Summary Epidermal growth factor receptor ( EGFR ) and v-Ki-ras 2 (KRAS; viral Kirsten rat sacoma 2 oncogene homolog) oncogenes are predictors of response to EGFR -targeted therapy in lung carcinomas. ...Morphologic heterogeneity of lung carcinomas is reflected at the molecular level and may confound interpretation of immunohistochemistry, fluorescence in situ hybridization, and mutational assays, which are all used for analysis of KRAS and EGFR genes. Furthermore, molecular characteristics may differ between the primary tumor and corresponding metastases. The aim of this study was to determine if the KRAS and/or EGFR status of primary and metastatic lung carcinoma differs. Three hundred thirty-six cases of primary lung carcinomas were tested for EGFR and KRAS , and 85 cases had a metastasis (25%). Of the 40 cases (47%) with sufficient material for EGFR and KRAS mutational analysis, there were 11 (27.5%) primary tumors and 4 (10%) metastases identified with a KRAS mutation. Of the cases with EGFR fluorescence in situ hybridization results, there were 3 (8%) primary tumors and 8 (24%) metastases that were fluorescence in situ hybridization positive. Overall, there were 9 cases (22.5%) with discordant KRAS status and 11 cases (32.5%) with discordant EGFR fluorescence in situ hybridization status. Our results suggest that the EGFR and KRAS status of primary lung carcinomas may not predict the status in the corresponding metastases. This observation may have important implications for molecular testing for targeted therapies.
The quasar 3C 454.3 underwent a uniquely structured multifrequency outburst in 2016 June. The blazar was observed in the optical R-band by several ground-based telescopes in photometric and ...polarimetric modes, at γ-ray frequencies by the Fermi Large Area Telescope, and at 43 GHz with the Very Long Baseline Array. The maximum flux density was observed on 2016 June 24 at both optical and γ-ray frequencies, reaching mJy and ph cm−2 s−1, respectively. The 2016 June outburst possessed a precipitous decay at both γ-ray and optical frequencies, with the source decreasing in flux density by a factor of 4 over a 24 hr period in the R-band. Intraday variability was observed throughout the outburst, with flux density changes between 1 and 5 mJy over the course of a night. The precipitous decay featured statistically significant quasiperiodic microvariability oscillations with an amplitude of ∼2%-3% about the mean trend and a characteristic period of 36 minutes. The optical degree of polarization jumped from ∼3% to nearly 20% during the outburst, while the position angle varied by ∼120°. A knot was ejected from the 43 GHz core on 2016 February 25, moving at an apparent speed . From the observed minimum timescale of variability and derived Doppler factor δ = 22.6, we find the size of the emission region r 2.6 × 1015 cm. If the quasiperiodic microvariability oscillations are caused by periodic variations of the Doppler factor of emission from a turbulent vortex, we derive the rotational speed of the vortex to be ∼0.2c.
In the course of the study, nanocrystalline cobalt monoboride was prepared by thermal decomposition of precursors Co(DMF)
An, where An = B
H
(
),
-B
H
(
) or B
Cl
(
) in an argon atmosphere. ...Three new salt-like compounds
-
were prepared when Co(NO
)
was allowed to react with (Et
NH)
An. Compound
is new; the structures of compounds
and
have been previously reported. Samples
-
were annealed at 900 °C in argon to form samples
-
, which were characterized by single crystal XRD for
and powder XRD for
. Powder XRD on the products showed the formation of BN and CoB for
in a 1:1 ratio;
gave a higher CoB:BN ratio but an overall decreased crystallinity. For
, only CoB was found. IR spectra of samples
-
as well as X-ray spectral fluorescence analysis for 3a confirmed these results. The nanoparticular character of the decomposition products
-
was shown using TEM; quite small particle sizes of about 10-15 nm and a quite normal size distribution were found for
and
a, while the decomposition of
gave large particles with 200-350 nm and a broad distribution.
Display omitted
•COC film was functionalized by diazonium salts with quaternary ammonium moieties (QAS-DS) with different alkyl chain lengths (C4, C8, C9, C10, C12).•The optimal length of the alkyl ...chain was found C4 for improved antibiofouling towards BSA due to the formation of an additional hydration layer.•COC-C4 improves the stability for insulin storage compared to COC, glass, polypropylene.•Functionalization procedure conserves the high permeability resistance, transparency, and mechanical stiffness.•Developed functionalization procedure improve surface properties of COC for prefilled biomedical devices.
Prefilled biomedical devices (PFD) are growing in the pharmaceutical market due to the ease of delivering a precise dose of protein drugs. As an appealing alternative to the fragile glass, cyclic olefin copolymer (COC) was suggested. However, in the case of COC, the stability of the drug may be negatively impacted by protein aggregation. To potentially improve the surface properties of COC for PFDs, we performed functionalization of COC with quaternary ammonium moieties (QAS) using the advantages of diazonium surface chemistry. The successful functionalization of COC using QAS-diazonium salts (QAS-DS) with different alkyl chain lengths (C4, C8, C9, C10, C12) was confirmed by Raman spectroscopy and XPS measurements. Optical and fluorescence measurements revealed the optimal length of the alkyl chain-COC-C4 for improved antibiofouling performance towards bovine serum albumin (BSA). Moreover, in contrast to glass, polypropylene (PP), and pristine COC, COC-C4 allows storing the insulin for at least 2 weeks without the changes in protein structure according to dynamic light scattering and TEM images. Additionally, diazonium functionalization allows for conserving the high permeability resistance, transparency, and mechanical stiffness. The improved stability of insulin in a COC-C4 container is explained by the formation of an additional hydration layer serving as a barrier to undesired interaction with biomolecules.
Despite prognostic grading and staging systems, it is a challenge to predict outcomes for patients with pancreatic neuroendocrine tumors (PanNETs). Sequencing studies of PanNETs have identified ...alterations in death domain-associated protein (DAXX) and alpha-thalassemia/mental retardation X-linked chromatin remodeler (ATRX). In tumors, mutations in DAXX or ATRX and corresponding loss of protein expression correlate with shorter times of disease-free survival and disease-specific survival of patients. However, DAXX or ATRX proteins were lost in only 50% of distant metastases analyzed. We performed whole-exome sequencing analyses of 20 distant metastases from 20 patients with a single nonsyndrome, nonfunctional PanNET. We found distant metastases contained alterations in multiple endocrine neoplasia type 1 (MEN1) (n = 8), ATRX (n = 5), DAXX (n = 5), TSC2 (n = 3), and DEP domain containing 5 (DEPDC5) (n = 3). We found copy number loss of cyclin dependent kinase inhibitor 2A (CDKN2A) in 15 metastases (75%) and alterations in genes that regulate chromatin remodeling, including set domain containing 2 (SETD2) (n = 4), AT-rich interaction domain 1A (ARID1A) (n = 2), chromodomain helicase DNA binding protein 8 (CHD8) (n = 2), and DNA methyl transferase 1 (DNMT1) (n = 2). In a separate analysis of 347 primary PanNETs, we found loss or deletion of DAXX and ATRX, disruption of SETD2 function (based on loss of H3 lysine 36 trimethylation), loss of ARID1A expression or deletions in CDKN2A in 81% of primary PanNETs with distant metastases. Among patients with loss or deletion of at least 1 of these proteins or genes, 39% survived disease-free for 5 years and 44% had disease-specific survival times of 10 years. Among patients without any of these alterations, 98% survived disease-free for 5 years and 95% had disease-specific survival times of 10 years. Therefore, primary PanNETs with loss of DAXX, ATRX, H3 lysine 36 trimethylation, ARID1A, and/or CDKN2A associate with shorter survival times of patients. Our findings indicate that alterations in chromatin-remodeling genes and CDKN2A contribute to metastasis of PanNETs.
Mitochondrial translation is a unique relic of the symbiotic origin of the organelle. Alterations of its components cause a number of severe human diseases. Hereby we report a study of mice devoid of ...Mettl15 mitochondrial 12S rRNA methyltransferase, responsible for the formation of m
C839 residue (human numbering). Homozygous
mice appeared to be viable in contrast to other mitochondrial rRNA methyltransferase knockouts reported earlier. The phenotype of
mice is much milder than that of other mutants of mitochondrial translation apparatus. In agreement with the results obtained earlier for cell cultures with an inactivated
gene, we observed accumulation of the RbfA factor, normally associated with the precursor of the 28S subunit, in the 55S mitochondrial ribosome fraction of knockout mice. A lack of Mettl15 leads to a lower blood glucose level after physical exercise relative to that of the wild-type mice.
mice demonstrated suboptimal muscle performance and lower levels of Cox3 protein synthesized by mitoribosomes in the oxidative soleus muscles. Additionally, we detected decreased learning capabilities in the
knockout mice in the tests with both positive and negative reinforcement. Such properties make
knockout mice a suitable model for mild mitochondriopathies.
-Next-generation sequencing (NGS) is revolutionizing the discipline of laboratory medicine, with a deep and direct impact on patient care. Although it empowers clinical laboratories with ...unprecedented genomic sequencing capability, NGS has brought along obvious and obtrusive informatics challenges. Bioinformatics and clinical informatics are separate disciplines with typically a small degree of overlap, but they have been brought together by the enthusiastic adoption of NGS in clinical laboratories. The result has been a collaborative environment for the development of novel informatics solutions. Sustaining NGS-based testing in a regulated clinical environment requires institutional support to build and maintain a practical, robust, scalable, secure, and cost-effective informatics infrastructure.
-To discuss the novel NGS informatics challenges facing pathology laboratories today and offer solutions and future developments to address these obstacles.
-The published literature pertaining to NGS informatics was reviewed. The coauthors, experts in the fields of molecular pathology, precision medicine, and pathology informatics, also contributed their experiences.
-The boundary between bioinformatics and clinical informatics has significantly blurred with the introduction of NGS into clinical molecular laboratories. Next-generation sequencing technology and the data derived from these tests, if managed well in the clinical laboratory, will redefine the practice of medicine. In order to sustain this progress, adoption of smart computing technology will be essential. Computational pathologists will be expected to play a major role in rendering diagnostic and theranostic services by leveraging "Big Data" and modern computing tools.
A series of 88 conventional follicular and Hürthle cell thyroid tumors were analyzed for RAS mutations and PAX8-PPARγ rearrangements using molecular methods and for galectin-3 and HBME-1 expression ...by immunohistochemistry. A novel LightCycler technology-based method was developed to detect point mutations in codons 12/13 and 61 of the H-RAS, K-RAS, and N-RAS genes. Forty-nine percent of conventional follicular carcinomas had RAS mutations, 36% had PAX8-PPARγ rearrangement, and only one (3%) had both. In follicular adenomas, 48% had RAS mutations, 4% had PAX8-PPARγ rearrangement, and 48% had neither. Follicular carcinomas with PAX8-PPARγ typically showed immunoreactivity for galectin-3 but not for HBME-1, tended to present at a younger patient age and be smaller size, and were almost always overtly invasive. In contrast, follicular carcinomas with RAS mutations most often displayed an HBME-1-positive/galectin-3-negative immunophenotype and were either minimally or overtly invasive. Hürthle cell tumors infrequently had PAX8-PPARγ rearrangement or RAS mutations. These results suggest that conventional follicular thyroid carcinomas develop through at least two distinct and virtually nonoverlapping molecular pathways initiated by either RAS point mutation or PAX8-PPARγ rearrangement.
Reductive leaching of vanadium from spent vanadium catalysts for sulfuric acid production by sulfur dioxide, with the use of weakly acidic aqueous solutions of sulfurous acid, is studied. It is shown ...that the rate and completeness of vanadium leaching is related to the presence of admixtures of polyvalent metals. For catalyst with high iron content (1.5%) the effect of different parameters on the kinetic of vanadium dissolution was determined. The acquired data was analyzed for correspondence to the mathematical models for heterogeneous processes. The best description of the leaching process is given by the model which assumes the process limitation by diffusion of two reactants trough the insoluble layer of forming product. It was found that these reactants are hydrogen and vanadyl ions reaction orders for which are 0.48 and −0.7, respectively. Temperature increase has a significant effect on the leaching rate (activation energy is 49.24kJ∙mol−1). This value of activation energy can be explained by the change in permeability of the film of insoluble product with temperature increase, which improves diffusion rate of reactants.
•A mechanism of vanadium leaching by sulfur dioxide is proposed.•Process limits because of diffusion of two reagents through the layer of insoluble product.•Determined reaction orders with respect to hydrogen ion and vanadyl cation.•Activation energy of process is calculated.•Increase in temperature and acidity leads to growth of the degree of vanadium extraction.
Values of technological settlement caused by technological impacts during protective measures installation were obtained for existing buildings in the zone of deep excavation influence. Neglecting ...the technological part in settlement prediction of adjacent buildings can lead to their unserviceability. The technological settlement was determined by following methods: geodetic measurements of buildings settlements, numerical modelling and analogy method. The technological settlement was determined for 4 types of geological conditions that can be applied to geo conditions of Moscow and soft soils of St. Petersburg and Hanoi (Vietnam). The authors recommend values of technological settlement for the underpinning with micropiles, jet-grouting columns, the installation of a jet-grouting cut-off wall and changing a foundation type to a slab. A formula is given for the calculation of technological settlement along the building due to changes in a protection design. A satisfactory converge of predicted settlements of buildings in the influence zone of deep excavations considering technological part with geodetic measurements data was achieved for construction projects in Moscow and St. Petersburg. Obtained values of technological settlement made it possible to propose recommendations on choice of protection measures ensuring safety of adjacent buildings.
PDF
