There is an increasing demand for accurate biomarkers for early non-invasive colorectal cancer detection. We employed a genome-scale marker discovery method to identify and verify candidate DNA ...methylation biomarkers for blood-based detection of colorectal cancer.
We used DNA methylation data from 711 colorectal tumors, 53 matched adjacent-normal colonic tissue samples, 286 healthy blood samples and 4,201 tumor samples of 15 different cancer types. DNA methylation data were generated by the Illumina Infinium HumanMethylation27 and the HumanMethylation450 platforms, which determine the methylation status of 27,578 and 482,421 CpG sites respectively. We first performed a multistep marker selection to identify candidate markers with high methylation across all colorectal tumors while harboring low methylation in healthy samples and other cancer types. We then used pre-therapeutic plasma and serum samples from 107 colorectal cancer patients and 98 controls without colorectal cancer, confirmed by colonoscopy, to verify candidate markers. We selected two markers for further evaluation: methylated THBD (THBD-M) and methylated C9orf50 (C9orf50-M). When tested on clinical plasma and serum samples these markers outperformed carcinoembryonic antigen (CEA) serum measurement and resulted in a high sensitive and specific test performance for early colorectal cancer detection.
Our systematic marker discovery and verification study for blood-based DNA methylation markers resulted in two novel colorectal cancer biomarkers, THBD-M and C9orf50-M. THBD-M in particular showed promising performance in clinical samples, justifying its further optimization and clinical testing.
Colorectal cancer (CRC) is a heterogeneous disease in which unique subtypes are characterized by distinct genetic and epigenetic alterations. Here we performed comprehensive genome-scale DNA ...methylation profiling of 125 colorectal tumors and 29 adjacent normal tissues. We identified four DNA methylation-based subgroups of CRC using model-based cluster analyses. Each subtype shows characteristic genetic and clinical features, indicating that they represent biologically distinct subgroups. A CIMP-high (CIMP-H) subgroup, which exhibits an exceptionally high frequency of cancer-specific DNA hypermethylation, is strongly associated with MLH1 DNA hypermethylation and the BRAF(V600E) mutation. A CIMP-low (CIMP-L) subgroup is enriched for KRAS mutations and characterized by DNA hypermethylation of a subset of CIMP-H-associated markers rather than a unique group of CpG islands. Non-CIMP tumors are separated into two distinct clusters. One non-CIMP subgroup is distinguished by a significantly higher frequency of TP53 mutations and frequent occurrence in the distal colon, while the tumors that belong to the fourth group exhibit a low frequency of both cancer-specific DNA hypermethylation and gene mutations and are significantly enriched for rectal tumors. Furthermore, we identified 112 genes that were down-regulated more than twofold in CIMP-H tumors together with promoter DNA hypermethylation. These represent ∼7% of genes that acquired promoter DNA methylation in CIMP-H tumors. Intriguingly, 48/112 genes were also transcriptionally down-regulated in non-CIMP subgroups, but this was not attributable to promoter DNA hypermethylation. Together, we identified four distinct DNA methylation subgroups of CRC and provided novel insight regarding the role of CIMP-specific DNA hypermethylation in gene silencing.
Taxonomy of representative smart material actuator-driven pumps reported in the literature.
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•Since 1975, a substantial amount of research has been performed on pumps operated by ...solid-state electromechanical actuators.•Actuators utilized have been unidirectional shape memory alloy (U-SMA)-, piezoelectric ceramic (PEC)-, dielectric elastomer (DE)-, ferroelectric polymer (FEP)-, ionic polymer metal composite (IPMC)- and conducting polymer (CP)-based.•Pumps developed have been macro- and micro- diaphragm and linear peristaltic.•The most prominent smart material actuator-driven pumps have been designed for applications in the drug delivery and biomedical fields, as well as for microelectromechanical systems.
There has been a substantial amount of research on liquid pumps operated by solid-state electroactive smart material actuators since the first such pump was developed in 1975, providing exciting opportunities for numerous fields. Aiming to motivate researchers to further develop this sector, a taxonomy of representative examples of smart material macro- and micro- diaphragm and linear peristaltic pumps was developed, categorizing them according to pump size and/or amount of fluid handled, method with which energy is imparted to the transported fluid and smart material actuator type with which they are driven. An extensive discussion of pumps operated by unidirectional shape memory alloy (U-SMA)-, piezoelectric ceramic (PEC)-, dielectric elastomer (DE)-, ferroelectric polymer (FEP)-, ionic polymer metal composite (IPMC)- and conducting polymer (CP)-based actuators was undertaken, focusing on actuator and pump design advancements. For qualitative and quantitative comparisons, the pumping technologies were also summarized in tables, presenting actuator and pump characteristics that influence pump performances.
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the ...biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.
We report the realization of quantum microwave circuits using hybrid superconductor-semiconductor Josephson elements comprised of InAs nanowires contacted by NbTiN. Capacitively shunted single ...elements behave as transmon circuits with electrically tunable transition frequencies. Two-element circuits also exhibit transmonlike behavior near zero applied flux but behave as flux qubits at half the flux quantum, where nonsinusoidal current-phase relations in the elements produce a double-well Josephson potential. These hybrid Josephson elements are promising for applications requiring microwave superconducting circuits operating in a magnetic field.
Background Imaging of Cosmic Extragalactic Polarization (BICEP) is a bolometric polarimeter designed to measure the inflationary B-mode polarization of the cosmic microwave background (CMB) at degree ...angular scales. During three seasons of observing at the South Pole (2006 through 2008), BICEP mapped ~2% of the sky chosen to be uniquely clean of polarized foreground emission. Here, we present initial results derived from a subset of the data acquired during the first two years. We present maps of temperature, Stokes Q and U, E and B modes, and associated angular power spectra. We demonstrate that the polarization data are self-consistent by performing a series of jackknife tests. We study potential systematic errors in detail and show that they are sub-dominant to the statistical errors. We measure the E-mode angular power spectrum with high precision at 21 <= ell <= 335, detecting for the first time the peak expected at ell ~ 140. The measured E-mode spectrum is consistent with expectations from a ΛCDM model, and the B-mode spectrum is consistent with zero. The tensor-to-scalar ratio derived from the B-mode spectrum is r = 0.02+0.31 -0.26, or r < 0.72 at 95% confidence, the first meaningful constraint on the inflationary gravitational wave background to come directly from CMB B-mode polarization.
Extensive changes in DNA methylation are common in cancer and may contribute to oncogenesis through transcriptional silencing of tumor-suppressor genes. Genome-scale studies have yielded important ...insights into these changes but have focused on CpG islands or gene promoters. We used whole-genome bisulfite sequencing (bisulfite-seq) to comprehensively profile a primary human colorectal tumor and adjacent normal colon tissue at single-basepair resolution. Regions of focal hypermethylation in the tumor were located primarily at CpG islands and were concentrated within regions of long-range (>100 kb) hypomethylation. These hypomethylated domains covered nearly half of the genome and coincided with late replication and attachment to the nuclear lamina in human cell lines. We confirmed the confluence of hypermethylation and hypomethylation within these domains in 25 diverse colorectal tumors and matched adjacent tissue. We propose that widespread DNA methylation changes in cancer are linked to silencing programs orchestrated by the three-dimensional organization of chromatin within the nucleus.
•Cardiovascular risk factors are associated with older brain age.•Blood pressure is more strongly associated with white matter compared to gray matter.•Resting state functional connectivity provides ...lower brain-age prediction accuracy.•Brain-age prediction accuracy depends on sample size and age range.
Brain age is becoming a widely applied imaging-based biomarker of neural aging and potential proxy for brain integrity and health. We estimated multimodal and modality-specific brain age in the Whitehall II (WHII) MRI cohort using machine learning and imaging-derived measures of gray matter (GM) morphology, white matter microstructure (WM), and resting state functional connectivity (FC). The results showed that the prediction accuracy improved when multiple imaging modalities were included in the model (R2 = 0.30, 95% CI 0.24, 0.36). The modality-specific GM and WM models showed similar performance (R2 = 0.22 0.16, 0.27 and R2 = 0.24 0.18, 0.30, respectively), while the FC model showed the lowest prediction accuracy (R2 = 0.002 -0.005, 0.008), indicating that the FC features were less related to chronological age compared to structural measures. Follow-up analyses showed that FC predictions were similarly low in a matched sub-sample from UK Biobank, and although FC predictions were consistently lower than GM predictions, the accuracy improved with increasing sample size and age range. Cardiovascular risk factors, including high blood pressure, alcohol intake, and stroke risk score, were each associated with brain aging in the WHII cohort. Blood pressure showed a stronger association with white matter compared to gray matter, while no differences in the associations of alcohol intake and stroke risk with these modalities were observed. In conclusion, machine-learning based brain age prediction can reduce the dimensionality of neuroimaging data to provide meaningful biomarkers of individual brain aging. However, model performance depends on study-specific characteristics including sample size and age range, which may cause discrepancies in findings across studies.
We present an improved analysis of the final data set from the QUaD experiment. Using an improved technique to remove ground contamination, we double the effective sky area and hence increase the ...precision of our cosmic microwave background (CMB) power spectrum measurements by ~30% versus that previously reported. In addition, we have improved our modeling of the instrument beams and have reduced our absolute calibration uncertainty from 5% to 3.5% in temperature. The robustness of our results is confirmed through extensive jackknife tests, and by way of the agreement that we find between our two fully independent analysis pipelines. For the standard six-parameter Delta *LCDM model, the addition of QUaD data marginally improves the constraints on a number of cosmological parameters over those obtained from the WMAP experiment alone. The impact of QUaD data is significantly greater for a model extended to include either a running in the scalar spectral index, or a possible tensor component, or both. Adding both the QUaD data and the results from the Arcminute Cosmology Bolometer Array Receiver experiment, the uncertainty in the spectral index running is reduced by ~25% compared to WMAP alone, while the upper limit on the tensor-to-scalar ratio is reduced from r < 0.48 to r < 0.33 (95% c.l.). This is the strongest limit on tensors to date from the CMB alone. We also use our polarization measurements to place constraints on parity-violating interactions to the surface of last scattering, constraining the energy scale of Lorentz violating interactions to <1.5 X 10-43 GeV (68% c.l.). Finally, we place a robust upper limit on the strength of the lensing B-mode signal. Assuming a single flat band power between = 200 and = 2000, we constrain the amplitude of B-modes to be <0.57 Delta *mK2 (95% c.l.).
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