated version of DIVERGE with the following improvements: 1) a feasible approach to examining functional divergence in nearly complete sequences by including deletions and insertions (indels); 2) the calculation of the false discovery rate of functionally diverging sites; 3) estimation of the effective number of functional divergence-related sites that is reliable and insensitive to cutoffs; 4) a statistical test for asymmetric functional divergence; and 5) a new method to infer functional divergence specific to a given duplicate cluster. In addition, we have made efforts to improve software design and produce a well-written software manual for the general user.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
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  • 3
    Publication Date: 2013-06-21
    Description: Aims L5 is the most negatively charged subfraction of human low-density lipoprotein (LDL) and is the only subfraction of LDL capable of inducing apoptosis in cultured vascular endothelial cells (ECs) by inhibiting fibroblast growth factor-2 (FGF2) transcription. We examined whether plasma L5 levels are elevated in patients with ST-segment elevation myocardial infarction (STEMI) and whether aspirin provides epigenetic protection of human coronary artery ECs (HCAECs) exposed to L5. Methods and results Plasma L5 levels were compared between patients with STEMI ( n = 10) and control subjects with chest pain syndrome but a normal coronary arteriogram ( n = 5). L5 was isolated from the plasma of STEMI patients and control subjects, and apoptosis, FGF2 expression, and FGF2 promoter methylation were examined in HCAECs treated with L5 and aspirin. Plasma L5 levels were significantly higher in STEMI patients than in control subjects ( P 〈 0.001). Treatment of HCAECs with L5 resulted in reduced survival and FGF2 expression and increased CpG methylation of the FGF2 promoter. Co-treatment of HCAECs with L5 and a physiologically relevant, low concentration of aspirin (0.2 mM) attenuated the adverse effects of L5 on HCAEC survival, FGF2 expression, and FGF2 promoter methylation. In contrast, high concentrations of aspirin (≥1.0 mM) accentuated the effects of L5. Conclusions Our results show that L5 levels are significantly increased in STEMI patients. Furthermore, L5 impairs HCAEC function through CpG methylation of the FGF2 promoter, which is suppressed in the presence of low-concentration aspirin. Our results provide evidence of a novel mechanism of aspirin in the prevention of MI.
    Print ISSN: 0008-6363
    Electronic ISSN: 1755-3245
    Topics: Medicine
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  • 4
    Publication Date: 2013-11-27
    Description: Aims As the transseptal (TS) puncture has become an integral part of many types of cardiac interventional procedures, its technique that was initial reported for measurement of left atrial pressure in 1950s, continue to evolve. Our laboratory adopted a modified technique which uses only coronary sinus catheter as the landmark to accomplishing TS punctures under fluoroscopy. The aim of this study is prospectively to evaluate the training and learning process for TS puncture guided by this modified technique. Methods and results Guided by the training protocol, TS puncture was performed in 120 consecutive patients by three trainees without previous personal experience in TS catheterization and one experienced trainer as a controller. We analysed the following parameters: one puncture success rate, total procedure time, fluoroscopic time, and radiation dose. The learning curve was analysed using curve-fitting methodology. The first attempt at TS crossing was successful in 74 (82%), a second attempt was successful in 11 (12%), and 5 patients failed to puncture the interatrial septal finally. The average starting process time was 4.1 ± 0.8 min, and the estimated mean learning plateau was 1.2 ± 0.2 min. The estimated mean learning rate for process time was 25 ± 3 cases. Important aspects of learning curve can be estimated by fitting inverse curves for TS puncture. Conclusions The study demonstrated that this technique was a simple, safe, economic, and effective approach for learning of TS puncture. Base on the statistical analysis, approximately 29 TS punctures will be needed for trainee to pass the steepest area of learning curve.
    Print ISSN: 1099-5129
    Electronic ISSN: 1532-2092
    Topics: Medicine
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  • 5
    Publication Date: 2013-10-30
    Description: Inherited variation in genes that regulate innate immunity and inflammation may contribute to colorectal neoplasia risk. To evaluate this association, we conducted a nested case–control study of 451 colorectal cancer cases, 694 colorectal advanced adenoma cases and 696 controls of European descent within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. A total of 935 tag single-nucleotide polymorphisms (SNPs) in 98 genes were evaluated. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association with colorectal neoplasia. Sixteen SNPs were associated with colorectal neoplasia risk at P 〈 0.01, but after adjustment for multiple testing, only rs2838732 ( ITGB2 ) remained suggestively associated with colorectal neoplasia (OR per T allele = 0.68, 95% CI: 0.57–0.83, P = 7.7 x 10 –5 , adjusted P = 0.07). ITGB2 codes for the CD18 protein in the integrin beta chain family. The ITGB2 association was stronger for colorectal cancer (OR per T allele = 0.41, 95% CI: 0.30–0.55, P = 2.4 x 10 – 9 ) than for adenoma (OR per T allele = 0.84, 95%CI: 0.69–1.03, P = 0.08), but it did not replicate in the validation study. The ITGB2 rs2838732 association was significantly modified by smoking status ( P value for interaction = 0.003). Among never and former smokers, it was inversely associated with colorectal neoplasia (OR per T allele = 0.5, 95% CI: 0.37–0.69 and OR per T allele = 0.72, 95% CI: 0.54–0.95, respectively), but no association was seen among current smokers. Other notable findings were observed for SNPs in BPI/LBP and MYD88 . Although the results need to be replicated, our findings suggest that genetic variation in inflammation-related genes may be related to the risk of colorectal neoplasia.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
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  • 6
    Publication Date: 2013-09-25
    Description: Programmed cell death in Caenorhabditis elegans requires activation of the caspase CED-3, which strictly depends on CED-4. CED-4 forms an octameric apoptosome, which binds the CED-3 zymogen and facilitates its autocatalytic maturation. Despite recent advances, major questions remain unanswered. Importantly, how CED-4 recognizes CED-3 and how such binding facilitates CED-3 activation remain completely unknown. Here we demonstrate that the L2' loop of CED-3 directly binds CED-4 and plays a major role in the formation of an active CED-4–CED-3 holoenzyme. The crystal structure of the CED-4 apoptosome bound to the L2' loop fragment of CED-3, determined at 3.2 Å resolution, reveals specific interactions between a stretch of five hydrophobic amino acids from CED-3 and a shallow surface pocket within the hutch of the funnel-shaped CED-4 apoptosome. Structure-guided biochemical analysis confirms the functional importance of the observed CED-4–CED-3 interface. Structural analysis together with published evidence strongly suggest a working model in which two molecules of CED-3 zymogen, through specific recognition, are forced into the hutch of the CED-4 apoptosome, consequently undergoing dimerization and autocatalytic maturation. The mechanism of CED-3 activation represents a major revision of the prevailing model for initiator caspase activation.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 7
    Publication Date: 2013-11-21
    Description: : We introduce a web-based tool, P eak A nnotation and Vis ualization (PAVIS), for annotating and visualizing ChIP-seq peak data. PAVIS is designed with non-bioinformaticians in mind and presents a straightforward user interface to facilitate biological interpretation of ChIP-seq peak or other genomic enrichment data. PAVIS, through association with annotation, provides relevant genomic context for each peak, such as peak location relative to genomic features including transcription start site, intron, exon or 5'/3'-untranslated region. PAVIS reports the relative enrichment P -values of peaks in these functionally distinct categories, and provides a summary plot of the relative proportion of peaks in each category. PAVIS, unlike many other resources, provides a peak-oriented annotation and visualization system, allowing dynamic visualization of tens to hundreds of loci from one or more ChIP-seq experiments, simultaneously. PAVIS enables rapid, and easy examination and cross-comparison of the genomic context and potential functions of the underlying genomic elements, thus supporting downstream hypothesis generation. Availability and Implementation: PAVIS is publicly accessed at http://manticore.niehs.nih.gov/pavis . Contact: li3@niehs.nih.gov Supplementary information: Supplementary data are available at Bioinformatics online
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
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  • 8
    Publication Date: 2012-07-14
    Description: The authors conducted a 2-year follow-up of 40 cardiovascular disease patients (mean age = 65.6 years (standard deviation, 5.8)) who underwent repeated measurements of cardiovascular response before and during the 2008 Beijing Olympics (Beijing, China), when air pollution was strictly controlled. Ambient levels of particulate matter with an aerodynamic diameter less than 2.5 µm (PM 2.5 ), black carbon, nitrogen dioxide, sulfur dioxide, ozone, and carbon monoxide were measured continuously, with validation of concurrent real-time measurements of personal exposure to PM 2.5 and carbon monoxide. Linear mixed-effects models were used with adjustment for individual risk factors, time-varying factors, and meteorologic effects. Significant heart rate variability reduction and blood pressure elevation were observed in association with exposure to air pollution. Specifically, interquartile-range increases of 51.8 µg/m 3 , 2.02 µg/m 3 , and 13.7 ppb in prior 4-hour exposure to PM 2.5 , black carbon, and nitrogen dioxide were associated with significant reductions in the standard deviation of the normal-to-normal intervals of 4.2% (95% confidence interval (CI): 1.9, 6.4), 4.2% (95% CI: 1.8, 6.6), and 3.9% (95% CI: 2.2, 5.7), respectively. Greater heart rate variability declines were observed among subjects with C-reactive protein values above the 90th percentile, subjects with a body mass index greater than 25, and females. The authors conclude that autonomic and vascular dysfunction may be one of the mechanisms through which air pollution exposure can increase cardiovascular disease risk, especially among persons with systemic inflammation and overweight.
    Print ISSN: 0002-9262
    Electronic ISSN: 1476-6256
    Topics: Medicine
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  • 9
    Publication Date: 2015-12-11
    Description: Concerns about high caffeine intake and coffee as a vehicle for added fat and sugar have raised questions about the net impact of coffee on health. Although inverse associations have been observed for overall mortality, data for cause-specific mortality are sparse. Additionally, few studies have considered exclusively decaffeinated coffee intake or use of coffee additives. Coffee intake was assessed at baseline by self-report in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Hazard ratios were estimated using Cox proportional hazards models. Among 90,317 US adults without cancer at study baseline (1998–2001) or history of cardiovascular disease at study enrollment (1993–2001), 8,718 deaths occurred during 805,644 person-years of follow-up from 1998 through 2009. Following adjustment for smoking and other potential confounders, coffee drinkers, as compared with nondrinkers, had lower hazard ratios for overall mortality (〈1 cup/day: hazard ratio (HR) = 0.99 (95% confidence interval (CI): 0.92, 1.07); 1 cup/day: HR = 0.94 (95% CI: 0.87, 1.02); 2–3 cups/day: HR = 0.82 (95% CI: 0.77, 0.88); 4–5 cups/day: HR = 0.79 (95% CI: 0.72, 0.86); ≥6 cups/day: HR = 0.84 (95% CI: 0.75, 0.95)). Similar findings were observed for decaffeinated coffee and coffee additives. Inverse associations were observed for deaths from heart disease, chronic respiratory diseases, diabetes, pneumonia and influenza, and intentional self-harm, but not cancer. Coffee may reduce mortality risk by favorably affecting inflammation, lung function, insulin sensitivity, and depression.
    Print ISSN: 0002-9262
    Electronic ISSN: 1476-6256
    Topics: Medicine
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  • 10
    Publication Date: 2016-08-05
    Description: The plastid genome (plastome) of heterotrophic plants like mycoheterotrophs and parasites shows massive gene losses in consequence to the relaxation of functional constraints on photosynthesis. To understand the patterns of this convergent plastome reduction syndrome in heterotrophic plants, we studied 12 closely related orchids of three different lifeforms from the tribe Neottieae (Orchidaceae). We employ a comparative genomics approach to examine structural and selectional changes in plastomes within Neottieae. Both leafy and leafless heterotrophic species have functionally reduced plastid genome. Our analyses show that genes for the NAD(P)H dehydrogenase complex, the photosystems, and the RNA polymerase have been lost functionally multiple times independently. The physical reduction proceeds in a highly lineage-specific manner, accompanied by structural reconfigurations such as inversions or modifications of the large inverted repeats. Despite significant but minor selectional changes, all retained genes continue to evolve under purifying selection. All leafless Neottia species, including both visibly green and nongreen members, are fully mycoheterotrophic, likely evolved from leafy and partially mycoheterotrophic species. The plastomes of Neottieae span many stages of plastome degradation, including the longest plastome of a mycoheterotroph, providing invaluable insights into the mechanisms of plastome evolution along the transition from autotrophy to full mycoheterotrophy.
    Electronic ISSN: 1759-6653
    Topics: Biology
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