Clinical and molecular spectra of BRAF-associated RASopathy.

Noonan syndrome (NS) and cardio-facio-cutaneous (CFC) syndrome are the most common subtypes of RASopathy. As an effector of Ras, BRAF is one of the molecules responsible for RASopathy. We investigated the phenotypic and genotypic features of 26 patients with BRAF-associated RASopathy. The clinical diagnoses were CFC (n = 21, 80.8%), NS (n = 3, 11.5%), NS/CFC (n = 1, 3.8%), and undefined syndromic intellectual disability (ID) (n = 1, 3.8%). The mostly shared phenotypes were ID (90.5%), cutaneous manifestations (84.6%), congenital heart defects (76.9%), short stature (76.9%), and dysmorphic features such as short neck (65.4%) and low-set ears (65.4%). Importantly, moderate to severe ID (57.1%) and epilepsy (26.9%) were noted. Eighteen different missense mutations were found, including a novel mutation, p.Phe498Tyr. p.Gln257Arg (n = 9, 34.6%) was the most common mutation, and the mutations were clustered in the cysteine-rich domain or protein kinase domain. A review of previously reported cases along with our findings revealed the existence of multiple sub-phenotypes of RASopathy within a single genotype, indicating that BRAF-associated RASopathy is not variant-specific. Our study further delineated the diverse and expanded clinical phenotypes of BRAF-associated RASopathy with their molecular genetic characteristics.

Flexible Transparent Electrode Characteristics of Graphene Oxide/Cysteamine/AgNP/AgNW Structure.

Graphene oxide (GO)-cysteamine-Ag nanoparticles (GCA)-silver nanowire (AgNW) fabricated by depositing GCA over sprayed AgNWs on PET films were proposed for transparent and flexible electrodes, and their optical, electrical, and mechanical properties were analyzed by energy-dispersive X-ray spectroscopy, Fourier-transform infrared spectroscopy, Raman spectroscopy, atomic force microscopy, scanning electron microscopy, transmission electron microscopy, current-voltage measurements, and bending test. GCA-AgNW electrodes show optical transmittance of >80% at 550 nm and exhibit a high figure-of-merit value of up to 116.13 in the samples with sheet resistances of 20-40 Ω/◻. It was observed that the detrimental oxidation of bare AgNWs over time was considerably decreased, and the mechanical robustness was improved. To apply the layer as an actual electrode in working devices, a Pt/GO/poly(3,4-ethylenedioxythiophene) polystyrene sulfonate/GCA-AgNW/polyethylene terephthalate structure was fabricated, and resistive switching memory was demonstrated. On the basis of these results, we confirm that the proposed GCA-AgNW layer can be used as transparent and flexible electrode.

Quantitative analysis of adsorption and desorption of volatile organic compounds on reusable zeolite filters using gas chromatography.

In this study, we propose a method to quantitatively analyze the concentration of VOCs adsorbed on zeolite filters via gas chromatography (GC). The sampled VOCs from the filters with ethanol as a solution were characterized using GC to determine the concentration of the adsorbed VOCs by comparing the areas of GC peaks of the detected VOCs and ethanol. The proposed method also enabled determination of the desorption (regeneration) conditions of the zeolite filters according to heating temperature and time for various VOCs. Repeated adsorption and desorption of VOCs on zeolite filters and GC analyses allow us to evaluate the durability and reusability of the filter and could help predict the lifetime of zeolite filters in practice.

Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consumption of a Methionine-rich diet.

BACKGROUND: Although alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). The aim of the current study was to predict changes in plasma methionine and homocysteine concentrations after simulated consumption of methionine-rich foods, following the development of a mathematical model for MMC in Zucker Diabetic Fatty (ZDF) rats, as a representative T2DM animal model. METHOD: The model building and simulation were performed using NONMEM® (ver. 7.3.0) assisted by Perl-Speaks-NONMEM (PsN, ver. 4.3.0). Model parameters were derived using first-order conditional estimation method with interactions permitted among the parameters (FOCE-INTER). NCA was conducted using Phoenix (ver. 6.4.0). For all tests, we considered a P-value < 0.05 to reflect statistical significance. RESULTS: Our model featured seven compartments that considered all parts of the cycle by applying non-linear mixed effects model. Conversion of S-adenosyl-L-homocysteine (SAH) to homocysteine increased and the metabolism of homocysteine was reduced under diabetic conditions, and consequently homocysteine accumulated in the elimination phase.Using our model, we performed simulations to compare the changes in plasma methionine and homocysteine concentrations between ZDF and normal rats, by multiple administrations of the methionine-rich diet of 1 mmol/kg, daily for 60 days. The levels of methionine and homocysteine were elevated approximately two- and three-fold, respectively, in ZDF rats, while there were no changes observed in the normal control rats. CONCLUSION: These results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods.

Clinical experience in ovarian squamous cell carcinoma arising from mature cystic teratoma: A rare entity.

OBJECTIVE: We sought to investigate the clinicopathologic features of ovarian squamous cell carcinomas arising from mature cystic teratomas (MCT) and to report our clinical experience and lessons learned. METHODS: From January 1993 to November 2012, a total of 6,260 women with ovarian MCT were surgically treated at Cheil General Hospital and Women's Healthcare Center. Among them, the cases with malignant transformation to squamous cell carcinoma were included in this analysis. Patient demographic characteristics, surgical findings, and prognosis were evaluated retrospectively. RESULTS: Of the 6,260 ovarian MCT patients, four (0.06%) had ovarian squamous cell carcinoma arising from MCT. The mean patient age was 43 years (range, 35-51 years), and the mean tumor size was 12 cm (range, 9-16 cm), with two patients in the International Federation of Gynecology and Obstetrics stage I and the other two in stage III. Upon preoperative imaging, all cases were expected to be benign ovarian tumors, but the preoperative squamous cell carcinoma antigen level was elevated from 1.5 ng/mL in stage Ia to 11.3 ng/mL in stage IIIc, suggesting malignancy, while the CA-125 level was normal in two of the three patients who received the test. Optimal debulking surgery was performed and adjuvant chemotherapy was used in all patients, but death from the recurrence of disease occurred in one patient, whose overall survival was 10 months. CONCLUSION: Ovarian squamous cell carcinoma arising from MCT is extremely rare, and it is rarely diagnosed preoperatively on imaging workups. Measuring the squamous cell carcinoma antigen level might be a useful diagnostic clue, and it might also be predictive of the tumor stage. An adequate staging surgery should be included in the standard treatment, but multicenter studies are needed to confirm this.

Phosphorylation of focal adhesion kinase at Tyrosine 407 negatively regulates Ras transformation of fibroblasts.

Focal adhesion kinase (FAK) mediates signal transduction in response to multiple extracellular inputs, via tyrosine phosphorylation at specific residues. We recently reported that FAK Tyr-407 phosphorylation negatively regulates the enzymatic and biological activities of FAK, unlike phosphorylation of other tyrosine residues. In this study, we further investigated the effect of FAK Tyr-407 phosphorylation on cell transformation. We found that FAK Tyr-407 phosphorylation was lower in H-Ras transformed NIH3T3 and K-Ras transformed rat-2 fibroblasts than in the respective untransformed control cells. Consistently, FAK Tyr-407 phosphorylation was decreased in parallel with cell transformation in H-Ras-inducible NIH3T3 cells and increased during trichostatin A-induced detransformation of both K-Ras transformed rat-2 fibroblasts and H-Ras transformed NIH3T3 cells. In addition, overexpression of a phosphorylation-mimicking FAK Tyr-407 mutant inhibited morphological transformation of H-Ras-inducible NIH3T3 cells and inhibited invasion activity and anchorage-independent growth of H-Ras-transformed NIH3T3 cells. Taken together, these data strongly suggest that FAK Tyr-407 phosphorylation negatively regulates transformation of fibroblasts.

Phosphorylation of focal adhesion kinase at tyrosine 861 is crucial for Ras transformation of fibroblasts.

Although elevated expression and increased tyrosine phosphorylation of focal adhesion kinase (FAK) are crucial for tumor progression, the mechanism by which FAK promotes oncogenic transformation is unclear. We have therefore determined the role of FAK phosphorylation at tyrosine 861 in the oncogenic transformation of NIH3T3 fibroblasts. FAK phosphorylation at tyrosine 861 was increased in both constitutively H-Ras-transformed and H-Ras-inducible NIH3T3 cells, in parallel with cell transformation. However, H-Ras-inducible cells transfected with the nonphosphorylatable mutant FAK Y861F showed decreased migration/invasion, focus forming activity and anchorage-independent growth, compared with either wild-type or kinase-defective FAK. In contrast to unaltered FAK/Src activity, the association of FAK and p130(CAS) was decreased in FAK Y861F-transfected cells, and FAK phosphorylation at tyrosine 861 enhanced this association in vitro. Consistently, FAK Y861F-transfected cells were defective in activation of c-Jun NH(2)-terminal kinase and in expression of matrix metalloproteinase-9 during transformation. Taken together, these results strongly suggest that FAK phosphorylation at tyrosine 861 is crucial for H-Ras-induced transformation through regulation of the association of FAK with p130(CAS).