Activated T and B cells participate in the development and progression of Sjögren's syndrome (SS). Metformin, a first-line anti-diabetic drug, exerts anti-inflammatory and immunomodulatory effects by ...activating AMPK. We investigated the therapeutic effect of metformin in non-obese diabetic (NOD)/ShiLtJ mice, an animal model of SS.
Metformin or vehicle was administered orally to the mice for 9 weeks. The salivary flow rate was measured at 11, 13, 15, 17, and 20 weeks. Histological analysis of the salivary glands from vehicle- and metformin-treated mice was conducted. CD4
T and B cell differentiation in the peripheral blood and/or spleen was determined by flow cytometry. Serum total IgG, IgG1, and IgG2a levels were determined by enzyme-linked immunosorbent assay.
Metformin reduced salivary gland inflammation and restored the salivary flow rate. Moreover, metformin reduced the interleukin (IL)-6, tumor necrosis factor-α, IL-17 mRNA, and protein levels in the salivary glands. Metformin reduced the Th17 and Th1 cell populations and increased the regulatory T cell population in the peripheral blood and spleen and modulated the balance between Tfh and follicular regulatory T cells. In addition, metformin reduced B cell differentiation into germinal center B cells, decreased the serum immunoglobulin G level, and maintained the balance between IL-10- and IL-17-producing B cells.
Metformin suppresses effector T cells, induces regulatory T cells, and regulates B cell differentiation in an animal model of SS. In addition, metformin ameliorates salivary gland inflammation and hypofunction, suggesting that it has potential for the treatment of SS.
This paper presents a linear-mode optical sensor for the feasible applications of unmanned vehicle LiDAR systems, in which a pulsed-erbium fiber laser is exploited as a light source and a 16-channel ...transimpedance amplifier (TIA) array is utilized in an optical Rx module with low-cost InGaAs PIN photodiodes. In particular, a voltage-mode CMOS feedforward (VCF-TIA) is newly proposed to achieve twice higher transimpedance gain with lower noise and similar bandwidth characteristics than a conventional inverter TIA, thereby enabling longer detection. Test chips of the 16-channel VCF-TIA array realized in a standard 0.18-μm CMOS process demonstrate 76.3-dBΩ transimpedance gain, 6.3-pA/sqrt(Hz) average noise current spectral density, less than -33-dB crosstalk between channels, and 29.8-mW power dissipation per channel from a single 1.8-V supply. Automatic gain control is also equipped to extend input dynamic range for near-range detection. Hence, the proposed linear-mode optical sensor clearly detects the reflected optical pulses from the target of 5% reflection rate within the range of 0.5-25 m.
Hepatic resection is the most curative treatment option for early‐stage hepatocellular carcinoma, but is associated with a high recurrence rate, which exceeds 50% at 5 years after surgery. ...Understanding the genetic basis of hepatocellular carcinoma at surgically curable stages may enable the identification of new molecular biomarkers that accurately identify patients in need of additional early therapeutic interventions. Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early‐stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high‐copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodeling pathways. RB1 mutations were significantly associated with cancer‐specific and recurrence‐free survival after resection (multivariate P = 0.038 and P = 0.012, respectively). FGF19 amplifications, known to activate Wnt signaling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (P = 0.017). Conclusion: RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti‐FGF19 treatment in these patients. (Hepatology 2014;60:1971–1981)
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Lung cancer shows substantial genetic and phenotypic heterogeneity across individuals, driving a need for personalised medicine. Here, we report lung cancer organoids and normal bronchial organoids ...established from patient tissues comprising five histological subtypes of lung cancer and non-neoplastic bronchial mucosa as in vitro models representing individual patient. The lung cancer organoids recapitulate the tissue architecture of the primary lung tumours and maintain the genomic alterations of the original tumours during long-term expansion in vitro. The normal bronchial organoids maintain cellular components of normal bronchial mucosa. Lung cancer organoids respond to drugs based on their genomic alterations: a BRCA2-mutant organoid to olaparib, an EGFR-mutant organoid to erlotinib, and an EGFR-mutant/MET-amplified organoid to crizotinib. Considering the short length of time from organoid establishment to drug testing, our newly developed model may prove useful for predicting patient-specific drug responses through in vitro patient-specific drug trials.
The importance of flow boiling and condensing mini/micro-channel devices to a large number of modern applications has spurred an unusually large number of research efforts that culminated in many ...types of predictive tools. These efforts have inadvertently contributed enormous confusion when selecting a suitable predictive method. This study reviews methods for predicting heat transfer in condensing and boiling mini/micro-channel flows. Systematic assessment of predictive accuracy of individual methods requires the development of consolidated mini/micro-channel databases for condensation heat transfer, dryout incipience quality, and saturated boiling heat transfer. These databases cover numerous working fluids and broad ranges of geometrical and flow parameters. It is shown that, despite the success of previous predictive methods for specific fluids and narrow databases, these methods are incapable of providing accurate predictions against entire consolidated databases. The consolidated databases are used to develop 'universal' correlations with very broad application range. These include two separate correlations for condensation heat transfer, one for annular flow and the other for slug and bubbly flows. Also developed are correlations for dryout incipience quality and saturated boiling heat transfer; the later is shown to accurately tackle both nucleate boiling dominated and convective boiling dominated regimes up to the location of incipient dryout.
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•CSE decreased the proliferation of mouse lung fibroblasts, which is essential for the maintenance of extracellular matrix.•CSE caused an abnormal inflammatory response and ROS/RNS-mediated stress by ...an imbalance in the cellular antioxidant defense system (GSH recycling and SOD activity), leading to the apoptosis of lung parenchymal fibroblasts.•The apoptosis of lung fibroblasts, through the phosphorylation of STAT1 at Tyr701/Ser727 and the up-regulation of the MAPK pathway by CSE, contributes to the pathogenesis of COPD.
Cigarette smoking is the major aetiologic factor in chronic obstructive pulmonary disease (COPD). Lung fibroblasts are key participants in the maintenance of the extracellular matrix within the lung parenchyma. However, it still remains unknown how pulmonary fibroblasts are affected by cigarette smoking. Therefore, in this study, we isolated lung fibroblasts from mice and determined the apoptotic mechanism in response to cigarette smoke extract (CSE). When the lung fibroblasts were exposed to CSE, the generation of ROS was increased as shown by H2-DCFDA staining and Flow Cytometry. By immunocytochemistry, Ki67 expressing cells gradually decreased in a dose-dependent manner. The nitrite concentration in the supernatants increased, while the SOD activity and GSH recycling decreased in response to CSE. CSE increased the mRNA levels of TNF-α and COX-2, and the secretory proteins TNF-α and IL-6 increased as measured by ELISA. We next determined whether this inflammatory process is associated with the Bax/Bcl-2 apoptosis pathway. The Bax/Bcl-2 mRNA ratio increased, and cleaved caspase-3 protein was activated in the lung fibroblasts treated with CSE. Moreover, CSE induced the phosphorylation of STAT1 at Tyr701/Ser727 and increased the activation of ERK1/2, p38, and JNK in the MAPK pathway. Taken together, these data suggest that CSE-mediated inflammation alters the redox regulation via the MAPK-STAT1 pathway, leading to intrinsic apoptosis of lung fibroblasts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The recent advent of DNA sequencing technologies facilitates the use of genome sequencing data that provide means for more informative and precise classification and identification of members of the ...Bacteria and Archaea. Because the current species definition is based on the comparison of genome sequences between type and other strains in a given species, building a genome database with correct taxonomic information is of paramount need to enhance our efforts in exploring prokaryotic diversity and discovering novel species as well as for routine identifications. Here we introduce an integrated database, called EzBioCloud, that holds the taxonomic hierarchy of the Bacteria and Archaea, which is represented by quality-controlled 16S rRNA gene and genome sequences. Whole-genome assemblies in the NCBI Assembly Database were screened for low quality and subjected to a composite identification bioinformatics pipeline that employs gene-based searches followed by the calculation of average nucleotide identity. As a result, the database is made of 61 700 species/phylotypes, including 13 132 with validly published names, and 62 362 whole-genome assemblies that were identified taxonomically at the genus, species and subspecies levels. Genomic properties, such as genome size and DNA G+C content, and the occurrence in human microbiome data were calculated for each genus or higher taxa. This united database of taxonomy, 16S rRNA gene and genome sequences, with accompanying bioinformatics tools, should accelerate genome-based classification and identification of members of the Bacteria and Archaea. The database and related search tools are available at www.ezbiocloud.net/.
This second part of a two-part study examines the prediction of saturated flow boiling heat transfer in mini/micro-channels. The first part culminated in a technique for determining the dryout ...incipience quality corresponding to substantial deterioration in the heat transfer coefficient. In this part, a consolidated database for flow boiling in mini/micro-channels is amassed from 31 sources, of which 10,805 data points are designated as pre-dryout. The pre-dryout database consists of 18 working fluids, hydraulic diameters of 0.19–6.5mm, mass velocities of 19–1608kg/m2s, liquid-only Reynolds numbers of 57–49,820, qualities of 0–1, and reduced pressures of 0.005–0.69. The pre-dryout database is used to evaluate prior correlations that have been recommended for both macro-channels and mini/micro-channels. A few of these correlations are shown to provide fair overall performance, but their accuracy is compromised against specific portions of the database, especially high pressures and very small diameters. A new generalized correlation is constructed by superpositioning the contributions of nucleate boiling and convective boiling. This correlation is shown to provide very good predictions against the entire pre-dryout database, evidenced by an overall MAE of 20.3%, with 79.9% and 95.5% of the data falling within ±30% and ±50% error bands, respectively. Evenly good predictions are achieved for all working fluids and all ranges of the database parameters.
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Background
Accurate and rapid measurement of the MRI volume of meningiomas is essential in clinical practice to determine the growth rate of the tumor. Imperfect automation and disappointing ...performance for small meningiomas of previous automated volumetric tools limit their use in routine clinical practice.
Purpose
To develop and validate a computational model for fully automated meningioma segmentation and volume measurement on contrast‐enhanced MRI scans using deep learning.
Study Type
Retrospective.
Population
A total of 659 intracranial meningioma patients (median age, 59.0 years; interquartile range: 53.0–66.0 years) including 554 women and 105 men.
Field Strength/Sequence
The 1.0 T, 1.5 T, and 3.0 T; three‐dimensional, T1‐weighted gradient‐echo imaging with contrast enhancement.
Assessment
The tumors were manually segmented by two neurosurgeons, H.K. and C.‐K.P., with 10 and 26 years of clinical experience, respectively, for use as the ground truth. Deep learning models based on U‐Net and nnU‐Net were trained using 459 subjects and tested for 100 patients from a single institution (internal validation set IVS) and 100 patients from other 24 institutions (external validation set EVS), respectively. The performance of each model was evaluated with the Sørensen‐Dice similarity coefficient (DSC) compared with the ground truth.
Statistical Tests
According to the normality of the data distribution verified by the Shapiro–Wilk test, variables with three or more categories were compared by the Kruskal–Wallis test with Dunn's post hoc analysis.
Results
A two‐dimensional (2D) nnU‐Net showed the highest median DSCs of 0.922 and 0.893 for the IVS and EVS, respectively. The nnU‐Nets achieved superior performance in meningioma segmentation than the U‐Nets. The DSCs of the 2D nnU‐Net for small meningiomas less than 1 cm3 were 0.769 and 0.780 with the IVS and EVS, respectively.
Data Conclusion
A fully automated and accurate volumetric measurement tool for meningioma with clinically applicable performance for small meningioma using nnU‐Net was developed.
Evidence Level
3
Technical Efficacy
Stage 2
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Previous models and correlations for the prediction of pressure drop in adiabatic and condensing mini/micro-channel flows have been validated for only a few working fluids and relatively narrow ...ranges of relevant parameters. A universal predictive approach for these flows must be capable of tackling many fluids with drastically different thermophysical properties and very broad ranges of all geometrical and flow parameters of practical interest. To achieve this goal, a new consolidated database of 7115 frictional pressure gradient data points for both adiabatic and condensing mini/micro-channel flows is amassed from 36 sources. The database consists of 17 working fluids, hydraulic diameters from 0.0695 to 6.22mm, mass velocities from 4.0 to 8528kg/m2s, liquid-only Reynolds numbers from 3.9 to 89,798, flow qualities from 0 to 1, and reduced pressures from 0.0052 to 0.91. It is shown that, while a few prior models and correlations provide fair predictions of the consolidated database, their predictive accuracy is highly compromised for certain subsets of the database. A universal approach to predicting two-phase frictional pressure drop is proposed by incorporating appropriate dimensionless relations in a separated flow model to account for both small channel size and different combinations of liquid and vapor states. This approach is shown to provide excellent predictions of the entire consolidated database and fairly uniform accuracy against all parameters of the database. This approach is also capable of tackling single and multiple channels as well as situations involving significant flow deceleration due to condensation.
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