To determine the expression of vascular endothelial growth factor-C (VEGF-C) in the synovial fluid of patients with rheumatoid arthritis (RA) and to investigate the regulation of VEGF-C production by ...major proinflammatory cytokines in fibroblast-like synoviocytes (FLS).
The concentrations of VEGF-C, tumor necrosis factor-alpha (TNF-alpha), and interleukin 1beta (IL-1beta) were measured using an ELISA method in synovial fluids obtained from 20 patients with RA and 20 with osteoarthritis (OA). Primary cultured RA FLS were stimulated with TNF-alpha or IL-1beta, and the expression levels of VEGF-C mRNA and protein were assessed by quantitative real-time polymerase chain reaction and ELISA.
Significantly higher levels of VEGF-C were found in RA synovial fluids compared to OA synovial fluids. VEGF-C levels showed a highly significant correlation with the levels of both TNF-alpha and IL-1beta in the synovial fluid of patients with RA. TNF-alpha stimulation significantly increased VEGF-C mRNA and protein expression in RA FLS in a dose-dependent manner. A tendency to increased expression of VEGF-C was also observed after IL-1beta stimulation in FLS.
Overexpression of VEGF-C in FLS by stimulation with TNF-alpha may play an important role in the progression of synovial inflammation and hyperplasia in RA by contributing to local lymphangiogenesis and angiogenesis.
Abstract Cytarabine arabinoside (ara-C) is the key agent for treating acute myeloid leukaemia (AML). Here, we genotyped 139 single nucleotide polymorphisms (SNPs) within the ara-C transport and ...metabolic pathway using the Illumina Golden Gate Assay in 97 patients with previously non-treated de novo AML other than M3. DCK rs4694362 (CC genotype) was a significant poor prognostic factor for overall survival (OS) (hazard ratio HR, 33.202 95% confidence interval (CI), 4.937–223.273, P < 0.0001, PBonferroni = 0.017). SLC29A1 rs3734703 (AA or AC genotype) in combination with TYMS rs2612100 (AA genotype) was significantly associated with shorter relapse free survival (RFS) (HR, 17.630 95% CI, 4.829–64.369, P < 0.0001, PBonferroni = 0.021). These SNPs showed moderate or large interethnic divergence in allele frequencies from African or Caucasian populations. The results of our study suggest that a single SNP and SNP–SNP interactions may help to predict the drug response and provide a guide in developing individualised chemotherapy for AML patients receiving ara-C based chemotherapy.
Survivin belongs to the family of inhibitor of apoptosis proteins and plays an important role in the hyperplastic growth of tissues and tumors. In this study, we assessed the expression of survivin ...in rheumatoid synovial fluids (SF) and synovial tissues (ST) of rheumatoid arthritis (RA) patients in order to investigate the role of extracellular survivin in the pathogenesis of RA. The survivin level from SF was significantly higher in RA patients (
n
= 38) than in osteoarthritis patients (
n
= 18; 10.68 ± 2.76 vs. 1.0 ± 0.56 pg/ml,
p
= 0.02). In addition, SF survivin level was higher in erosive RA patients (
n
= 23) than in non-erosive RA patients (
n
= 15; 15.26 ± 4.26 vs. 4.47 ± 1.12 pg/ml,
p
= 0.05). SF survivin level in RA was positively correlated with disease activity score 28, but did not reach statistical significance (
r
= 0.309,
p
= 0.07). RA SF survivin level was also positively correlated with peripheral blood leukocyte counts (
r
= 0.443,
p
= 0.005). The immunohistochemical staining and Western blot analysis revealed survivin expression in the ST and fibroblast-like synoviocytes of RA patients, respectively. These findings suggest that extracellular survivin may be produced from rheumatoid FLS and may play an important role in the destructive RA process.
This article presents the efficient mixed model analysis, often called global–local approach, to obtain interlaminar stresses at free edges in the laminated composite system under extension and ...flexure. For the proposed analysis, first, the discrete-layer elements are adopted as three-dimensional elements in the local region. Second, the equivalent single-layer elements are considered as two-dimensional elements in the global region. Finally, the mixed-dimensional transition elements are formulated to connect two different element types used in the global as well as the local regions, respectively. All the elements have higher order shape functions derived from the Lobatto shape function. Modes of the elements are classified into nodal and nodeless modes. The nodal modes have physical meaning, while nodeless modes with respect to the increase of order of the Lobatto shape function do not have physical meaning but improve accuracy of analysis. Therefore, fixing mesh arrangement of present analysis, the quality of the analysis can be enhanced without remeshing work. Some results obtained by the proposed approach are verified with comparison with published references. Also, efficiency of the mixed model analysis using the mixed-dimensional transition element is shown through comparison with numerical results obtained by the single model analysis using only discrete-layer elements.
Bortezomib has been known as the most promising anti-cancer drug for multiple myeloma (MM). However, recent studies reported that not all MM patients respond to bortezomib. To overcome such a ...stumbling-block, studies are needed to clarify the mechanisms of bortezomib resistance. In this study, we established a bortezomib-resistant cell line (U266/velR), and explored its biological characteristics. The U266/velR showed reduced sensitivity to bortezomib, and also showed crossresistance to the chemically unrelated drug thalidomide. U266/velR cells had a higher proportion of CD138 negative subpopulation, known as stem-like feature, compared to parental U266 cells. U266/velR showed relatively less inhibitory effect of prosurvival NF-κB signaling by bortezomib. Further analysis of RNA microarray identified genes related to ubiquitination that were differentially regulated in U266/velR. Moreover, the expression level of CD52 in U266 cells was associated with bortezomib response. Our findings provide the basis for developing therapeutic strategies in bortezomib-resistant relapsed and refractory MM patients.
Animals with a targeted disruption of genes can be produced by somatic cell nuclear transfer (SCNT). However, difficulties in clonal selection of somatic cells with a targeted mutation often result ...in heterogeneous nuclear donor cells, including gene-targeted and non-targeted cells, and impose a risk of producing undesired wildtype cloned animals after SCNT. In addition, the efficiency of cloning by SCNT has remained extremely low. Most cloned embryos die in utero, and the few that develop to term show a high incidence of postnatal death and abnormalities. In the present study, resurrection of an alpha-1,3-galactosyltransferase (αGT) gene-targeted miniature pig by recloning using postmortem ear skin fibroblasts was attempted. Three cloned piglets were produced from the first round of SCNT, including one stillborn and two who died immediately after birth due to respiratory distress syndrome and cardiac dysfunction. Among the three piglets, two were confirmed to be αGT gene-targeted. Fibroblasts derived from postmortem ear skin biopsies were used as nuclear donor cells for the second round of SCNT, and a piglet was produced. As expected, PCR and Southern analyses confirmed that the piglet produced from recloning was αGT gene-targeted. Currently, the piglet is fourteen months of age, and no overt health problems have been observed. Results from the present study demonstrate that loss of an invaluable animal, such as a gene-targeted miniature pig, may be rescued by recloning, with assurance of the desired genetic modification.
In this paper the p-convergent global–local model based on layerwise theory is presented to predict the complicated patterns of stress fields around a circular hole of composite laminates under ...tension. A distinction of this model is to combine two-dimensional elements with three-dimensional elements in a designed mesh. In the local region with high stress gradient, three-dimensional displacement fields can be defined by layer-by-layer representation, while equivalent single-layer elements are adopted in the global region with smooth stress gradient. Also, the p-refinement in local as well as global regions is simultaneously implemented using Lobatto shape functions. Higher-order shape functions for three-dimensional elements are derived by the combination of one- and two-dimensional shape functions in a layerwise sense. In this study the orders of the shape functions are kept to be fixed as p-level (in-plane direction)=8 and q-level (thickness direction)=5 from the convergence test of in-plane and transverse stresses. The proposed model achieves compatibility displacements and stress equilibrium at the junction or interface between the different element types. Also, exact mapping of curved boundary is undertaken using blending functions. Numerical examples of curved free-edge problems have been taken into account to illustrate the performance of the present approach. Numerical results show that the proposed model is capable of predicting in-plane stresses around a circular hole as well as interlaminar stresses at the interface between layers.
► We formulate the refined p-convergent global–local model for composite laminates with a circular hole. ► Lobatto shape functions with the orthogonality are considered. ► Exact mapping of curved boundary is undertaken using blending functions. ► Convergence characteristics of the present model are investigated in the curved free-edge problems. ► We not only show accuracy of the present model, but also simple-modeling approach.
Background/Aims: Risk prediction models using a deep neural network (DNN) have not been reported to predict the risk of advanced colorectal neoplasia (ACRN). The aim of this study was to compare DNN ...models with simple clinical score models to predict the risk of ACRN in colorectal cancer screening.
Methods: Databases of screening colonoscopy from Kangbuk Samsung Hospital (n=121,794) and Kyung Hee University Hospital at Gangdong (n=3,728) were used to develop DNN-based prediction models. Two DNN models, the Asian-Pacific Colorectal Screening (APCS) model and the Korean Colorectal Screening (KCS) model, were developed and compared with two simple score models using logistic regression methods to predict the risk of ACRN. The areas under the receiver operating characteristic curves (AUCs) of the models were compared in internal and external validation databases.
Results: In the internal validation set, the AUCs of DNN model 1 and the APCS score model were 0.713 and 0.662 (p<0.001), respectively, and the AUCs of DNN model 2 and the KCS score model were 0.730 and 0.667 (p< 0.001), respectively. However, in the external validation set, the prediction performances were not significantly different between the two DNN models and the corresponding APCS and KCS score models (both p >0.1).
Conclusions: Simple score models for the risk prediction of ACRN are as useful as DNN-based models when input variables are limited. However, further studies on this issue are warranted to predict the risk of ACRN in colorectal cancer screening because DNN-based models are currently under improvement. (Gut Liver 2021;15:85-91)
This study aimed to identify the feasibility of the maximum standardized uptake value (SUVmax) on baseline 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) as a ...predictive factor for prognosis in early stage primary lung cancer treated with stereotactic body radiotherapy (SBRT).
Twenty-seven T1-3N0M0 primary lung cancer patients treated with curative SBRT between 2010 and 2018 were retrospectively evaluated. Four patients (14.8%) treated with SBRT to address residual tumor after wedge resection and one patient (3.7%) with local recurrence after resection were included. The SUVmax at baseline PET/CT was assessed to determine its relationship with prognosis after SBRT. Patients were divided into two groups based on maximum SUVmax on pre-treatment FDG PET/CT, estimated by receiver operating characteristic curve.
The median follow-up period was 17.7 months (range, 2.3 to 60.0 months). The actuarial 2-year local control, progressionfree survival (PFS), and overall survival were 80.4%, 66.0%, and 78.2%, respectively. With regard to failure patterns, 5 patients exhibited local failure (in-field failure, 18.5%), 1 (3.7%) experienced regional nodal relapse, and other 2 (7.4%) developed distant failure. SUVmax was significantly correlated with progression (p = 0.08, optimal cut-off point SUVmax > 5.1). PFS was significantly influenced by pretreatment SUVmax (SUVmax > 5.1 vs. SUVmax ≤ 5.1; p = 0.012) and T stage (T1 vs. T2-3; p = 0.012).
SUVmax at pre-treatment FDG PET/CT demonstrated a predictive value for PFS after SBRT for lung cancer.
Epigenetic modification influences reprogramming and subsequent development of somatic cell nuclear transfer (SCNT) embryos. Such modification includes an increase in histone acetylation. Histone ...deacetylase inhibitors (HDACi), such as trichostatin A (TSA) and valproic acid (VPA), have been known to maintain a high cellular level of histone acetylation. Hence, treatment of nuclear transfer embryos with HDACi may increase the efficiency of cloning. The present study attempted direct comparison of TSA and VPA with regard to the potency of enhancement of in vitro development in porcine SCNT embryos. Reconstructed oocytes using fetal fibroblasts were cultured in PZM-3 containing no HDACi (control), 5 mM VPA, or 50 nM TSA for 24 h, and another 5 d thereafter without HDACi. The frequency of blastocyst formation was significantly higher (P < 0.05) in embryos treated with VPA than the frequencies with TSA and without HDACi (125/306, 40.8% vs. 94/313, 30.2% vs. 80/329, 23.4%). In addition, VPA treatment significantly increased (P < 0.05) the number of inner cell mass (ICM) cells compared with the control (15.6 ± 1.7 vs. 10.8 ± 2.6), whereas no differences were observed between the TSA treatment and control groups (12.9 ± 3.0 vs. 10.8 ± 2.6). The present study demonstrates that VPA enhances in vitro development of porcine SCNT embryos, particularly by an increase in blastocyst formation and in the number of ICM cells, suggesting that VPA may be more potent than TSA in supporting developmental competence of cloned embryos.
PDF
