Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that ...normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.
Purpose
To develop a tissue correction for GABA‐edited magnetic resonance spectroscopy (MRS) that appropriately addresses differences in voxel gray matter (GM), white matter (WM), and cerebrospinal ...fluid (CSF) fractions.
Materials and Methods
Simulations compared the performance of tissue correction approaches. Corrections were then applied to in vivo data from 16 healthy volunteers, acquired at 3T. GM, WM, and CSF fractions were determined from T1‐weighted images. Corrections for CSF content, GM/WM GABA content, and water relaxation of the three compartments are combined into a single, fully corrected measurement.
Results
Simulations show that CSF correction increases the dependence of GABA measurements on GM/WM fraction, by an amount equal to the fraction of CSF. Furthermore, GM correction substantially (and nonlinearly) increases the dependence of GABA measurements on GM/WM fraction, for example, by a factor of over four when the voxel GM tissue fraction is 50%. At this tissue fraction, GABA is overestimated by a factor of 1.5. For the in vivo data, correcting for voxel composition increased measured GABA values (P < 0.001 for all regions), but did not reduce intersubject variance (P > 0.5 for all regions). Corrected GABA values differ significantly based on the segmentation procedure used (P < 0.0001) and tissue parameter assumptions made (P < 0.0001).
Conclusion
We introduce a comprehensive tissue correction factor that adjusts GABA measurements to correct for different voxel compositions of GM, WM, and CSF. J. Magn. Reson. Imaging 2015;42:1431–1440.
Our understanding of the evolutionary history of primates is undergoing continual revision due to ongoing genome sequencing efforts. Bolstered by growing fossil evidence, these data have led to ...increased acceptance of once controversial hypotheses regarding phylogenetic relationships, hybridization and introgression, and the biogeographical history of primate groups. Among these findings is a pattern of recent introgression between species within all major primate groups examined to date, though little is known about introgression deeper in time. To address this and other phylogenetic questions, here, we present new reference genome assemblies for 3 Old World monkey (OWM) species: Colobus angolensis ssp. palliatus (the black and white colobus), Macaca nemestrina (southern pig-tailed macaque), and Mandrillus leucophaeus (the drill). We combine these data with 23 additional primate genomes to estimate both the species tree and individual gene trees using thousands of loci. While our species tree is largely consistent with previous phylogenetic hypotheses, the gene trees reveal high levels of genealogical discordance associated with multiple primate radiations. We use strongly asymmetric patterns of gene tree discordance around specific branches to identify multiple instances of introgression between ancestral primate lineages. In addition, we exploit recent fossil evidence to perform fossil-calibrated molecular dating analyses across the tree. Taken together, our genome-wide data help to resolve multiple contentious sets of relationships among primates, while also providing insight into the biological processes and technical artifacts that led to the disagreements in the first place.
Summary Background In the Medical Research Council (MRC) COIN trial, the epidermal growth factor receptor (EGFR)-targeted antibody cetuximab was added to standard chemotherapy in first-line treatment ...of advanced colorectal cancer with the aim of assessing effect on overall survival. Methods In this randomised controlled trial, patients who were fit for but had not received previous chemotherapy for advanced colorectal cancer were randomly assigned to oxaliplatin and fluoropyrimidine chemotherapy (arm A), the same combination plus cetuximab (arm B), or intermittent chemotherapy (arm C). The choice of fluoropyrimidine therapy (capecitabine or infused fluouroracil plus leucovorin) was decided before randomisation. Randomisation was done centrally (via telephone) by the MRC Clinical Trials Unit using minimisation. Treatment allocation was not masked. The comparison of arms A and C is described in a companion paper. Here, we present the comparison of arm A and B, for which the primary outcome was overall survival in patients with KRAS wild-type tumours. Analysis was by intention to treat. Further analyses with respect to NRAS, BRAF , and EGFR status were done. The trial is registered, ISRCTN27286448. Findings 1630 patients were randomly assigned to treatment groups (815 to standard therapy and 815 to addition of cetuximab). Tumour samples from 1316 (81%) patients were used for somatic molecular analyses; 565 (43%) had KRAS mutations. In patients with KRAS wild-type tumours (arm A, n=367; arm B, n=362), overall survival did not differ between treatment groups (median survival 17·9 months IQR 10·3–29·2 in the control group vs 17·0 months 9·4–30·1 in the cetuximab group; HR 1·04, 95% CI 0·87–1·23, p=0·67). Similarly, there was no effect on progression-free survival (8·6 months IQR 5·0–12·5 in the control group vs 8·6 months 5·1–13·8 in the cetuximab group; HR 0·96, 0·82–1·12, p=0·60). Overall response rate increased from 57% (n=209) with chemotherapy alone to 64% (n=232) with addition of cetuximab (p=0·049). Grade 3 and higher skin and gastrointestinal toxic effects were increased with cetuximab (14 vs 114 and 67 vs 97 patients in the control group vs the cetuximab group with KRAS wild-type tumours, respectively). Overall survival differs by somatic mutation status irrespective of treatment received: BRAF mutant, 8·8 months (IQR 4·5–27·4); KRAS mutant, 14·4 months (8·5–24·0); all wild-type, 20·1 months (11·5–31·7). Interpretation This trial has not confirmed a benefit of addition of cetuximab to oxaliplatin-based chemotherapy in first-line treatment of patients with advanced colorectal cancer. Cetuximab increases response rate, with no evidence of benefit in progression-free or overall survival in KRAS wild-type patients or even in patients selected by additional mutational analysis of their tumours. The use of cetuximab in combination with oxaliplatin and capecitabine in first-line chemotherapy in patients with widespread metastases cannot be recommended. Funding Cancer Research UK, Cancer Research Wales, UK Medical Research Council, Merck KGgA.
MINI: Trends in lumbar spinal stenosis surgery are largely unknown outside of the United States. This population-based health record linkage study revealed that complex fusion surgery had a four-fold ...increase from 2003-2013 in Australia. This surgical procedure increased the risk of complications and resource use compared with decompression surgery alone.
Population-based health record linkage study.
The aim of this study was to determine trends in hospital admissions and surgery for lumbar spinal stenosis, as well as complications and resource use in Australia.
In the United States, rates of decompression surgery have declined, whereas those of fusion have increased. It is unclear whether this trend is also happening elsewhere.
We included patients 18 years and older admitted to a hospital in New South Wales between 2003 and 2013 who were diagnosed with lumbar spinal stenosis. We investigated the rates of hospital admission and surgical procedures, as well as hospital costs, length of hospital stay, and complications. Surgical procedures were: decompression alone, simple fusion (one to two disc levels, single approach), and complex fusion (three or more disc levels or a combined posterior and anterior approach).
The rates of decompression alone increased from 19.0 to 22.1 per 100,000 people. Simple fusion rates increased from 1.3 to 2.8 per 100,000 people, whereas complex fusion increased from 0.6 to 2.4 per 100,000 people. The odds of major complications for complex fusion compared with decompression alone was 4.1 (95% confidence interval CI: 1.7-10.1), although no significant difference was found for simple fusion (odds ratio 2.0, 95% CI: 0.7-6.1). Mean hospital costs with decompression surgery were AU $12,168, whereas simple and complex fusion cost AU $30,811 and AU $32,350, respectively.
In Australia, decompression rates for lumbar spinal stenosis increased from 2003 to 2013. The fastest increasing surgical procedure was complex fusion. This procedure increased the risk of major complications and resource, although recent evidence suggest fusion provides no additional benefits to the traditional decompression surgery.
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•Optimization of unilamellar liposome manufacturing via microfluidic system;•Comparison of thin-film hydration method and microfluidic system in liposome properties;•Drug co-loaded ...liposomes as novel formulation for breast cancer treatment;•Effect of prenyloxy coumarin as fluidity moderator in lipid bilayer;
Developing more efficient manufacturing methods for nano therapeutic systems is becoming important, not only to better control their physico-chemical characteristics and therapeutic efficacy but also to ensure scale-up is cost-effective. The principle of cross-flow chemistry allows precise control over manufacturing parameters for the fabrication of uniform liposomal formulations, as well as providing reproducible manufacturing scale-up compared to conventional methods. We have herein investigated the use of microfluidics to produce PEGylated DSPC liposomes loaded with doxorubicin and compared their performance against identical formulations prepared by the thin-film method. The isoprenylated coumarin umbelliprenin was selected as a co-therapeutic. Umbelliprenin-loaded and doxorubicin:umbelliprenin co-loaded liposomes were fabricated using the optimised microfluidic set-up. The role of umbelliprenin as lipid bilayer fluidity modulation was characterized, and we investigated its role on liposomes size, size distribution, shape and stability compared to doxorubicin-loaded liposomes. Finally, the toxicity of all liposomal formulations was tested on a panel of human breast cancer cells (MCF-7, MDA-MB 231, BT-474) to identify the most potent formulation by liposomal fabrication method and loaded compound(s). We herein show that the microfluidic system is an alternative method to produce doxorubicin:umbelliprenin co-loaded liposomes, allowing fine control over liposome size (100–250 nm), shape, uniformity and doxorubicin drug loading (>80%). Umbelliprenin was shown to confer fluidity to model lipid biomembranes, which helps to explain the more homogeneous size and shape of co-loaded liposomes compared to liposomes without umbelliprenin. The toxicity of doxorubicin:umbelliprenin co-loaded liposomes was lower than that of free doxorubicin, due to the delayed release of doxorubicin from liposomes. An alternative, rapid and easy manufacturing method for the production of liposomes has been established using microfluidics to effectively produce uniform doxorubicin:umbelliprenin co-loaded liposomal formulations with proven cytotoxicity in human breast cancer cell lines in vitro.
To constrain global warming, we must strongly curtail greenhouse gas emissions and capture excess atmospheric carbon dioxide
. Regrowing natural forests is a prominent strategy for capturing ...additional carbon
, but accurate assessments of its potential are limited by uncertainty and variability in carbon accumulation rates
. To assess why and where rates differ, here we compile 13,112 georeferenced measurements of carbon accumulation. Climatic factors explain variation in rates better than land-use history, so we combine the field measurements with 66 environmental covariate layers to create a global, one-kilometre-resolution map of potential aboveground carbon accumulation rates for the first 30 years of natural forest regrowth. This map shows over 100-fold variation in rates across the globe, and indicates that default rates from the Intergovernmental Panel on Climate Change (IPCC)
may underestimate aboveground carbon accumulation rates by 32 per cent on average and do not capture eight-fold variation within ecozones. Conversely, we conclude that maximum climate mitigation potential from natural forest regrowth is 11 per cent lower than previously reported
owing to the use of overly high rates for the location of potential new forest. Although our data compilation includes more studies and sites than previous efforts, our results depend on data availability, which is concentrated in ten countries, and data quality, which varies across studies. However, the plots cover most of the environmental conditions across the areas for which we predicted carbon accumulation rates (except for northern Africa and northeast Asia). We therefore provide a robust and globally consistent tool for assessing natural forest regrowth as a climate mitigation strategy.
During 2006–2021, Canada had 55 laboratory-confirmed outbreaks of foodborne botulism, involving 67 cases. The mean annual incidence was 0.01 case/100,000 population. Foodborne botulism in Indigenous ...communities accounted for 46% of all cases, which is down from 85% of all cases during 1990–2005. Among all cases, 52% were caused by botulinum neurotoxin type E, but types A (24%), B (16%), F (3%), and AB (1%) also occurred; 3% were caused by undetermined serotypes. Four outbreaks resulted from commercial products, including a 2006 international outbreak caused by carrot juice. Hospital data indicated that 78% of patients were transferred to special care units and 70% required mechanical ventilation; 7 deaths were reported. Botulinum neurotoxin type A was associated with much longer hospital stays and more time spent in special care than types B or E. Foodborne botulism often is misdiagnosed. Increased clinician awareness can improve diagnosis, which can aid epidemiologic investigations and patient treatment.
Rapid, quantitative, and group-targeting detection of total benzodiazepines (BZDs) is critical to create an accurate judgement in emergent medical and forensic settings. Large-size (111) faceted Ag ...nanosheets decorated with small ZnO nanoparticles were designed as the prominent surface-enhanced Raman scattering substrate, which possessed advantages of specific metal facets and additional charge-transfer (CT) effect from the semiconductor. The vital and bridge role of ZnO in the CT effect was systematically studied via experimental investigations and molecular dynamics simulation, which proves the essentiality of an appropriate ZnO decoration density. Upon determining optimal Ag NS/ZnO hybrids, a calibration curve of estazolam was established with a 0.5 nM detection limit. Based on the obtained curve, group-targeting screening was achieved toward total concentrations of five BZDs (estazolam, oxazepam, alprazolam, triazolam, and lorazepam). Importantly, the total concentrations of BZDs in mice serum were accurately monitored with changing analytical time during the metabolic process, which was in agreement with the tendency measured by liquid chromatography with tandem mass spectrometry.
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