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  • Wiley-Blackwell  (474,668)
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  • 1
    Publication Date: 2018-03-09
    Description: Genomic studies have been used to identify genes underlying many important plant secondary metabolic pathways. However, genes for salicinoid phenolic glycosides (SPGs)—ecologically important compounds with significant commercial, cultural, and medicinal applications—remain largely undescribed. We used a linkage map derived from a full-sib population of hybrid cottonwoods ( Populus spp.) to search for quantitative trait loci (QTL) for the SPGs salicortin and HCH-salicortin. SSR markers and primer sequences were used to anchor the map to the V3.0 P. trichocarpa genome. We discovered 21 QTL for the two traits, including a major QTL for HCH-salicortin ( R 2  = .52) that colocated with a QTL for salicortin on chr12. Using the V3.0 Populus genome sequence, we identified 2,983 annotated genes and 1,480 genes of unknown function within our QTL intervals. We note ten candidate genes of interest, including a BAHD-type acyltransferase that has been potentially linked to Populus SPGs. Our results complement other recent studies in Populus with implications for gene discovery and the evolution of defensive chemistry in a model genus. To our knowledge, this is the first study to use a full-sib mapping population to identify QTL intervals and gene lists associated with SPGs. Salicinoid phenolic glycosides (SPGs) are important secondary metabolites with numerous ecological, commercial, and ethnobotanical applications. However, the pathways controlling the expression of SPGs remain conspicuously underscribed. Here, discuss 25 quantitative trait loci (QTL) associated with the salicinoid phenolic gylcosides, salicortin and HCH-salicortin, and a number of potential candidate genes that occur within our QTL intervals.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 2
    Publication Date: 2018-03-09
    Description: Aims Most gastric carcinomas develop in association with mucosal atrophy and hypochlorhydria, whereas benign peptic ulcers are acid-related. Given that acid sterilizes gastric contents, we hypothesized that ulcerated gastric cancers may be associated with increased luminal microbes compared with peptic ulcers, and that this feature may represent a helpful diagnostic clue to the presence of malignancy. We performed this study to determine whether features of luminal debris, including microorganisms, from ulcerated gastric cancers were significantly different from those of debris associated with benign ulcers. Methods and Results We retrospectively identified 50 ulcerated adenocarcinomas and 50 site-matched peptic ulcers. Luminal debris was evaluated for nature of inflammation, necrosis, and presence of mixed bacterial colonies or yeast. Non-lesional mucosa was assessed for chronic gastritis, Helicobacter pylori , chemical gastropathy, and intestinal metaplasia. Patients in both groups were adults (mean age: 69 and 62 years, respectively) with similar amounts of inflammation and cellular necrosis in biopsy material. However, 76% of ulcerated cancers harbored non- H.pylori bacterial colonies, compared with only 22% of peptic ulcers (p〈0.01). Filamentous bacteria and fungi were highly specific for carcinoma (98% and p=0.02 for both comparisons). Background intestinal metaplasia was more common among gastric cancers compared with peptic ulcers (50% vs. 26%, p=0.02), whereas chemical gastropathy was more commonly associated with the latter (50% versus 10%, p〈0.01). Conclusion Gastric cancers may be colonized by non- H. pylori microbes. Detection of numerous bacterial colonies, filamentous bacteria, or fungi in biopsy material obtained from ulcerated gastric lesions should raise suspicion for underlying malignancy. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 3
    Publication Date: 2018-03-09
    Description: Background The incremental value of dynamic contrast-enhanced (DCE) imaging in localizing radiorecurrent prostate cancer is uncertain. Purpose To assess the added-value of DCE imaging to the combination T 2 -weighted imaging (T 2 W)+diffusion-weighted imaging (DWI) in detecting locally radiorecurrent prostate cancer (PCa), by radiologists with different levels of experience. Study Type Analytic retrospective study. Population In all, 52 men with biological suspected PCa recurrence after radiotherapy were retrospectively included. Field Strength/Sequence All men underwent prostatic MRI (1.5T or 3T), including T 2 W, DWI, and DCE imagings, before biopsies. Assessment Two junior (6 months' experience) and two senior readers (more than 3 years' experience) independently assigned a Likert score for each prostatic sextant on T 2 W+DW+DCE imagings, then on T 2 W+DW imagings, 4 weeks later. Statistical Tests The reference standard was prostatic biopsies. For two levels of positivity of Likert score, 3/5 and 4/5, sensitivity, specificity, area under the receiver operating curve (AUC), and interreader agreement were compared. Results T 2 W+DWI+DCE and T 2 W+DWI imaging had similar AUC at lobe and sextant level (0.853–0.946 vs. 0.819–0.955, P from 0.071–0.534). Using a Likert score ≥4/5, T 2 W+DWI+DCE significantly improved the sensitivity for junior readers at the patient, lobe, and sextant level (40–80% vs. 22–66%, P  〈 0.0001–0.041). Sensitivity was not significantly modified with DCE imaging for senior readers (54–95% vs. 50–91%, P from 0.074–1). Specificity was not modified for all readers (50–100% vs. 50%–100%, P from 0.134–1). DCE imaging improved interreader agreement for a Likert score ≥4/5 (kappa from 0.6–0.73 vs. 0.38–0.73). Data Conclusion The addition of DCE imaging did not significantly improve accuracy in recurrent PCa detection after radiotherapy, whatever the level of experience of the readers. However, the addition of DCE imaging slightly improved the sensitivity for less-experienced readers and increased their diagnostic confidence. Level of Evidence : 3 Technical Efficacy : Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 4
    Publication Date: 2018-03-09
    Description: BACKGROUND The coexistence of hepatic iron and fat is common in patients with hyperferritinemia, which plays an interactive and aggressive role in the progression of diseases (fibrosis, cirrhosis, and hepatocellular carcinomas). PURPOSE To evaluate a modified high-speed T 2 -corrected multi-echo, single voxel spectroscopy sequence (HISTOV) for liver iron concentration (LIC) quantification in patients with hyperferritinemia, with simultaneous fat fraction (FF) estimation. STUDY TYPE Retrospective cohort study. POPULATION Thirty-eight patients with hyperferritinemia were enrolled. FIELD STRENGTH/SEQUENCE HISTOV, a fat-saturated multi-echo gradient echo (GRE) sequence, and a spin echo sequence (FerriScan) were performed at 1.5T. ASSESSMENT R 2 of the water signal and FF were calculated with HISTOV, and values were derived from the GRE sequence, with R 2 and LIC from FerriScan serving as the references. STATISTICAL TESTS Linear regression, correlation analyses, receiver operating characteristic analyses, and Bland-Altman analyses were conducted. RESULTS Abnormal hepatic iron load was detected in 32/38 patients, of whom 10/32 had coexisting steatosis. Strong correlation was found between and FerriScan-LIC ( R 2 = 0.861), and between HISTOV-R 2_ water and FerriScan-R 2 ( R 2  = 0.889). Furthermore, HISTOV-R 2_ water was not correlated with HISTOV-FF. The area under the curve (AUC) for HISTOV-R 2_ water was 0.974, 0.971, and 1, corresponding to clinical FerriScan-LIC thresholds of 1.8, 3.2, and 7.0 mg/g dw, respectively. No significant difference in the AUC was found between HISTOV-R 2_ water and at any of the LIC thresholds, with P -values of 0.42, 0.37, and 1, respectively. HISTOV-LIC showed excellent agreement with FerriScan-LIC, with a mean bias of 0.00 ± 1.18 mg/g dw, whereas the mean bias between GRE-LIC and FerriScan-LIC was 0.53 ± 1.49 mg/g dw. DATA CONCLUSION HISTOV is useful for the quantification and grading of liver iron overload in patients with hyperferritinemia, particularly in cases with coexisting steatosis. HISTOV-LIC showed no systematic bias compared with FerriScan-LIC, making it a promising alternative for iron quantification. Level of Evidence : 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 5
    Publication Date: 2018-03-09
    Description: As a novel candidate tumor suppressor, NDRG4 is largely unstudied in human malignancies. In this study, we investigated the protein expression level of NDRG4 in gastric cancer and its association with outcome of patients. In the present study, we recruited 286 patients with gastric cancer and investigated the protein and mRNA expression of NDRG4 in cancer and adjacent normal specimens by immunohistochemistry assay and real-time PCR. The association of NDRG4 level with clinicopathological characteristics was investigated by appropriate statistical analysis. NDRG4 overexpression and knockdown cell lines were established in order to detect its impact on proliferation and apoptosis. Significant decreased protein and mRNA expression of NDRG4 was found in gastric cancer, compared with adjacent normal specimens. Besides, it was found that NDRG4 protein expression in gastric cancer was significantly associated with tumor differentiation, invasion, metastasis and stage. Patients with tumors of decreased NDRG4 level were more likely to have unfavorable disease-free and overall survival, in both univariate and multivariate analysis. In addition, overexpression of NDRG4 suppressed cell proliferation of gastric cancer cells in vitro; conversely, the proliferation of gastric cancer cells were enhanced by knockdown of NDRG4. These results proved for the first time that NDRG4 could be a potential tumor suppressor and prognostic marker of gastric cancer. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 6
    Publication Date: 2018-03-09
    Description: Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In the present study, we show that a short time exposure (3 hours) to Triptolide,which did not trigger apoptosis, could specifically increase breast cancer cells sensitivity to Doxorubicin rather than other chemotherapy drugs including Paclitaxel, Fluorouracil, and Mitomycin .C. Further studies revealed Triptolide downregulated ATM expression and inhibited DNA damage response to DNA double- strand breaks. Moreover, the chemosensitization effect to Doxorubicin from Triptolide was attenuated by overexpression of ATM in breast cancer cells. Our findings suggest that Triptolide specifically chemosensitizes breast cancer cells to Doxorubicin prior to apoptosis initiation through downregulating ATM expression and inhibiting DNA damage response. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 7
    Publication Date: 2018-03-09
    Description: The aim of this work was to develop and evaluate a fast phase contrast magnetic resonance imaging (PC-MRI) technique with hybrid one- and two-sided flow encodings only (HOTFEO) for accurate blood flow and velocity measurements of three-directional velocity encoding PC-MRI. Four-dimensional (4D) PC-MRI acquires flow-compensated (FC) and three-directional flow-encoded (FE) echoes in an interleaved fashion. We hypothesize that the blood flow velocity direction (not magnitude) has minimal change between two consecutive cardiac phases. This assumption provides a velocity direction constraint that can achieve 4/3-fold acceleration using three-directional FE data to calculate FC data instead of acquiring them. The HOTFEO acquisition pattern can address the ill-conditioned constraint and improve the calculation accuracy. HOTFEO was evaluated in healthy volunteers and compared with conventional two-dimensional (2D) and 4D flow imaging techniques with FC and three-directional FE acquisitions (FC/3FE). Compared with FC/3FE, Bland–Altman tests showed that the 4/3-fold accelerated HOTFEO technique resulted in relatively small bias error for total volumetric flow (0.89% for prospective 2D data, –1.19% for retrospective 4D data and –3.40% for prospective 4D data) and maximum peak velocity (0.50% for prospective 2D data, –0.17% for retrospective 4D data and –2.00% for prospective 4D data) measurements in common carotid arteries. HOTFEO can accelerate three-directional velocity encoding PC-MRI whilst maintaining the measurement accuracy of the total volumetric flow and maximum peak velocity. We hypothesize that the blood flow velocity direction (not magnitude) shows minimum change between two consecutive cardiac phases. This assumption provides a velocity direction constraint that can achieve 4/3-fold acceleration using three-directional flow encoding data to calculate flow compensation data instead of acquiring them. Hybrid one- and two-sided flow encodings only (HOTFEO) can accelerate three-directional velocity encoding phase contrast magnetic resonance imaging (PC-MRI) whilst maintaining the measurement accuracy of the total volumetric flow and maximum total peak velocity.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 8
    Publication Date: 2018-03-09
    Description: Mass spectrometry (MS)-based immunopeptidomics has developed as one of the leading methodologies for comprehensive characterization of in vivo presented Human Leukocyte Antigen (HLA)-bound peptides. Unveiling the identity of HLA-bound peptides derived from diseased cells is crucial to gain knowledge on the constitution of efficient disease-specific T cell responses. The HLA-presented peptidome reflects the status of the cellular proteome, hence disease-related aberrations of post-translational modifications (PTMs) might lead to presentation of peptides harboring PTMs. Therefore, characterization of HLA-bound PTM peptides could shed light on their relevance in immune and disease processes. In this issue, Ramarathinam et al. investigate the presentation of HIV envelope (HIVenv) peptides bound to the HLA-B*57:01 allele. Among these peptides, the authors specifically focused on a kynurenine modified peptide. To this end, they characterize the possible origin of the kynurenine modification, its effect on HLA binding affinity, stability, conformation within the complex and its immunogenicity compared to the native counterpart. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 9
    Publication Date: 2018-03-12
    Description: Ongoing controversy over logging the ancient Białowieża Forest in Poland symbolizes a global problem for policies and management of the increasing proportion of the earth's intact forest that is subject to post-disturbance logging. We review the extent of, and motivations for, post-disturbance logging in protected and unprotected forests globally. An unprecedented level of logging in protected areas and other places where green-tree harvest would not normally occur is driven by economic interests and a desire for pest control. To avoid failure of global initiatives dedicated to reducing the loss of species, five key policy reforms are necessary: (1) salvage logging must be banned from protected areas; (2) forest planning should address altered disturbance regimes for all intact forests to ensure that significant areas remain undisturbed by logging; (3) new kinds of integrated analyses are needed to assess the potential economic benefits of salvage logging against its ecological, economic, and social costs; (4) global and regional maps of natural disturbance regimes should be created to guide better spatio-temporal planning of protected areas and undisturbed forests outside reserves; and (5) improved education and communication programs are needed to correct widely-held misconceptions about natural disturbances. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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  • 10
    Publication Date: 2018-03-12
    Description: Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 11
    Publication Date: 2018-03-12
    Description: The pentacyclic acridine RHPS4 is a highly potent and specific G-quadruplex (G4) ligand, which binds and stabilizes telomeric G4 leading to the block of the replication forks at telomeres and consequently to telomere dysfunctionalization. In turn, the cell recognizes unprotected telomeres as DNA double-strand breaks with consequent activation of DNA repair response at telomeres, cellular growth impairment and death. Data from the literature showed the capability of this compound to sensitize U251MG glioblastoma radioresistant cell line to X-rays sparsely ionizing radiations. In the present paper it was investigated whether RHPS4 is also able to increase the effect of clinical carbon-ion beams (cells irradiated in the middle of a spread-out-Bragg-peak, in the energy range of 246-312 MeV/u and a dose-averaged linear energy transfer of 46 keV/μ). Interestingly, also for charged particles whose damage inflicted to DNA is more complex than that of sparsely ionizing radiations and results in higher Relative Biological Effectiveness (RBE), RHPS4 significantly potentiated the radiation effect in terms of cell killing, delayed rejoining of DNA double-strand breaks (γ-H2AX and 53BBP1 immunofluorescence staining), chromosome aberrations (pan-centromeric/telomeric FISH and multicolor-FISH) and G 2 /M-phase accumulation in GBM cells. Overall, the results provide the first evidence that the combined administration of the G4-ligand RHPS4 with charged particles interfere with cellular processes involved in cell survival leading to radiosensitization of highly radioresistant tumor cells. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 12
    Publication Date: 2018-03-12
    Description: Arf levels are tightly regulated in cells and correlate with the level of ribosome biogenesis and proliferative status of cells. Through multivalent interactions with NPM1 – a regulator of ribosome biogenesis, and Mdm2 – a regulator of cellular fate, Arf integrates within the nucleolar matrix, altering its structure, dynamics and function and therefore modulates the cell cycle.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 13
    Publication Date: 2018-03-12
    Description: Purpose To map the cerebral metabolic rate of oxygen (CMRO 2 ) by estimating the oxygen extraction fraction (OEF) from gradient echo imaging (GRE) using phase and magnitude of the GRE data. Theory and Methods 3D multi-echo gradient echo imaging and perfusion imaging with arterial spin labeling were performed in 11 healthy subjects. CMRO 2 and OEF maps were reconstructed by joint quantitative susceptibility mapping (QSM) to process GRE phases and quantitative blood oxygen level-dependent (qBOLD) modeling to process GRE magnitudes. Comparisons with QSM and qBOLD alone were performed using ROI analysis, paired t-tests, and Bland-Altman plot. Results The average CMRO 2 value in cortical gray matter across subjects were 140.4 ± 14.9, 134.1 ± 12.5, and 184.6 ± 17.9 μmol/100 g/min, with corresponding OEFs of 30.9 ± 3.4%, 30.0 ± 1.8%, and 40.9 ± 2.4% for methods based on QSM, qBOLD, and QSM+qBOLD, respectively. QSM+qBOLD provided the highest CMRO 2 contrast between gray and white matter, more uniform OEF than QSM, and less noisy OEF than qBOLD. Conclusion Quantitative CMRO 2 mapping that fits the entire complex GRE data is feasible by combining QSM analysis of phase and qBOLD analysis of magnitude.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 14
    Publication Date: 2018-03-12
    Description: Purpose Proton MRSI is a noninvasive modality capable of generating volumetric maps of in vivo tissue metabolism without the need for ionizing radiation or injected contrast agent. Magnetic resonance spectroscopic imaging has been shown to be a viable imaging modality for studying several neuropathologies. However, a key hurdle in the routine clinical adoption of MRSI is the presence of spectral artifacts that can arise from a number of sources, possibly leading to false information. Methods A deep learning model was developed that was capable of identifying and filtering out poor quality spectra. The core of the model used a tiled convolutional neural network that analyzed frequency-domain spectra to detect artifacts. Results When compared with a panel of MRS experts, our convolutional neural network achieved high sensitivity and specificity with an area under the curve of 0.95. A visualization scheme was implemented to better understand how the convolutional neural network made its judgement on single-voxel or multivoxel MRSI, and the convolutional neural network was embedded into a pipeline capable of producing whole-brain spectroscopic MRI volumes in real time. Conclusion The fully automated method for assessment of spectral quality provides a valuable tool to support clinical MRSI or spectroscopic MRI studies for use in fields such as adaptive radiation therapy planning.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 15
    Publication Date: 2018-03-12
    Description: Purpose To investigate the feasibility of measuring the subtle disruption of blood-brain barrier (BBB) using DCE-MRI with a scan duration shorter than 10 min. Methods The extended Patlak-model (EPM) was introduced to include the effect of plasma flow ( F p ) in the estimation of vascular permeability–surface area product ( PS ). Numerical simulation studies were carried out to investigate how the reduction in scan time affects the accuracy in estimating contrast kinetic parameters. DCE-MRI studies of the rat brain were conducted with Fisher rats to confirm the results from the simulation. Intracranial F98 glioblastoma models were used to assess areas with different levels of permeability. In the normal brain tissues, the Patlak model (PM) and EPM were compared, whereas the 2-compartment-exchange-model (TCM) and EPM were assessed in the peri-tumor and the tumor regions. Results The simulation study results demonstrated that scan time reduction could lead to larger bias in PS estimated by PM (〉2000%) than by EPM (〈47%), especially when F p is low. When F p was high as in the gray matter, the bias in PM- PS (〉900%) were larger than that in EPM- PS (〈42%). The animal study also showed similar results, where the PM parameters were more sensitive to the scan duration than the EPM parameters. It was also demonstrated that, in the peri-tumor region, the EPM parameters showed less change by scan duration than the TCM parameters. Conclusion The results of this study suggest that EPM can be used to measure PS with a scan duration of 10 min or less.
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    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 16
    Publication Date: 2018-03-12
    Description: Purpose To develop a rapid, non-CPMG high-resolution volumetric imaging approach, exhibiting a speed and in-plane resilience to field inhomogeneities comparable to RARE/turbo-spin-echo (TSE) while endowed with unique downsampling characteristics. Methods A multi-scan extension of cross-term spatiotemporal encoding (xSPEN) is introduced and analyzed. The method simultaneously yields k y / k z data containing low and high frequency components, as well as transposed, low-resolution z / y images. This dual k -/spatial-domain information is captured by a multi-scan procedure that phase-encodes k y while simultaneously slice-selecting z . A reconstruction scheme converting this information into high resolution 3D images with fully multiplexed volumetric coverage is introduced and exemplified. Results Phase-encoded xSPEN was tested by human brain imaging at sub-mm resolutions. The method exceeded 2D TSE's sensitivity by factors of ≈3–4, while providing similar resolution and SNR as 3D TSE in ≈50% acquisition times. The method's contrast is dominated by T 2 and is free from “bright-fat” effects associated to spin-echo trains. Further acceleration is enabled by the method's downsampling abilities. Tradeoffs between encoding time, number of measurements, spatial resolution, SNR, and artifact levels are also laid out. Conclusion A new MRI strategy is introduced delivering high in- and through-plane resolutions while enjoying full Fourier multiplexing, leading to fast acquisitions with high SNR.
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    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 17
    Publication Date: 2018-03-12
    Description: Purpose Magnetic resonance imaging has been used extensively to track in vivo implanted cells that have been previously labeled with relaxation enhancers. However, this approach is not suitable to track multiple cell populations, as it may lead to confounding results in case the contrast agent is released from the labeled cells. This paper demonstrates how the use of CEST agents can overcome these issues. After encapsulating paramagnetic lanthanide shift reagents, we may shift the absorption frequency of the intracellular water resonance (δ In ), thus generating frequency-encoding CEST responsive cells that can be visualized in the MR image by applying the proper RF irradiation. Methods Eu-HPDO3A, Dy-HPDO3A, and Tm-HPDO3A were used as shift reagents for labeling murine breast cancer cells and murine macrophages by hypotonic swelling and pinocytosis. The CEST-MR images were acquired at 7 T, and the saturation transfer effect was measured. Samples at different dilution of cells were analyzed to quantify the detection threshold. In vitro experiments of cell proliferation were carried out. Finally, murine breast cancer cells were injected subcutaneously in mice, and MR images were acquired to assess the proliferation index in vivo. Results It was found that entrapment of the paramagnetic complexes into endosomes (i.e., using the pinocytosis route) leads to an enhanced shift of the intracellular water resonance. δ In appears to be proportional to the effective magnetic moment (μ eff ) and to the concentration of the loaded lanthanide complex. Moreover, a higher shift is present when the complexes are entrapped in the endosomes. The cell proliferation index was assessed both in vitro and in vivo by evaluating the reduction of δ In value in the days after the cell labeling. Conclusion Cells can be visualized by CEST MRI after loading with paramagnetic shift reagent, by exploiting the large ensemble of the properly shifted intracellular water molecules. A better performance is obtained when the complexes are entrapped inside the endosomes. The observed (δ In ) value is strongly correlated to the chemical nature of the probe, and to its concentration and cellular localization. Two applications of this method are reported in this paper: (1) for in vivo cell visualization and (2) for the monitoring of the cellular proliferation process, as this method is accompanied by a change in δ In that may be exploited as a longitudinal reporter of the proliferation rate.
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    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 18
    Publication Date: 2018-03-12
    Description: Polycomb group (PcG) protein BMI1 is an important regulator of oncogenic phenotype and is often overexpressed in several human malignancies including breast cancer. Aberrant expression of BMI1 is associated with metastasis and poor prognosis in cancer patients. At present, therapy reagents that can efficiently inhibit the expression of BMI1 are not very well known. Here, we report that Timosaponin A-III (TA-III), a steroidal saponin obtained from the rhizomes of an herb, Anemarrhena asphodeloides , strongly inhibits expression of BMI1 in breast cancer cells. Treatment of breast cancer cells with TA-III resulted in inhibition of oncogenic phenotypes such as proliferation, migration and invasion, and induction of cellular senescence. Inhibition of these oncogenic phenotypes was accompanied by downregulation of BMI1 expression and histone posttranslational modification activity of PRC1. The mechanistic analysis of TA-III-induced inhibition of oncogenic activity and BMI1 expression suggests that downregulation of c-Myc mediates TA-III effect on BMI1. We further show that exogenous BMI1 overexpression can overcome TA-III-induced inhibition of oncogenic phenotypes. We also show that TA-III induces expression of tumor suppressive miR-200c and miR-141, which are negatively regulated by BMI1. In summary, our data suggest that TA-III is a potent inhibitor of BMI1 and that it can be successfully used to inhibit the growth of tumors where PcG protein BMI1 and PcG activities are upregulated. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 19
    Publication Date: 2018-03-12
    Description: ABSTRACT Nickel (Ni) is an environmental and occupational carcinogen, and exposure to Ni is associated with lung and nasal cancers in humans. Furthermore, Ni exposure is implicated in several lung diseases including chronic inflammatory airway diseases, asthma and fibrosis. However, the mutagenic potential of Ni is low and does not correlate with its potent toxicity and carcinogenicity. Therefore, mechanisms underlying Ni exposure-associated diseases remain poorly understood. Since the health risks of environmental exposures often continue post exposure, understanding the exposure effects that persist after the termination of exposure could provide mechanistic insights into diseases. By examining the persistent effects of Ni exposure, we report that Ni induces epithelial-mesenchymal transition (EMT) and that the mesenchymal phenotype remains irreversible even after the termination of exposure. Ni-induced EMT was dependent on the irreversible upregulation of ZEB1, an EMT master regulator, via resolution of its promoter bivalency. ZEB1, upon activation, downregulated its repressors as well as the cell-cell adhesion molecule, E-cadherin, resulting in the cells undergoing EMT and switching to persistent mesenchymal status. ZEB1 depletion in cells exposed to Ni attenuated Ni-induced EMT. Moreover, Ni exposure did not induce EMT in ZEB1-depleted cells. Activation of EMT, during which the epithelial cells lose cell-cell adhesion and become migratory and invasive, plays a major role in asthma, fibrosis, and cancer and metastasis, lung diseases associated with Ni exposure. Therefore, our finding of irreversible epigenetic activation of ZEB1 by Ni exposure and the acquisition of persistent mesenchymal phenotype would have important implications in understanding Ni-induced diseases. This article is protected by copyright. All rights reserved
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    Topics: Medicine
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  • 20
    Publication Date: 2018-03-13
    Description: AKT-mTOR and androgen receptor (AR) signaling pathways are aberrantly activated in prostate cancer due to frequent PTEN deletions or SPOP mutations. A clinical barrier is that targeting one of them often activates the other. Here, we demonstrate that HDAC3 augments AKT phosphorylation in prostate cancer cells and its overexpression correlates with AKT phosphorylation in patient samples. HDAC3 facilitates lysine-63-chain polyubiquitination and phosphorylation of AKT, and this effect is mediated by AKT deacetylation at lysine 14 and 20 residues and HDAC3 interaction with the scaffold protein APPL1. Conditional homozygous deletion of Hdac3 suppresses prostate tumorigenesis and progression by concomitant blockade of AKT and AR signaling in the Pten knockout mouse model. Pharmacological inhibition of HDAC3 using a selective HDAC3 inhibitor RGFP966 inhibits growth of both PTEN-deficient and SPOP-mutated prostate cancer cells in culture, patient-derived organoids and xenografts in mice. Our study identifies HDAC3 as a common upstream activator of AKT and AR signaling and reveals that dual inhibition of AKT and AR pathways is achievable by single-agent targeting of HDAC3 in prostate cancer. Both AKT and AR signaling pathways are activated in PTEN-deficient or SPOP-mutated prostate cancers and inhibition of one pathway often activates the other. AKT and AR pathways in PTEN-deficient or SPOP-mutated prostate cancers are both inhibited by the same HDAC3 inhibitor RGFP966.
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  • 21
    Publication Date: 2018-03-13
    Print ISSN: 0270-9139
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  • 22
    Publication Date: 2018-03-13
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  • 23
    Publication Date: 2018-03-13
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  • 24
    Publication Date: 2018-03-13
    Description: Aims The diagnosis of IgG4-related disease (IgG4-RD) requires a multidisciplinary approach, in which histology plays an important role. Although a diagnosis was previously established using surgically resected specimens, there is increasing clinical demand to diagnose this systemic condition by biopsies. The present study aimed to elucidate how useful transbronchial lung biopsies (TBLBs) are for this diagnostic purpose. Methods and Results The study cohort consisted of 20 consecutive patients diagnosed with IgG4-RD in other organs who underwent TBLBs for potential pulmonary involvement. One case showing multiple granulomas suggestive of other conditions was excluded. Seven of the remaining 19 cases (37%) showed apparently normal lung tissue, indicating a sampling error, while 12 (63%) had microscopic abnormalities. Nine cases (47%) with a dense lymphoplasmacytic infiltrate met the number and ratio criteria of IgG4-positive plasma cell infiltration (〉20 cells/high power field [HPF] and 〉40% IgG4/IgG-positive cell ratio). Obliterative phlebitis and storiform fibrosis were observed in one case each. In 43 control cases of various inflammatory conditions, tissue IgG4 elevations appeared to be uncommon with only 2 cases (5%) each meeting the number or ratio criterion and one case (2%) fulfilling both. All control cases with tissue IgG4 elevations were of eosinophilic pneumonia. Conclusions TBLBs provided histological findings that were supportive for the diagnosis of IgG4-RD in 47% of cases with 98% diagnostic specificity. Therefore, they have potential as a useful and acceptable diagnostic approach for IgG4-related lung disease. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2559
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  • 25
  • 26
    Publication Date: 2018-03-13
    Description: Adrenocortical carcinoma (ACC) is a tumor with poor prognosis in which overexpression of a panel of microRNAs has been associated with malignancy but a very limited number of investigations on their role in ACC pathogenesis have been conducted. We examined the involvement of miR-483-5p and miR-139-5p in adrenocortical cancer aggressiveness. Using bioinformatics predictions and mRNA/miRNA expression profiles, we performed an integrated analysis to identify inversely correlated miRNA-mRNA pairs in ACC. We identified N-Myc Downstream-Regulated Gene family members 2 and 4 (NDRG2 and NDRG4) as targets of miR-483-5p and miR-139-5p, respectively. NDRG2 and NDRG4 expressions were inversely correlated respectively with miR-483-5p and miR-139-5p levels in aggressive ACC samples from two independent cohorts of 20 and 44 ACC. Moreover, upregulation of miR-139-5p and downregulation of NDRG4 demonstrated a striking prognostic value. A direct interaction between miR-483-5p or miR-139-5p and their targets was demonstrated in reporter assays. Downregulation of miR-483-5p or miR-139-5p in the ACC cell lines NCI-H295R and SW13 increased NDRG2 or NDRG4 mRNA and protein expression, compromised adrenocortical cancer cell invasiveness and anchorage-independent growth. MiR-483-5p or miR-139-5p overexpression and NDRG2 or NDRG4 inhibition produce similar changes, which are rescued by NDRG2 or NDRG4 ectopic expression. We established that key factors mediating epithelial-to-mesenchymal transition are downstream effectors of miR-483-5p/NDRG2 and miR-139-5p/NDRG4 pathways. Collectively, our data show for the first time that miR-483-5p/NDRG2 and miR-139-5p/NDRG4 axes promote ACC aggressiveness, with potential implications for prognosis and therapeutic interventions in adrenocortical malignancies. This article is protected by copyright. All rights reserved.
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  • 27
    Publication Date: 2018-03-13
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
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  • 28
    Publication Date: 2018-03-13
    Description: Background Myocardial infarction (MI) survivors are at risk of complications including heart failure and malignant arrhythmias. Purpose We undertook serial imaging of swine following MI with the aim of characterizing the longitudinal left ventricular (LV) remodeling in a translational model of ischemia-reperfusion-mediated MI. Animal Model Eight Yorkshire swine underwent mid left anterior descending coronary artery balloon occlusion to create an ischemia-reperfusion experimental model of MI. Field Strength/Sequences 1.5T Philips Achieva scanner. Serial cardiac MRI was performed at 16, 33, and 62 days post-MI, including cine imaging, native and postcontrast T 1 , T 2 and dark-blood late gadolinium enhanced (DB-LGE) scar imaging. Assessment Regions of interest were selected on the parametric maps to assess native T 1 and T 2 in the infarct and in remote tissue. Volume of enhanced tissue, nonenhanced tissue, and gray zone were assessed from DB-LGE imaging. Volumes, cardiac function, and strain were calculated from cine imaging. Statistical Tests Parameters estimated at more than two timepoints were compared with a one-way repeated measures analysis of variance. Parametric mapping data were analyzed using a generalized linear mixed model corrected for multiple observations. A result was considered statistically significant at P  〈 0.05. Results All animals developed anteroseptal akinesia and hyperenhancement on DB-LGE with a central core of nonenhancing tissue. Mean hyperenhancement volume did not change during the observation period, while the central core contracted from 2.2 ± 1.8 ml at 16 days to 0.08 ± 0.19 ml at 62 days ( P  = 0.008). Native T 1 of ischemic myocardium increased from 1173 ± 93 msec at 16 days to 1309 ± 97 msec at 62 days ( P  〈 0.001). Mean radial and circumferential strain rate magnitude in remote myocardium increased with time from the infarct ( P  〈 0.05). Date Conclusion In this swine model of MI, serial quantitative cardiac MR exams allow characterization of LV remodeling and scar formation. Level of Evidence : 2 Technical Efficacy : Stage 2 J. Magn. Reson. Imaging 2018.
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  • 29
    Publication Date: 2018-03-13
    Description: Hemopexin (Hpx) binds heme with extraordinary affinity, and after haptoglobin may provide a second line of defense against the toxicity of extracellular hemoglobin (Hb). In this series of experiments, the hypothesis that Hpx protects neurons from Hb neurotoxicity was evaluated in murine primary cultures containing neurons and glial cells. Contrary to hypothesis, Hpx increased neuronal loss due to micromolar concentrations of Hb by 4-12-fold, as measured by LDH release assay; conversely, the neurotoxicity of hemin was completely prevented. The endogenous fluorescence of Hpx was quenched by Hb, consistent with transfer of Hb-bound heme to Hpx. This was associated with precipitation of globin chains, as detected by immunostaining and fluorescent Hb labeling. A portion of this precipitate attached firmly to cells and could not be removed by multiple washes. Concomitant treatment with haptoglobin (Hp) prevented globin precipitation and most of the increase in neuronal loss. Hpx weakly attenuated the increase in culture non-heme iron produced by Hb treatment, quantified by ferrozine assay. However, Hb-Hpx toxicity was iron-dependent, and was blocked by deferoxamine and ferrostatin-1. Upregulation of cell ferritin expression, a primary cell defense against Hb toxicity, was not observed on Western blots of culture lysates that had been concomitantly treated with Hpx. These results suggest that Hpx destabilizes Hb in the absence of haptoglobin, leading to globin precipitation and exacerbation of iron-dependent oxidative cell injury. Combined therapy with hemopexin plus haptoglobin may be preferable to hemopexin alone after CNS hemorrhage. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
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  • 30
    Publication Date: 2018-03-13
    Description: Sepsis-associated encephalopathy (SAE), characterized as diffuse brain dysfunction and neurological manifestations secondary to sepsis, is a common complication in critically ill patients and can give rise to poor outcome, but understanding the molecular basis of this disorder remains a major challenge. Given the emerging role of G protein-coupled receptor 2 (GRK2), first identified as a G protein-coupled receptor (GPCR) regulator, in the regulation of non-GPCR-related molecules contributing to diverse cellular functions and pathology, including inflammation, we tested the hypothesis that GRK2 may be linked to the neuropathogenesis of SAE. When mouse MG6 microglial cells were challenged with lipopolysaccharide (LPS), GRK2 cytosolic expression was highly upregulated. The ablation of GRK2 by small interfering RNAs (siRNAs) prevented an increase in intracellular reactive oxygen species generation in LPS-stimulated MG6 cells. Furthermore, the LPS-induced upregulation of inducible nitric-oxide synthase expression and increase in nitric oxide production were negated by GRK2 inhibitor or siRNAs. However, GRK2 inhibition was without effect on overproduction of tumor necrosis factor-α, interleukin (IL)-6, and IL-1β in LPS-stimulated MG cells. In mice with cecal ligation and puncture-induced sepsis, treatment with GRK2 inhibitor reduced high levels of oxidative and nitrosative stress in the mice brains, where GRK2 expression was upregulated, alleviated neurohistological damage observed in cerebral cortex sections, and conferred a significant survival advantage to CLP mice. Altogether, these results uncover the novel role for GRK2 in regulating cellular oxidative and nitrosative stress during inflammation and suggest that GRK2 may have a potential as an intriguing therapeutic target to prevent or treat SAE. This article is protected by copyright. All rights reserved.
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  • 31
    Publication Date: 2018-03-13
    Description: Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P Ryan The above article, published May 20 2015 in EMBO Molecular Medicine , has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork. GAO'T disagrees with the text of this retraction notice, albeit not with the retraction. The following issues are noted: Table 1 contains clinical data described in the paper as being derived from a cohort of asthma patients. However, the provenance of this data is unclear. Based on the evidence available, the University of Dundee investigation concluded that the majority of the patient cohort is likely to be a subset of a cohort of cystic fibrosis patients reported in PLoS One 8(12): e82432 ( https://doi.org/10.1371/journal.pone.0082432 ), although in a number of cases the patient's gender is at odds between the two reports. The RNAseq data are unavailable on the European Nucleotide Archive under the reported accession number ERG003569. RNAseq data were uploaded with accession number ERS654066 before publication. The paper describes use of both prednisolone and prednisone, yet only the latter was used in the study.
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  • 32
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    Publication Date: 2018-03-13
    Description: Our front cover features pseudocolored serial confocal z-stack images of B cells expressing one of two different isoforms of human membrane-bound IgE (mIgE), which were visualized by staining with fluorophore-labeled anti-IgE antibodies after fixation and permeabilization of the cells. The images are taken from Vanshylla et al. (pp. 441–453), who show that the short isoform of human mIgE is readily expressed on the B cell surface as part of the B cell antigen receptor, whereas the long isoform of human and primate mIgE is efficiently retained in the endoplasmic reticulum and as a consequence has limited potential to signal activation of IgE-switched B cells.
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    Electronic ISSN: 1521-4141
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  • 33
    Publication Date: 2018-03-13
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    Electronic ISSN: 1521-4141
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  • 34
    Publication Date: 2018-03-13
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  • 35
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    Publication Date: 2018-03-13
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  • 36
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    Wiley-Blackwell
    Publication Date: 2018-03-13
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  • 37
    Publication Date: 2018-03-13
    Description: ABSTRACT Hepatitis B virus (HBV) RNA in serum is a novel biomarker for intrahepatic HBV replication and treatment response. For its proper use it is essential to identify factors influencing serum HBV RNA level. Using a RACE PCR technique (lower limit of detection 800 copies/mL [c/mL]), serum HBV RNA levels were measured in samples of 488 untreated individuals with chronic HBV infection who were eligible to treatment according to currently used recommendations. We explored the association of serum levels of HBV RNA with patient and virus associated factors. HBV genotype distribution was 21/10/20/46/3% for A/B/C/D/other. Mean HBV RNA serum level was 5.9 (1.6) log 10 c/mL (HBeAg-positive CHB: 6.5 [1.2] log c/mL, HBeAg-negative CHB: 4.1 [1.2] log c/mL; p〈 0.001). By multivariable linear regression, factors associated with lower HBV RNA level were HBeAg-negativity ( β =-0.69, p 〈0.001), HBV genotypes A ( β =-0.13, p= 0.002), B ( β =-0.07, p =0.049) and C ( β =-0.61, p 〈0.001) in comparison to D, and presence of HBV basal core promoter mutation either alone ( β =-0.14, p =0.001) or in combination with precore mutation ( β =-0.22, p 〈0.001). Higher serum ALT was associated with higher HBV RNA ( β =0.23, p〈0.001). HBV RNA correlated strongly with HBV DNA (HBeAg-pos: r=0.72, p〈0.001; HBeAg-neg: r=0.78, p〈0.001), and moderately with qHBsAg (HBeAg-pos: r=0.54, p〈0.001; HBeAg-neg: r=0.19, p=0.04) and qHBeAg (r=0.41, p〈0.001). Conclusion. In this multi-ethnic cohort of 488 untreated individuals with chronic hepatitis B, factors associated with serum HBV RNA level were HBeAg status, serum ALT, HBV genotype, and presence of basal core promotor mutations. For the future use of serum HBV RNA as a clinical marker it seems mandatory to take these factors in consideration. This article is protected by copyright. All rights reserved.
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  • 38
    Publication Date: 2018-03-13
    Description: Obesity is associated with both endoplasmic reticulum (ER) stress and chronic metabolic inflammation. ER stress activates the unfolded protein response (UPR) and has been implicated in a variety of cancers, including hepatocellular carcinoma (HCC). It is unclear whether individual UPR pathways are mechanistically linked to HCC development, however. Here we report a dual role for inositol-requiring enzyme 1α (IRE1α), the ER-localized UPR signal transducer, in obesity-promoted HCC development. We found that genetic ablation of IRE1α in hepatocytes not only markedly reduced the occurrence of diethylnitrosamine (DEN)-induced HCC in LKO mice when fed a normal chow (NC) diet, but also protected against the acceleration of HCC progression during high-fat diet (HFD) feeding. Irrespective of their adiposity states, LKO mice showed decreased hepatocyte proliferation and STAT3 activation, even in the face of increased hepatic apoptosis. Furthermore, IRE1α abrogation blunted obesity-associated activation of hepatic IKKβ-NF-κB pathway, leading to reduced production of the tumor-promoting inflammatory cytokines TNF and IL-6. Importantly, higher IRE1α expression along with elevated STAT3 phosphorylation was also observed in the tumor tissues from human HCC patients, correlating with their poorer survival rate. Conclusion: These results demonstrate that IRE1α acts in a feed-forward loop during obesity-induced metabolic inflammation to promote HCC development through STAT3-mediated hepatocyte proliferation. This article is protected by copyright. All rights reserved.
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  • 39
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    Publication Date: 2018-03-13
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  • 40
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    Publication Date: 2018-03-13
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  • 41
    Publication Date: 2018-03-13
    Description: Preeclampsia and hyperemesis are pregnancy complications associated with altered sex hormone levels. Previous studies suggest preeclampsia may be associated with a decreased risk of subsequent breast cancer and hyperemesis with an increased risk, but the evidence remains unclear. We used data from the Generations Study, a large prospective study of women in the United Kingdom, to estimate relative risks of breast cancer in relation to a history of preeclampsia and hyperemesis using Cox Regression adjusting for known breast cancer risk factors. During 7.5 years average follow-up of 82,053 parous women, 1,969 were diagnosed with invasive or in-situ breast cancer. Women who had experienced preeclampsia during pregnancy had a significantly decreased risk of premenopausal breast cancer (hazard ratio (HR) =0.67, 95% confidence interval (CI): 0.49-0.90) and of HER2-enriched tumours (HR=0.33, 95% CI: 0.12-0.91), but there was no association with overall (HR=0.90, 95% CI: 0.80-1.02) or postmenopausal (HR=0.97, 95% CI: 0.85-1.12) breast cancer risk. Risk reductions among premenopausal women were strongest within 20 years since the last pregnancy with preeclampsia. Hyperemesis was associated with a significantly increased risk of HER2-enriched tumours (HR=1.76, 95% CI: 1.07-2.87), but not with other intrinsic subtypes or breast cancer risk overall. These results provide evidence that preeclampsia is associated with a decreased risk of premenopausal and HER2-enriched breast cancer and that hyperemesis, although not associated with breast cancer risk overall, may be associated with raised risk of HER2-enriched tumours. This article is protected by copyright. All rights reserved.
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  • 42
    Publication Date: 2018-03-13
    Description: Caspase-3 ( CASP3 ) is a major mediator of apoptosis activated during cellular exposure to cytotoxic drugs, radiotherapy, or immunotherapy. It is often used as a marker for efficacy of cancer therapy. However, recent reports indicate that caspase-3 also has non-apoptotic roles such as promotion of tumor relapse and tumor angiogenesis. Therefore, the roles of caspase-3 in tumor progression remains to be defined clearly. In this study, we established caspase-3 knockout (KO) colon cancer cell lines by use of the CRISPR technology. In vitro, caspase-3 knockout HCT116 cells were significantly less clonogenic in soft agar assays. They were also significantly less invasive and more sensitive to radiation and mitomycin C than control cells. In vivo , CASP3KO cells formed tumors at rates similar to control cells but were significantly more sensitive to radiotherapy. They were also less prone to pulmonary metastasis when inoculated either subcutaneously or intravenously. At the mechanistic level, caspase-3 gene knockout appeared to cause reduced EMT phenotypes when compared with parental HCT116 cells. Indeed, they showed significantly increased E-cadherin expression, reduced N-cadherin, Snail, Slug, and ZEB1 expression than control cells. Therefore, therapeutic targeting of caspase-3 may not only increase the sensitivity of cancer cell to chemotherapy and radiotherapy, but also inhibit cancer cell invasion and metastases. This article is protected by copyright. All rights reserved.
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  • 43
    Publication Date: 2018-03-13
    Description: Free fatty acid receptor 2 (FFAR2, also named GPR43), is activated by short-chain fatty acids (SCFAs), such as butyrate, that are produced when gut bacteria ferment dietary fiber. FFAR2 has been suggested to regulate colonic inflammation, which is a major risk factor for the development of colon cancer and is also linked to epigenetic dysregulation in colon carcinogenesis. The current study assessed whether FFAR2, acting as an epigenetic regulator, protects against colon carcinogenesis. To mimic the mild inflammation that promotes human colon cancer, we treated mice with dextran sodium sulfate (DSS) overnight, which avoids excessive inflammation but induces mild inflammation that promotes colon carcinogenesis in the Apc Min/+ and the azoxymethane (AOM)-treated mice. Our results showed that FFAR2 deficiency promotes the development of colon adenoma in the Apc Min/+ /DSS mice and the progression of adenoma to adenocarcinoma in the AOM/DSS mice. FFAR2's downstream cAMP–PKA–CREB pathway was enhanced, leading to overexpression of histone deacetylases (HDACs) in the FFAR2-deficient mice. ChIP-qPCR analysis revealed differential binding of H3K27me3 and H3K4me3 histone marks onto the promoter regions of inflammation suppressors ( e.g ., sfrp1 , dkk3 , socs1 ), resulting in decreased expression of these genes in the FFAR2-deficient mice. Also, more neutrophils infiltrated into tumors and colon lamina propria of the FFAR2-deficient mice. Depletion of neutrophils blocked the progression of colon tumors. In addition, FFAR2 is required for butyrate to suppress HDAC expression and hypermethylation of inflammation suppressors. Therefore, our results suggest that FFAR2 is an epigenetic tumor suppressor that acts at multiple stages of colon carcinogenesis. This article is protected by copyright. All rights reserved.
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  • 44
    Publication Date: 2018-03-13
    Description: Resistance of solid tumors to chemo- and radiotherapy remains a major obstacle in anti-cancer treatment. Herein, the membrane protein Caveolin-1 (CAV1) came into focus as it is highly expressed in many tumors and high CAV1 levels were correlated with tumor progression, invasion and metastasis, and thus, a worse clinical outcome. Increasing evidence further indicates that the heterogeneous tumor microenvironment, also known as the tumor stroma, contributes to therapy resistance resulting in poor clinical outcome. Again, CAV1 seems to play an important role in modulating tumor host interactions by promoting tumor growth, metastasis, therapy resistance and cell survival. However, the mechanisms driving stroma-mediated tumor growth and radiation resistance remain to be clarified. Understanding these interactions and thus, targeting CAV1 may offer a novel strategy for preventing cancer therapy resistance and improving clinical outcomes. In this review, we will summarize the resistance-promoting effects of CAV1 in tumors, and emphasize its role in the tumor-stroma communication as well as the resulting malignant phenotype of epithelial tumors. This article is protected by copyright. All rights reserved.
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  • 45
    Publication Date: 2018-03-13
    Description: Recent evidence suggested a weak relationship between alcohol consumption and pancreatic cancer (PC) risk. In this study, the association between lifetime and baseline alcohol intakes and the risk of PC was evaluated, including the type of alcoholic beverages and potential interaction with smoking. Within the European Prospective Investigation into Cancer and Nutrition (EPIC) study, 1,283 incident PC (57% women) were diagnosed from 476,106 cancer-free participants, followed up for 14 years. Amounts of lifetime and baseline alcohol were estimated through lifestyle and dietary questionnaires, respectively. Cox proportional hazard models with age as primary time variable were used to estimate PC hazard ratios (HR) and their 95% confidence interval (CI). Alcohol intake was positively associated with PC risk in men. Associations were mainly driven by extreme alcohol levels, with HRs comparing heavy drinkers (〉60 g/day) to the reference category (0.1-4.9 g/day) equal to 1.77 (95% CI: 1.06, 2.95) and 1.63 (95% CI: 1.16, 2.29) for lifetime and baseline alcohol, respectively. Baseline alcohol intakes from beer (〉40 g/day) and spirits/liquors (〉10 g/day) showed HRs equal to 1.58 (95% CI: 1.07, 2.34) and 1.41 (95% CI: 1.03, 1.94), respectively, compared to the reference category (0.1-2.9 g/day). In women, HR estimates did not reach statistically significance. The alcohol and PC risk association was not modified by smoking status. Findings from a large prospective study suggest that baseline and lifetime alcohol intakes were positively associated with PC risk, with more apparent risk estimates for beer and spirits/liquors than wine intake. This article is protected by copyright. All rights reserved.
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  • 46
    Publication Date: 2018-03-13
    Description: HPV-16 and -18 account for about 80% of cervical cancers. We evaluated the performance of HPV-16/18 oncoprotein to predict precancer and cancer in corresponding tissue biopsy specimens. 1008 women attending cervical cancer screening program and 638 women referred to colposcopy with biopsy-confirmed cervical intraepithelial neoplasia grade 2 or worse (CIN2+) from 4 hospitals were recruited (1646 in total). All women were tested Onco E6 (AVC), Liquid Based Cytology (Hologic) and cobas HPV test (Roche). Colposcopy was performed on women with any abnormal results. The final diagnoses were based on a consensus panel review of the histology. There were 919 normal, 69 CIN1, 53 CIN2, 91 CIN3,474 squamous cell carcinoma(SCC) and 40 adenocarcinoma (ADC) cases, the prevalence of OncoE6 was 1.7%, 10.1%, 13.2%, 44.0%, 80.4% and 65.0%, respectively. The percent positive for cobas was higher than that of OncoE6 in detection of HPV16/18 in entire population (P〈0.001). However, the disparity of positive rate between these two tests became tiny among cervical cancer patients (CIN2: 26.4% vs. 13.2%, CIN3: 73.6% vs. 44.0%, SCC: 84.0% vs. 80.4%, ADC: 67.5% vs. 65.0%). OncoE6 was less sensitive than cobas (73.9% versus 93.6%, P〈0.001), but more specific (97.1% versus 75.4%, P〈0.001) for CIN3+ in entire population; OncoE6 yielded a sensitivity of 77.7% and a specificity of 91.0% for CIN3+ among cobas positive women, which can reduce nearly half of the colposcopy referral numbers. OncoE6 can be considered as a useful tool for cervical cancer screening and a potential powerful biomarker for HPV positive triage. This article is protected by copyright. All rights reserved.
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  • 47
    Publication Date: 2018-03-13
    Description: The association between diabetes and cancer risk remains controversial. Hence, we examined whether midlife diabetes is related to the risk of cancer in late-life, and whether genetic and early-life environmental factors play a role in this association. This study included 25,154 twin individuals born in 1958 or earlier from the Swedish Twin Registry. Information on cancer diagnosis in late life (aged ≥ 65) during 1998-2014, was derived from the National Patient and Cancer Registries. Diabetes was ascertained based on self- or informant-reported history, patient registry, and antidiabetic medication use. Midlife diabetes was defined when diabetes was diagnosed before 65 years. Data were analyzed following two strategies: 1) unmatched case-control analysis for all participants using generalized estimating equation (GEE) models, and 2) co-twin control analysis for cancer-discordant twin pairs using conditional logistic regression. Overall, 1,766 (7.0%) had midlife diabetes and 5293 (21.0%) had cancer in late-life. In multi-adjusted GEE models, the odds ratios (95% CIs) of diabetes were 10.55 (2.95-37.67) for pharynx cancer, 5.78 (1.72-19.40) for small intestine cancer, 2.37 (1.14-4.91) for liver cancer, and 0.48 (0.35-0.67) for prostate cancer. In people with diabetes, diabetes duration was dose-dependently associated with cancer risk. In conditional logistic regression analysis of 176 prostate cancer-discordant twin pairs, the association between midlife diabetes and prostate cancer in later life became stronger. Midlife diabetes increases the risk of pharynx, small intestine and liver cancers, but reduces prostate cancer risk in late life. Genetic and early-life environmental factors may partially contribute to the diabetes-prostate cancer association. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 48
    Publication Date: 2018-03-13
    Description: Few prospective cohort studies in the UK have specifically focused on the associations between commonly consumed dietary patterns and colorectal cancer (CRC). The aim of this study was to assess whether red meat, poultry, fish and vegetarian dietary patterns are associated with differences in the incidence of cancers of colon and rectum in the UKWCS. Four common dietary patterns were defined based on a hierarchy of consumption of red meat, poultry, and fish for each cohort participant, using a 217-item food frequency questionnaire. Cox proportional hazards regression was used to provide adjusted hazard ratios (HR) and 95% confidence intervals (CI) for CRC. A total of 32,147 women recruited and surveyed between 1995 and 1998 were followed up for a mean of 17.2 years (426,798 person-years). A total of 462 incident CRC cases were documented; 335 colon cancers (172 proximal and 119 distal) and 152 in the rectum. In multivariable-adjusted models, there was no evidence of a reduction in risk of overall CRC (HR=0.86, 95% CI: 0.66 to 1.12), colon cancer (HR=0.77, 95% CI: 0.56 to 1.05), or rectal cancer (HR=1.04, 95% CI: 0.66 to 1.63) when comparing grouped red meat free diets with diets containing red meat. Exploratory analysis suggested a reduced risk of distal colon cancer in grouped red meat free diets (HR=0.56, 95% CI: 0.34 to 0.95), though numbers with this outcome were small. These results indicate that a protective association of red meat free diets specifically on distal colon cancer merits confirmation in a larger study. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 49
    Publication Date: 2018-03-13
    Description: Intervertebral disc (IVD) degeneration (IDD) is a major contributor to low back pain. During IDD progression, ROS can be produced in the form of H 2 O 2 in nucleus pulposus cells (NPCs) in response to elevated cytokines, leading to subsequent alternations of cell fate and metabolic processes. Genetic factors are considered as main contributors to IDD pathopoiesis. Herein, we investigated the detailed function and mechanism of H19, one of the most up-regulated lncRNAs in IDD specimens, in H 2 O 2 -induced cell senescence model in NPCs. H19 could accelerate H 2 O 2 -induced degenerative changes by promoting cell senescence, increasing ADAMTS-5 and MMPs protein levels and Collagen I content, as well as suppressing NPC proliferation through activating Wnt/β-catenin signaling. Moreover, miR-22, a direct target of H19, could bind to the 3′UTR of LEF1 to inhibit its expression and reverse the effect of H19 on NPCs, thus inhibiting Wnt/β-catenin signaling. Taken together, H19 acts as a ceRNA to compete with LEF1 for miR-22, thus modulating downstream Wnt/β-catenin signaling in NPCs; H19/miR-22/LEF1 might be a novel target for improving H 2 O 2 -induced NPC senescence and treatment for IDD. In the present study, we demonstrated that H19 could promote H2O2-induced NPC cell senescence and ECM-degrading enzymes MMP2, 3, 9, and aggrecanase ADAMTS-5 protein levels through Wnt/β-catenin signaling pathway; miR-22 is a direct downstream target of H19; in the meantime, it can bind to the 3′UTR of LEF1, an essential transcriptional activator of Wnt/β-catenin signaling pathway, to inhibit its expression; H19 serves as a sponge of miR-22, and compete with LEF1 for miR-22 binding, thus attenuating the suppressive effect of miR-22 on Wnt/β-catenin signaling and H2O2-induced NPC cell senescence in NPCs.
    Electronic ISSN: 0091-7419
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 50
    Publication Date: 2018-03-13
    Description: Biomarkers for α-synuclein are needed for diagnosis and prognosis in Parkinson's disease (PD). Endogenous auto-antibodies to α-synuclein could serve as biomarkers for underlying synucleinopathy, but previous assessments of auto-antibodies have shown variability and inconsistent clinical correlations. We hypothesized that auto-antibodies to α-synuclein could be diagnostic for PD and explain its clinical heterogeneity. To test this hypothesis, we developed an enzyme-linked immunosorbent assay for measuring α-synuclein auto-antibodies in human samples. We evaluated 69 serum samples (16 healthy controls (HC) and 53 PD patients) and 145 CSF samples (52 HC and 93 PD patients) from our Institution. Both serum and CSF were available for 24 participants. Males had higher auto-antibody levels than females in both fluids. CSF auto-antibody levels were significantly higher in PD patients as compared to HC, whereas serum levels were not significantly different. CSF auto-antibody levels did not associate with amyloid-β 1-42 , total tau, or phosphorylated tau. CSF auto-antibody levels correlated with performance on the Montreal Cognitive Assessment, even when controlled for CSF amyloidβ 1-42 . CSF hemoglobin levels, as a proxy for contamination of CSF by blood during lumbar puncture, did not influence these observations. Using recombinant α-synuclein with N- and C-terminal truncations, we found that CSF auto-antibodies target amino acids 100 through 120 of α-synuclein. We conclude that endogenous CSF auto-antibodies are significantly higher in PD patients as compared to HC, suggesting that they could indicate the presence of underlying synucleinopathy. These auto-antibodies associate with poor cognition, independently of CSF amyloidβ 1-42 ., and target a select C-terminal region of α-synuclein. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
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  • 51
    Publication Date: 2018-03-13
    Description: Staphylococcus aureus , a bacterial, food-borne pathogen of humans, can contaminate raw fruits and vegetables. While physical and chemical methods are available to control S. aureus , scientists are searching for inhibitory phytochemicals from plants. One promising compound from pomegranate is punicalagin, a natural antibiotic. To get a broader understanding of the inhibitory effect of punicalagin on S. aureus growth, we used high-throughput mass spectrometry and quantitative isobaric labeling to investigate the proteome of S. aureus after exposure to a sub-lethal dose of punicalagin. Nearly half of the proteins encoded by the small genome were interrogated, and nearly half of those exhibited significant changes in accumulation. Punicalagin treatment altered the accumulation of proteins and enzymes needed for iron acquisition, and it altered amounts of enzymes for glycolysis, citric acid cycling, protein biosynthesis, and purine and pyrimidine biosynthesis. Punicalagin treatment also induced an SOS cellular response to damaged DNA. Transcriptional comparison of marker genes showed that the punicalagin-induced iron-starvation, and SOS responses resembled those produced by EDTA and ciprofloxacin. These results show that punicalagin adversely alters bacterial growth by disrupting iron homeostasis and that it induces SOS, possibly through DNA biosynthesis inhibition. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 52
    Publication Date: 2018-03-13
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 53
    Publication Date: 2018-03-14
    Description: Rosacea is a common facial skin disorder affecting middle-aged adults. Its aetiology is unknown and pathogenesis uncertain. Activation of the host innate immune response has been identified as important. The Demodex mite population in the skin of these patients is significantly higher than in subjects with normal skin suggesting they may be of etiological importance in this disorder. Little is known of the role of these mites in human skin and their potential to interact with the host immune system has not been elucidated. Live Demodex mites were extracted from normal facial skin of control subjects and used in cell stimulation experiments with the immortalised SZ95 sebocyte line. Time and mite dose dependent experiments were performed. Direct Demodex effects and the effects of medium in which Demodex had been cultured were evaluated on the TLR-signalling pathway on both a gene and protein expression level. Mites modulated TLR signalling events on both mRNA and protein levels in SZ95 sebocytes. An initial trend towards down modulation of genes in this pathway was observed. A subsequent switch to positive gene up-regulation was recorded after 48 hours of co-culture. Demodex secreted bioactive molecules that affected TLR2 receptor expression by sebocytes. High numbers of Demodex induced pro-inflammatory cytokine secretion whereas lower numbers did not. Demodex mites have the capacity to modulate the TLR signalling pathway of an immortalised human sebocyte line. Mites have the capacity to secrete bioactive molecules that affect the immune reactivity of sebocytes. Increasing mite numbers influenced IL8 secretion by these cells. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 54
    Publication Date: 2018-03-14
    Description: The treatment landscape for mantle cell lymphoma (MCL) has changed dramatically in recent years, with findings from clinical trials reporting improvements in survival. Data on the general patient population are, however, sparse; and it is unclear whether the effects observed in clinical trials have translated into the real-world setting. To investigate this, we examined first-line and relapsed/refractory (RR) disease management in 335 MCL patients diagnosed between 2004 and 2015 in an established population-based patient cohort, along with data on demographic, diagnostic and prognostic factors. Marked treatment and survival changes were observed; first-line rituximab immunotherapy, for example, increased from 32% to 86% over the 11-year period, and median survival increased from 2·0 years among those first treated in 2004–2011 to 3·5 years among those treated in 2012–2015. Outcomes for RR disease also improved, from 8 months in 2004–2011 to 16·8 months in 2012–2015, coinciding with the introduction of agents, such as bendamustine and ibrutinib. Encouragingly, improvements were seen across all ages; 1-year overall survival among patients over 70 years treated for RR disease almost doubled. Our analyses underscore the importance of monitoring the impact of treatment changes in the real-world setting.
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
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  • 55
  • 56
    Publication Date: 2018-03-14
    Description: Substantial data from preclinical studies have revealed the biphasic effects of statins on cardiovascular angiogenesis. Although some have reported the anti-angiogenic potential of statins in malignant tumors, however, the underlying mechanism remains poorly understood. The aim of this study is to elucidate the mechanism by which simvastatin, a member of the statin family, inhibits tumor angiogenesis. Simvastatin significantly suppressed tumor cells-conditioned medium (TCM)-induced angiogenic promotion in vitro, and resulted in a dose-dependent anti-angiogenesis in vivo. Further genetic silencing of HIF-1α reduced VEGF and FGF-2 expressions in 4T1 cells and correspondingly ameliorated HUVECs proliferation facilitated by TCM. Additionally, simvastatin induced angiogenic inhibition via a mechanism of post-transcriptional down-regulation of HIF-1α by increasing phosphorylation level of AMP kinase (AMPK). These results were further validated by the fact that AICAR reduced HIF-1α protein level and ameliorated the angiogenic ability of endothelial cells in vitro and in vivo. Critically, inhibition of AMPK phosphorylation by compound C almost completely abrogated simvastatin-induced anti-angiogenesis, which was accompanied by the reduction of protein levels of HIF-1α and its downstream pro-angiogenic factors. These findings demonstrate the mechanism in which simvastatin induces tumor anti-angiogenesis, and therefore identify the target that explains the beneficial effects of statins on malignant tumors. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 57
    Publication Date: 2018-03-14
    Description: The advent of facile genome engineering technologies has made the generation of knock-in gene-expression or fusion-protein reporters more tractable. Fluorescent protein labeling of specific genes combined with surface marker profiling can more specifically identify a cell population. However, the question of which fluorescent proteins to utilize to generate reporter constructs is made difficult by the number of candidate proteins and the lack of updated experimental data on newer fluorescent proteins. Compounding this problem, most fluorescent proteins are designed and tested for use in microscopy. To address this, we cloned and characterized the detection sensitivity, spectral overlap, and spillover spreading of 13 monomeric fluorescent proteins to determine utility in multicolor panels. We identified a group of five fluorescent proteins with high signal to noise ratio, minimal spectral overlap, and low spillover spreading making them compatible for multicolor experiments. Specifically, generating reporters with combinations of three of these proteins would allow efficient measurements even at low-level expression. Because the proteins are monomeric, they could function either as gene-expression or as fusion-protein reporters. Additionally, this approach can be generalized as new fluorescent proteins are developed to determine their usefulness in multicolor panels. © 2018 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 58
    Publication Date: 2018-03-14
    Description: Upon activation granulocytes upregulate several adhesion molecules (CD11b) and granule proteins (CD35, CD66b) and shed surface l -selectin (CD62L). These changes in expression, as assessed by flow cytometry, can be used as markers for activation. Whereas these markers are usually studied in fresh blood samples, a new method is required when samples are collected at a field site with no direct access to a flow cytometer. Therefore, we developed and tested a field-applicable method in which fixed leukocytes were cryopreserved. Using this method, the intensity of granulocyte activation markers was compared to samples that were either stained fresh, or fixed prior to staining but not cryopreserved. In addition, the response to an in vitro stimulation with fMLF was determined. While we observed differences in marker intensities when comparing fresh and fixed granulocytes, similar intensities were found between fixed cells that had been cryopreserved and fixed cells that did not undergo cryopreservation. Although fixation using FACS lysing solution might lead to membrane permeabilization, activation markers, and the responsiveness to fMLF or eotaxin could still be clearly measured. This method will, therefore, enable future studies of granulocyte activation in settings with limited resources and will allow simultaneous analysis of samples collected at different time points. © 2018 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 59
    Publication Date: 2018-03-14
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 60
    Publication Date: 2018-03-14
    Description: Ice Binding Proteins (IBPs) contribute to the survival of many living beings at sub-zero temperature by controlling the formation and growth of ice crystals. This work investigates the structural basis of the ice binding properties of Efc IBP, obtained from Antarctic bacteria. Efc IBP is endowed with a unique combination of thermal hysteresis (TH) and ice recrystallization inhibition (IRI) activity. The three-dimensional structure, solved at 0.84 Å resolution, shows that Efc IBP belongs to the IBP-1 fold family, and is organized in a right-handed β-solenoid with a triangular cross-section that forms three protein surfaces, named A, B and C faces. However, Efc IBP diverges from other IBP-1 fold proteins in relevant structural features including the lack of a “capping” region on top of the β-solenoid, and in the sequence and organization of the regions exposed to ice that, in Efc IBP, reveal the presence of threonine-rich ice-binding motifs. Docking experiments and site-directed mutagenesis pinpoint that Efc IBP binds ice crystals not only via its B face, as common to other IBPs, but also via ice binding sites on the C face. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 61
    Publication Date: 2018-03-14
    Description: Placental development is a complex and highly controlled process during which trophoblast stem cells differentiate to various trophoblast subtypes. The early embryonic death of systemic gene knockout models hampers the investigation of these genes that might play important roles during placentation. A trophoblast specific Cre mouse model would be of great help for dissecting out the potential roles of these genes during placental development. For this purpose, we generate a transgenic mouse with the Cre recombinase inserted into the endogenous locus of Elf5 gene that is expressed specifically in placental trophoblast cells. To analyze the specificity and efficiency of Cre recombinase activity in Elf5-Cre mice, we mated Elf5-Cre mice with Rosa26 mT/mG reporter mice, and found that Elf5-Cre transgene is expressed specifically in the trophoectoderm as early as embryonic day 4.5 (E4.5). By E12.5, the activity of Elf5-Cre transgene was detected exclusively in all derivatives of trophoblast lineages, including spongiotrophoblast, giant cells, and labyrinth trophoblasts. In addition, Elf5-Cre transgene was also active during spermatogenesis, from spermatids to mature sperms, which is consistent with the endogenous Elf5 expression in testis. Collectively, our results provide a unique tool to delete specific genes selectively and efficiently in trophoblast lineage during placentation. This article is protected by copyright. All rights reserved.
    Topics: Biology , Medicine
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  • 62
    Publication Date: 2018-03-14
    Description: ABSTRACT Alcohol liver disease (ALD) is one of the major chronic liver diseases worldwide, ranging from fatty liver, alcoholic hepatitis, cirrhosis, and potentially hepatocellular carcinoma. Epidemiological studies suggest a potential link between ALD and impaired circadian rhythms, but the role of hepatic circadian proteins in the pathogenesis of ALD remains unknown. Here we show that the circadian clock protein BMAL1 in hepatocytes is both necessary and sufficient to protect mice from alcohol liver disease. Ethanol diet-fed mice with liver-specific knockout ( Bmal1-LKO ) or depletion of Bmal1 develop more severe liver steatosis and injury as well as a simultaneous suppression of both de novo lipogenesis and fatty acid oxidation, which can be rescued by the supplementation of synthetic PPARα ligands. Restoring de novo lipogenesis in the liver of Bmal1-LKO mice by constitutively active AKT not only elevates hepatic fatty acid oxidation but also alleviates ethanol-induced fatty liver and liver injury. Furthermore, hepatic over-expression of lipogenic transcription factor ChREBP, but not SREBP-1c, in the liver of Bmal1-LKO mice also increases fatty acid oxidation and partially reduces ethanol-induced fatty liver and liver injury. Conclusion : we identified a novel protective role of BMAL1 in hepatocytes against ALD. The protective action of BMAL1 during alcohol consumption depends on its ability to couple ChREBP-induced de novo lipogenesis with PPARα-mediated fatty oxidation. This article is protected by copyright. All rights reserved.
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 63
    Publication Date: 2018-03-14
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 64
    Publication Date: 2018-03-14
    Description: Approximately 5-10% of individuals, who are vaccinated with a hepatitis B (HB) vaccine designed based on the HBV genotype C, fail to acquire protective levels of antibodies. Here, host genetic factors behind low immune response to this HB vaccine were investigated by a genome wide association study (GWAS) and HLA association tests. A GWAS and HLA association tests were carried out using a total of 1,193 Japanese individuals including 107 low responders, 351 intermediate responders, and 735 high responders. Classical HLA class II alleles were statistically imputed using the genome-wide SNP typing data. The GWAS identified independent associations of HLA-DRB1-DQB1 , HLA-DPB1 and BTNL2 genes with immune response to a HB vaccine designed based on the HBV genotype C. Five HLA-DRB1-DQB1 haplotypes and two DPB1 alleles showed significant associations with response to the HB vaccine in a comparison of three groups of 1,193 HB vaccinated individuals. When frequencies of DRB1-DQB1 haplotypes and DPB1 alleles were compared between low immune responders and HBV patients, significant associations were identified for three DRB1-DQB1 haplotypes, and no association was identified for any of the DPB1 alleles. In contrast, no association was identified for DRB1-DQB1 haplotypes and DPB1 alleles in a comparison between high immune responders and healthy individuals. The findings in this study clearly show the importance of HLA-DR-DQ (i.e. recognition of a vaccine related HB surface antigen (HBsAg) by specific DR-DQ haplotypes) and BTNL2 molecules (i.e. high immune response to HB vaccine) for response to a HB vaccine designed based on the HBV genotype C. This article is protected by copyright. All rights reserved.
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
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  • 65
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    Wiley-Blackwell
    Publication Date: 2018-03-14
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 66
    Publication Date: 2018-03-14
    Description: Human papillomavirus (HPV) is required but not sufficient for cervical carcinoma (CxCa). Estradiol (E 2 ) promotes CxCa development in K14E7 transgenic mice expressing the HPV16 E7 oncoprotein under the control of the keratin 14 (K14) promoter. E 2 mainly works through estrogen receptor α (ERα). However, the role of ERα in human CxCa has been underappreciated largely because it is not expressed in carcinoma cells. We have shown that deletion of Esr1 (the ERα-coding gene) in the cervical stroma of K14E7 mice promotes regression of cervical intraepithelial neoplasia (CIN), the precursor lesion of CxCa. Here, we deleted Esr1 in the cervical epithelium but not stroma. We found that E 2 induced cervical epithelial cell proliferation in epithelial ERα-deficient mice. We also found that E 2 promoted the development of CIN and CxCa in epithelial ERα-deficient K14E7 mice, and all neoplastic epithelial cells were negative for ERα. In addition, proliferation indices were similar between ERα – and ERα + CxCa. These results indicate that epithelial ERα is not necessary for E 2 -induced CIN and CxCa. Taken together, we conclude that stromal ERα, rather than epithelial ERα, mediates oncogenic E 2 signaling in CxCa. Our results support stromal ERα signaling as a therapeutic target for the disease.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
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  • 67
    Publication Date: 2018-03-14
    Description: In recent years, undifferentiated small round cell sarcoma (USRCS) have been divided into a variety of new, rare, sarcoma subtypes including the group of Ewing-like sarcoma that has the morphological appearance of Ewing sarcoma but carries CIC - DUX4 , BCOR - CCNB3 and other gene fusions different from the classical EWSR1-ETS . Using high-throughput RNA-seq analyses we identified a novel recurrent gene fusion, CRTC1-SS18 , in two cases of USRCS that lacked any known translocation. RNA-seq results were confirmed by RT-PCR, long-range PCR and FISH. In vitro , we show that the cells expressing the gene fusion were morphologically distinct and demonstrated enhanced oncogenic potential compared to control cells. Expression profile comparisons with tumours of other sarcoma subtypes demonstrated that both cases clustered close to EWSR1-CREB1 -positive tumours. Moreover, these analyses indicated an enhanced NTRK1 expression in CRTC1 - SS18 -positive tumours. We conclude that the novel gene fusion identified in this study adds a new subtype to the USRCS with unique gene signatures and maybe of therapeutic relevance.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
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  • 68
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    Wiley-Blackwell
    Publication Date: 2018-03-14
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 69
    Publication Date: 2018-03-14
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 70
    Publication Date: 2018-03-14
    Description: Environmental factors strongly influence the ecology and evolution of vector-borne infectious diseases. However, our understanding of the influence of climatic variation on host–parasite interactions in tropical systems is rudimentary. We studied five species of birds and their haemosporidian parasites ( Plasmodium and Haemoproteus ) at 16 sampling sites to understand how environmental heterogeneity influences patterns of parasite prevalence, distribution, and diversity across a marked gradient in water availability in northern South America. We used molecular methods to screen for parasite infections and to identify parasite lineages. To characterize spatial heterogeneity in water availability, we used weather-station and remotely sensed climate data. We estimated parasite prevalence while accounting for spatial autocorrelation, and used a model selection approach to determine the effect of variables related to water availability and host species on prevalence. The prevalence, distribution, and lineage diversity of haemosporidian parasites varied among localities and host species, but we found no support for the hypothesis that the prevalence and diversity of parasites increase with increasing water availability. Host species and host × climate interactions had stronger effects on infection prevalence, and parasite lineages were strongly associated with particular host species. Because climatic variables had little effect on the overall prevalence and lineage diversity of haemosporidian parasites across study sites, our results suggest that independent host–parasite dynamics may influence patterns in parasitism in environmentally heterogeneous landscapes. Our work focuses on the ecology and evolution of host–pathogen interactions in relation to environmental heterogeneity. We aimed to understand the role of water-related climatic variables on the prevalence, diversity, and distribution of avian malaria parasites in northern South America across a steep climatic gradient. We studied five codistributed bird species with contrasting ecologies and evolutionary histories. We took advantage of field methods in ecology and ornithology, molecular screening of parasites, and statistical methods to examine relationships between parasitic infections and climatic data derived from remote-sensed variables.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 71
    Publication Date: 2018-03-14
    Description: Purpose To characterize and suppress stripe artifact associated with velocity-selective (VS) magnetization for unenhanced MRA. Methods Extended phase graph formalism was used to show that the stripe artifact contains multiples of the fundamental frequency that is determined by the area of unipolar VS gradient. Four VS preparation pulses whose excitation profiles are spatially shifted by quarter the fundamental period of the stripes, were applied alternately. For further suppression of the artifact, k-space data at k z  = 0 were averaged over the 4 VS preparations. The proposed schemes were tested in a chicken breast phantom and healthy human subjects. Results When the standard VS preparation scheme was used, stripe artifact was shown in all the reconstructed images and appeared as artifactual peaks in k-space that corresponded to the first and second order harmonics of the fundamental frequency. Alternate application of the 4 phase-shifted VS preparation pulses suppressed the stripes, but not completely, as evidenced by residual erroneous peaks in k-space. After the k-space averaging, the stripe artifact was nearly eliminated. Conclusion Stripe artifact in VS-MRA consists of multiples of the fundamental frequency and can be effectively suppressed through alternate application of phase-shifted VS preparations along with k-space averaging.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 72
  • 73
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    Wiley-Blackwell
    Publication Date: 2018-03-15
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 74
    Publication Date: 2018-03-15
    Description: Nanosheet HZSM-5 film vertically grown on the substrate with the tailorable macro- and meso-pores between the layers of nanosheets is hydrothermally synthesized by seed-assisted secondary growth method. The as-prepared nanosheet HZSM-5 film exhibits reaction rate enhancement up to 312% in catalytic cracking of n -dodecane as well as twice light olefins selectivity, ascribed to the better mass transfer of reactants in the hierarchical porous structure and the ultra-thin b -axis pores of nanosheets. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 75
    Publication Date: 2018-03-15
    Description: A nickel (Ni) nanoparticle catalyst, supported on 4-channel α-Al 2 O 3 hollow fibers, was synthesized by atomic layer deposition (ALD). Highly-dispersed Ni nanoparticles were successfully deposited on the outside surfaces and the inside porous structures of hollow fibers. The catalyst was employed to catalyze the dry reforming of methane (DRM) reaction and showed a methane reforming rate of 2040 Lh −1 gNi −1 at 800°C. NiAl 2 O 4 spinel was formed when Ni nanoparticles were deposited on alpha-alumina substrates by ALD, which enhanced the Ni-support interaction. Different cycles (two, five, and ten) of Al 2 O 3 ALD films were applied on the Ni/hollow fiber catalysts to further improve the interaction between the Ni nanoparticles and the hollow fiber support. Both the catalyst activity and stability were improved with the deposition of Al 2 O 3 ALD films. Among the Al 2 O 3 ALD coated catalysts, the catalyst with five cycles of Al 2 O 3 ALD showed the best performance. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 76
    Publication Date: 2018-03-15
    Description: The turbulent flow of surfactant solution in the wide-rib rectangular grooved channels was studied by direct numerical simulation. Moreover, the variations of near-wall streamwise vortices with time were discussed and the distributions of streamwise vortex radius, swirling strength and density were quantitatively investigated. It was found that the influence of microgrooves on the fluid mainly occurred within the buffer layer and microgrooves could induce numerous streamwise vortices with small size and swirling strength within the grooved valleys. The drag-reducing enhancement mechanism of microgroove in the surfactant solution could be mainly considered as the competing results between the “restriction effect” and “tip effect” of microgroove, and the essential factor should be the numerous secondary streamwise vortices with small size and swirling strength within the grooved valleys. Furthermore, a predicted method for the optimal drag-reducing size of microgroove was proposed, and the prediction values agreed well with the numerical results. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 77
    Publication Date: 2018-03-15
    Description: BACKGROUND Although sexual dysfunction is common after hematopoietic stem cell transplantation (HCT), interventions to address sexual function are lacking. METHODS We conducted a pilot study to assess the feasibility and preliminary efficacy of a multimodal intervention to address sexual dysfunction in allogeneic HCT survivors. Transplant clinicians screened HCT survivors ≥3 months post-HCT for sexual dysfunction causing distress. Those who screened positive attended monthly visits with a trained transplant clinician who: 1) performed an assessment of the causes of sexual dysfunction; 2) educated and empowered the patient to address his or her sexual concerns; and 3) implemented therapeutic interventions targeting the patient's needs. Feasibility was defined as having approximately 75% of patients who screened positive agreeing to participate and 80% attending at least 2 intervention visits. We administered the Patient-Reported Outcomes Measurement Information System (PROMIS) sexual function and satisfaction measure, the Functional Assessment of Cancer Therapy–Bone Marrow Transplant (FACT-BMT), and the Hospital Anxiety and Depression Scale (HADS) to evaluate sexual function, quality of life (QOL), and mood, respectively, at baseline and 6 months postintervention. RESULTS Approximately 33.1% of patients (50 of 151 patients) screened positive for sexual dysfunction causing distress and 94.0% (47 of 50 patients) agreed to participate, with 100% attending 2 intervention visits. Participants reported improvements in satisfaction ( P 〈.0001) and interest in sex ( P 〈.0001), as well as orgasm ( P 〈.0001), erectile function ( P 〈.0001), vaginal lubrication ( P = .0001), and vaginal discomfort ( P = .0005). At baseline, approximately 32.6% of participants were not sexually active, compared with 6.5% after the intervention ( P = .0005). Participants reported improvement in their QOL ( P 〈.0001), depression ( P = .0002), and anxiety ( P = .0019). CONCLUSIONS A multimodal intervention to address sexual dysfunction integrated within the transplant clinic is feasible with encouraging preliminary efficacy for improving sexual function, QOL, and mood in HCT survivors. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell