Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
  • 1
    Publication Date: 2018-11-08
    Description: Cerebral cavernous malformation (CCM) is a common cerebrovascular disease that can occur sporadically or be inherited. They are major causes of stroke, cerebral hemorrhage, and neurological deficits in the younger population. Loss-of-function mutations in three genes, CCM1 , CCM2 , and CCM3 , have been identified as the cause of human CCMs. Currently, no drug is available to treat CCM disease. Hyperactive mitogen-activated protein kinase kinase Kinase 3 (MEKK3) kinase signaling as a consequence of loss of CCM genes is an underlying cause of CCM lesion development. Using a U.S. Food and Drug Administration–approved kinase inhibitor library combined with virtual modeling and biochemical and cellular assays, we have identified a clinically approved small compound, ponatinib, that is capable of inhibiting MEKK3 activity and normalizing expression of downstream kruppel-like factor (KLF) target genes. Treatment with this compound in neonatal mouse models of CCM can prevent the formation of new CCM lesions and reduce the growth of already formed lesions. At the ultracellular level, ponatinib can normalize the flattening and disorganization of the endothelium caused by CCM deficiency. Collectively, our study demonstrates ponatinib as a novel compound that may prevent CCM initiation and progression in mouse models through inhibition of MEKK3-KLF signaling.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2018-01-03
    Description: Hepatitis B virus (HBV) infection is a prevalent infectious disease with serious outcomes like chronic and acute hepatitis, cirrhosis, and hepatocellular carcinoma. However, the metabolic alteration by HBV is rarely taken into consideration. With the high prevalence of alcohol consumption and chronic HBV infection, their overlap is assumed to be an increasing latent hazard; although the extent has not been calculated. Moreover, the impact of chronic alcohol consumption combined with HBV on cholesterol metabolism is unknown. Six-week-old male FVB/Ncrl mice were hydrodynamically injected with a pGEM-4Z-1.3HBV vector and then fed an ethanol diet for 6 weeks. Serum biomarkers and liver histology, liver cholesterol levels, and cholesterol metabolism-related molecules were measured. In vitro assays with HBx, hepatitis B surface (HBs), or hepatitis B core (HBc) protein expression in HepG2 cells costimulated with ethanol were conducted to assess the cholesterol metabolism. HBV expression synergistically increased cholesterol deposition in the setting of alcoholic fatty liver. The increase of intrahepatic cholesterol was due to metabolic alteration in cholesterol metabolism, including increased cholesterol synthesis, decreased cholesterol degradation, and impaired cholesterol uptake. Overexpression of HBV component HBc, but not HBs or HBx, selectively promoted the hepatocellular cholesterol level.
    Print ISSN: 0022-2275
    Electronic ISSN: 1539-7262
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
    Keywords: POPULATION ; RISK ; MELANOMA ; BRCA1 MUTATION CARRIERS ; CONSORTIUM ; TUMOR SUBTYPES
    Abstract: Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci.
    Type of Publication: Journal article published
    PubMed ID: 22976474
    Signatur Availability
    BibTip Others were also interested in ...
  • 4
    Publication Date: 2018-05-31
    Description: Glioblastoma (GBM) is the most lethal primary brain tumor and is highly resistant to current treatments. GBM harbors glioma stem cells (GSCs) that not only initiate and maintain malignant growth but also promote therapeutic resistance including radioresistance. Thus, targeting GSCs is critical for overcoming the resistance to improve GBM treatment. Because the bone marrow and X-linked (BMX) nonreceptor tyrosine kinase is preferentially up-regulated in GSCs relative to nonstem tumor cells and the BMX-mediated activation of the signal transducer and activator of transcription 3 (STAT3) is required for maintaining GSC self-renewal and tumorigenic potential, pharmacological inhibition of BMX may suppress GBM growth and reduce therapeutic resistance. We demonstrate that BMX inhibition by ibrutinib potently disrupts GSCs, suppresses GBM malignant growth, and effectively combines with radiotherapy. Ibrutinib markedly disrupts the BMX-mediated STAT3 activation in GSCs but shows minimal effect on neural progenitor cells (NPCs) lacking BMX expression. Mechanistically, BMX bypasses the suppressor of cytokine signaling 3 (SOCS3)–mediated inhibition of Janus kinase 2 (JAK2), whereas NPCs dampen the JAK2-mediated STAT3 activation via the negative regulation by SOCS3, providing a molecular basis for targeting BMX by ibrutinib to specifically eliminate GSCs while preserving NPCs. Our preclinical data suggest that repurposing ibrutinib for targeting GSCs could effectively control GBM tumor growth both as monotherapy and as adjuvant with conventional therapies.
    Print ISSN: 1946-6234
    Electronic ISSN: 1946-6242
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Publication Date: 2018-06-28
    Description: A method developed based on the capillary effect and capillary condensation theory was used to synthesize an innovative Fe/C/Pd composite in this study. This composite (Fe@CNTs@Pd) consists of carbon nanotubes (CNTs) with nanoscale zerovalent iron (NZVI) on the inner surface and palladium nanoparticles supported on the outer surface of CNTs. This structure successfully addresses the problems of high iron corrosion rate and lower utilization rate of hydrogen in the application of bimetal nanoparticles for trichloroethylene (TCE) removal. TCE degradation experiments and electrochemical tests were conducted to investigate the material properties and reaction mechanisms of the composite. It is found that the prepared composite material contribute a high level of TCE dechlorination rate and substantially reduced hydrogen production during iron corrosion in water compared with the conventional CNTs-supported bimetal materials (Fe/Pd@CNTs). Hydrogen spillover effect helps the reactivity of Fe@CNTs@Pd for TCE degradation and suppressed the galvanic cell effect, which results in a stronger resistance to corrosion. Although the K obs of Fe@CNTs@Pd was 16.87% lower than that of Fe/Pd@CNTs, the hydrogen production rate of Fe@CNTs@Pd was 10 times slower than that of Fe/Pd@CNTs. Therefore, Fe@CNTs@Pd shows a significant reduction in the corrosion rate at a cost of slightly slower degradation of TCE. In sum, the prepared composites demonstrate important characteristics, including alleviating NZVI agglomeration, maintaining high TCE removal efficiency and reducing the corrosion of NZVI.
    Keywords: nanotechnology, environmental chemistry, environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Publication Date: 2018-07-03
    Description: Purpose: The third-generation EGFR tyrosine kinase inhibitor osimertinib is approved to treat patients with EGFR T790M-positive non–small cell lung cancer (NSCLC) who have developed resistance to earlier-generation drugs. Acquired EGFR C797S mutation has been reported to mediate osimertinib resistance in some patients. However, the remaining resistance mechanisms are largely unknown. Experimental Design: We performed mutation profiling using targeted next-generation sequencing (NGS) for 416 cancer-relevant genes on 93 osimertinib-resistant lung cancer patients' samples, mainly cell-free DNAs (cfDNAs), and matched pretreatment samples of 12 patients. In vitro experiments were conducted to functionally study the secondary EGFR mutations identified. Results: EGFR G796/C797, L792, and L718/G719 mutations were identified in 24.7%, 10.8%, and 9.7% of the cases, respectively, with certain mutations coexisting in one patient with different prevalence. L792 and L718 mutants markedly increased the half inhibitory concentration (IC 50 ) of osimertinib in vitro , among which the L718Q mutation conferred the greatest resistance to osimertinib, as well as gefitinib resistance when not coexisting with T790M. Further analysis of the 12 matched pretreatment samples confirmed that these EGFR mutations were acquired during osimertinib treatment. Alterations in parallel or downstream oncogenes such as MET, KRAS , and PIK3CA were also discovered, potentially contributing to the osimertinib-resistance in patients without EGFR secondary mutations. Conclusions: We present comprehensive mutation profiles of a large cohort of osimertinib-resistance lung cancer patients using mainly cfDNA. Besides C797 mutations, novel secondary mutations of EGFR L718 and L792 residues confer osimertinib resistance, both in vitro and in vivo , and are of great clinical and pharmaceutical relevance. Clin Cancer Res; 24(13); 3097–107. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Publication Date: 2018-07-06
    Description: The crystallization problem is an outstanding challenge in the chemistry of porous covalent organic frameworks (COFs). Their structural characterization has been limited to modeling and solutions based on powder x-ray or electron diffraction data. Single crystals of COFs amenable to x-ray diffraction characterization have not been reported. Here, we developed a general procedure to grow large single crystals of three-dimensional imine-based COFs (COF-300, hydrated form of COF-300, COF-303, LZU-79, and LZU-111). The high quality of the crystals allowed collection of single-crystal x-ray diffraction data of up to 0.83-angstrom resolution, leading to unambiguous solution and precise anisotropic refinement. Characteristics such as degree of interpenetration, arrangement of water guests, the reversed imine connectivity, linker disorder, and uncommon topology were deciphered with atomic precision—aspects impossible to determine without single crystals.
    Keywords: Chemistry, Materials Science
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Publication Date: 2018-03-14
    Description: Motivation As a highly heterogeneous disease, the progression of tumor is not only achieved by unlimited growth of the tumor cells, but also supported, stimulated, and nurtured by the microenvironment around it. However, traditional qualitative and/or semi-quantitative parameters obtained by pathologist’s visual examination have very limited capability to capture this interaction between tumor and its microenvironment. With the advent of digital pathology, computerized image analysis may provide a better tumor characterization and give new insights into this problem. Results We propose a novel bioimage informatics pipeline for automatically characterizing the topological organization of different cell patterns in the tumor microenvironment. We apply this pipeline to the only publicly available large histopathology image dataset for a cohort of 190 patients with papillary renal cell carcinoma obtained from The Cancer Genome Atlas project. Experimental results show that the proposed topological features can successfully stratify early- and middle-stage patients with distinct survival, and show superior performance to traditional clinical features and cellular morphological and intensity features. The proposed features not only provide new insights into the topological organizations of cancers, but also can be integrated with genomic data in future studies to develop new integrative biomarkers. Availability and implementation https://github.com/chengjun583/KIRP-topological-features Contact 1271992826@qq.com or kunhuang@iu.edu Supplementary information Supplementary dataSupplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Publication Date: 2018-03-14
    Description: Cresol is a prototype molecule in understanding intermolecular interactions in material and biological systems, because it offers different binding sites with various solvents and protonation states under different pH values. It is found that the UV/Vis absorption spectra of o -cresol in aromatic solvents (benzene, toluene) are characterized by a sharp peak, unlike the broad double-peaks in 11 non-aromatic solvents. Both molecular dynamics simulations and electronic structure calculations revealed the formation of intermolecular -complexation between o -cresol and aromatic solvents. The thermal movements of solvent and solute molecules render the conformations of o -cresol changing between trans and cis isomers. The -interaction makes the cis configuration a dominant isomer, hence leading to the single keen-edged UV/Vis absorption peak at approximately 283 nm. The free conformation changes between trans and cis in aqueous solution rationalize the broader absorption peaks in the range of 260–280 nm. The pH dependence of the UV/Vis absorption spectra in aqueous solutions is also rationalized by different protonation states of o -cresol. The explicit solvent model with long-ranged interactions is vital to describe the effects of -complexation and electrostatic interaction on the UV/Vis absorption spectra of o -cresol in toluene and alkaline aqueous (pH 〉 10.3) solutions, respectively.
    Keywords: computational chemistry
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Publication Date: 2018-05-03
    Description: A heterogeneous catalyst (ZnO/SFCCR) composed of ZnO supported on spent fluid cracking catalyst by wet impregnation was synthesized and applied to the esterification of colophony acids with methanol under subcritical CO 2 conditions. The catalyst was characterized by SEM-EDS, BET, ICP, FTIR, XRD and Py-IR. An experimental set-up involving a new injection technique was designed to promote the heterogeneous methyl esterification, and the subcritical CO 2 played a role in auxiliary acid catalysis (a pH range of 3.54–3.91), increasing the lifespan of ZnO/SFCCR, reducing the viscosity of the system to promote gas–liquid mass transfer. A maximum conversion rate of 97.01% was obtained in a relatively short time of 5 h. Kinetic experiments were performed from 190 to 220°C using a special high-temperature sampling device and analysing aliquots with high-performance liquid chromatography. A new reaction pathway, involving methyl abietate, methyl dehydroabietate, methyl neoabietate and methyl palustrate along with other kinds of colophony acids, was developed. The kinetic parameters were obtained using the Levenberg–Marquardt nonlinear least-squares method, and the activation energies for the isomerizations of neoabietic and palustric acids and for the methyl esterification of neoabietic, abietic, palustric and dehydroabietic acids were found to be 107.09, 113.95, 68.99, 49.85, 75.43 and 59.20 kJ mol –1 , respectively. The results from the kinetic model were in good agreement with experimental values.
    Keywords: synthetic chemistry, chemical engineering
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
    Signatur Availability
    BibTip Others were also interested in ...
Close ⊗
This website uses cookies and the analysis tool Matomo. More information can be found here...