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  • 1
    Publication Date: 2018-01-17
    Description: Purpose: Metabolic reprogramming is frequently identified in hepatocellular carcinoma (HCC), which is the most common type of liver malignancy. The reprogrammed cellular metabolisms promote tumor cell survival, proliferation, angiogenesis, and metastasis. However, the mechanisms of this process remain unclear in HCC. Experimental Design: The global nontargeted metabolic study in 69 paired hepatic carcinomas and adjacent tissue specimens was performed using capillary electrophoresis-time of flight mass spectrometry–based approach. Key findings were validated by targeted metabolomic approach. Biological studies were also performed to investigate the role of proline biosynthesis in HCC pathogenesis. Results: Proline metabolism was markedly changed in HCC tumor tissue, characterized with accelerated consumption of proline and accumulation of hydroxyproline, which significantly correlated with α-fetoprotein levels and poor prognosis in HCC. In addition, we found that hydroxyproline promoted hypoxia- and HIF-dependent phenotype in HCC. Moreover, we demonstrated that hypoxia activated proline biosynthesis via upregulation of ALDH18A1 , subsequently leading to accumulation of hydroxyproline via attenuated PRODH2 activity. More importantly, we showed that glutamine, proline, and hydroxyproline metabolic axis supported HCC cell survival through modulating HIF1α stability in response to hypoxia. Finally, inhibition of proline biosynthesis significantly enhanced cytotoxicity of sorafenib in vitro and in vivo . Conclusions: Our results demonstrate that hypoxic microenvironment activates proline metabolism, resulting in accumulation of hydroxyproline that promotes HCC tumor progression and sorafenib resistance through modulating HIF1α. These findings provide the proof of concept for targeting proline metabolism as a potential therapeutic strategy for HCC. Clin Cancer Res; 24(2); 474–85. ©2017 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Keywords: CANCER ; EXPRESSION ; COMBINATION ; LUNG ; MODEL ; MODELS ; TOXICITY ; CLASSIFICATION ; liver ; GENE ; GENE-EXPRESSION ; microarray ; validation ; QUALITY ; BREAST ; breast cancer ; BREAST-CANCER ; PERFORMANCE ; gene expression ; MICROARRAY DATA ; HUMANS ; microarrays ; PREDICTION ; PROJECT ; FOLLICULAR LYMPHOMA ; MULTIPLE-MYELOMA ; rodent ; neuroblastoma ; development ; methods ; GENE-EXPRESSION DATA ; DNA MICROARRAYS ; rodents ; RECOMMENDATIONS ; EXPRESSION DATA ; CONTROL MAQC PROJECT ; PUBLISHED MICROARRAY ; RISK-STRATIFICATION
    Abstract: Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, 〉30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis
    Type of Publication: Journal article published
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  • 3
    Publication Date: 2018-05-31
    Description: Nitric oxide (NO) may cause serious environmental problems, such as acid rain, haze weather, global warming and even death. Herein, a new low-cost, highly efficient and green method for the elimination of NO using zirconium nitride (ZrN) is reported for the first time, which does not produce any waste or any by-product. Relevant experimental parameters, such as reaction temperature and gas concentration, were investigated to explore the reaction mechanism. Interestingly, NO can be easily decomposed into nitrogen (N 2 ) by ZrN powders at 600°C with ZrN simultaneously transformed into zirconium dioxide (ZrO 2 ) gradually. The time for the complete conversion of NO into N 2 was approximately 14 h over 0.5 g of ZrN at a NO concentration of 500 ppm. This green elimination process of NO demonstrated good atom economy and practical significance in mitigating environmental problems.
    Keywords: inorganic chemistry, green chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 4
    Publication Date: 2018-04-05
    Description: CYP2C11 is involved in the metabolism of many drugs in rats. To assess the roles of CYP2C11 in physiology and drug metabolism, a CYP2C11 -null rat model was generated using the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 method. A 2-base pair insertion was added to exon 6 of CYP2C11 in Sprague-Dawley rats. CYP2C11 was not detected by western blotting in liver microsomes of CYP2C11 -null rats. No off-target effects were found at 11 predicted sites of the knockout model. The CYP2C11 -null rats were viable and had no obvious abnormalities, with the exception of reduced fertility. Puberty in CYP2C11 -null rats appeared to be delayed by ~20 days, and the average litter size fell by 43%. Tolbutamide was used as a probe in this drug metabolism study. In the liver microsomes of CYP2C11 -null rats, the V max and intrinsic clearance values decreased by 22% and 47%, respectively, compared with those of wild-type rats. The K m values increased by 47% compared with that of wild types. However, our pharmacokinetics study showed no major differences in any parameters between the two strains, in both males and females. In conclusion, a CYP2C11 -null rat model was successfully generated and is a valuable tool to study the in vivo function of CYP2C11.
    Print ISSN: 0090-9556
    Electronic ISSN: 1521-009X
    Topics: Chemistry and Pharmacology , Medicine
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  • 5
    Publication Date: 2018-04-24
    Description: Coccidiosis, caused by different species of Eimeria parasites, is an economically important disease of poultry and livestock worldwide. Here we report previously unknown alterations in the gut microbes and metabolism of BALB/c mice infected with Eimeria falciformis . Specifically, we observed a significant shift in the abundance of cecal bacteria and disrupted metabolism in parasitized animals. The relative abundances of Lachnospiraceae bacterium NK4A136, Ruminiclostridium , Alistipes , and Lactobacillus declined in response to E. falciformis infection, whereas Escherichia , Shigella , Helicobacter , Klebsiella , and Bacteroides were increased. Carbohydrate and amino acid metabolites in the serum samples of infected mice were significantly altered compared to naïve controls. Levels of amino acids, including asparagine, histidine, l -cysteine, tryptophan, lysine, glycine, serine, alanine, proline, ornithine, methionine, and valine, decreased on day 7 postinfection before returning to baseline on day 14. In addition, increased levels of indolelactate and mannitol and a reduced amount of oxalic acid indicated impaired carbon metabolism upon parasitic infection. These data demonstrate that intestinal coccidial infection perturbs the microbiota and disrupts carbon and nitrogen metabolism.
    Print ISSN: 0019-9567
    Electronic ISSN: 1098-5522
    Topics: Medicine
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  • 6
    Publication Date: 2018-05-17
    Description: The combustion of multi-hole pyrophoric activated metal is solid combustion and the combustion mechanism is quite complex, which is a difficult problem to be solved. Once the pyrophoric activated metal is exposed to air, the oxygen diffuses to the interior of the activated metal within plenty of holes and reacts with it, which enlarges the contact area with oxygen. Consequently, the whole combustion is vigorous and the temperature rises rapidly. To study the combustion mechanism of the chaff, the surface heat balance equation is established in this work by taking Mg as the activated metal. To solve this equation, the chaff adiabatic wall temperature distribution is computed by computational fluid dynamics in the presence of high-speed airflow. Then, the chaff surface temperature distribution is obtained by solving the heat balance equations. Finally, numerical and experimental results obtained via an infrared thermal imager are compared to demonstrate the effectiveness of the established equation.
    Keywords: thermodynamics, spectroscopy, chemical physics
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 7
    Publication Date: 2018-02-14
    Description: A CNOT gate between multiphoton qubits encoded in two cavities A CNOT gate between multiphoton qubits encoded in two cavities, Published online: 13 February 2018; doi:10.1038/s41467-018-03059-5 Quantum computing platforms allowing quantum error correction usually rely on complex redundant encoding within multiple two-level systems. Here, instead, the authors realize a CNOT gate between two qubits encoded in the multiphoton states of two microwave cavities nonlinearly coupled by a transmon.
    Electronic ISSN: 2041-1723
    Topics: Biology , Chemistry and Pharmacology , Natural Sciences in General , Physics
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  • 8
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2018-01-13
    Description: Organic thin-film transistors (OTFTs) can be fabricated at moderate temperatures and through cost-effective solution-based processes on a wide range of low-cost flexible and deformable substrates. Although the charge mobility of state-of-the-art OTFTs is superior to that of amorphous silicon and approaches that of amorphous oxide thin-film transistors (TFTs), their operational stability generally remains inferior and a point of concern for their commercial deployment. We report on an exhaustive characterization of OTFTs with an ultrathin bilayer gate dielectric comprising the amorphous fluoropolymer CYTOP and an Al 2 O 3 :HfO 2 nanolaminate. Threshold voltage shifts measured at room temperature over time periods up to 5.9 x 10 5 s do not vary monotonically and remain below 0.2 V in microcrystalline OTFTs (μc-OTFTs) with field-effect carrier mobility values up to 1.6 cm 2 V –1 s –1 . Modeling of these shifts as a function of time with a double stretched-exponential (DSE) function suggests that two compensating aging mechanisms are at play and responsible for this high stability. The measured threshold voltage shifts at temperatures up to 75°C represent at least a one-order-of-magnitude improvement in the operational stability over previous reports, bringing OTFT technologies to a performance level comparable to that reported in the scientific literature for other commercial TFTs technologies.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 9
    Publication Date: 2018-01-14
    Description: Background The short-term outcomes and prognostic factors of patients with spinal dural arteriovenous fistulas (SDAVFs) have not been defined in large cohorts. Objective To define the short-term clinical outcomes and prognostic factors in patients with SDAVFs. Methods A prospective cohort of 112 patients with SDAVFs were included consecutively in this study. The patients were serially evaluated with the modified Aminoff and Logue’s Scale (mALS) one day before surgery and at 3 months, 6 months and 12 months after treatment. Univariate and multivariate analyses were performed to identify demographic, clinical and procedural factors related to favourable outcome. Results A total of 94 patients (mean age 53.5 years, 78 were men) met the criteria and are included in the final analyses. Duration of symptom ranged from 0.5 to 66 months (average time period of 12.7 months). The location of SDAVFs was as follows: 31.6% above T7 level, 48.4% between T7 and T12 level (including T7 and T12) and 20.0% below T12 level. A total of 81 patients (86.2%) underwent neurosurgical treatment, 10 patients (10.6%) underwent endovascular treatment, and 3 patients (3.2%) underwent neurosurgical treatment after unsuccessful embolisation. A total of 78 patients demonstrated an improvement in mALS score of one point or greater at 12 months. Preoperative mALS score was associated with clinical improvement after adjusting for age, gender, duration of symptoms, location of fistula and treatment modality using unconditional logistic regression analysis (p〈0.05). Conclusion Approximately four fifths of the patients experienced clinical improvement at 12 months and preoperative mALS was the strongest predictor of clinical improvement in the cohort.
    Keywords: Open access, Research methods
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 10
    Publication Date: 2018-02-22
    Description: Patients with low-immunogenic tumors respond poorly to immune checkpoint blockade (ICB) targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. Conversely, patients responding to ICB can experience various side effects. We have thus engineered a therapeutic scaffold that, when formed in situ, allows the local release of gemcitabine (GEM) and an anti–PD-L1 blocking antibody (aPDL1) with distinct release kinetics. The scaffold consists of reactive oxygen species (ROS)–degradable hydrogel that releases therapeutics in a programmed manner within the tumor microenvironment (TME), which contains abundant ROS. We found that the aPDL1-GEM scaffold elicits an immunogenic tumor phenotype and promotes an immune-mediated tumor regression in the tumor-bearing mice, with prevention of tumor recurrence after primary resection.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
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