LKB1 loss is a frequent homozygous deletion and/or gene mutation found in lung adenocarcinomas. However, few cases of LKB1 loss by either deletion or mutation are seen in Asian patients. Our ...preliminary data showed that LKB1 loss was associated with p53 mutation in lung tumors from Taiwanese adenocarcinoma patients and p53 transcription is directly regulated by NKX2-1. Therefore, we hypothesized that LKB1 loss could occur due to aberration of p53 regulation mediated by NKX2-1. In the present study, 16 lung adenocarcinoma cell lines were investigated to determine if LKB1 transcription could be deregulated by NKX2-1-mediated p53 aberration. Mechanistic studies indicated that LKB1 was directly upregulated by p53 and that NKX2-1-mediated p53 expression may positively regulate LKB1 expression in p53 wild-type cells. However, in p53-mutated cells, LKB1 transcription was deregulated by NKX2-1 via suppression of SP1 binding onto the LKB1 promoter. Therefore, the action of the NKX2-1/p53 pathway on LKB1 loss differed in p53 wild-type versus p53-mutated cells. As expected, soft-agar growth and invasion capability was significantly reduced by ectopic expression of NKX2-1 in p53 wild-type cells, but it was markedly elevated by silencing NKX2-1 in p53-mutated cells. Similar reciprocal observations were also seen in lung tumors from lung adenocarcinoma patients with either wild-type or mutated p53 tumors. Cox regression analysis showed that patients with low-LKB1 tumors had poorer overall survival (OS) and relapse-free survival (RFS) when compared with patients with high-LKB1 tumors. In p53 wild-type patients, shorter OS and RFS periods were predicted for low-NKX2-1/low-LKB1 tumors than for high-NKX2-1/high-LKB1 tumors. In patients with p53-mutated tumors, poorer OS and RFS were predicted for high-NKX2-1/low-LKB1 tumors than for low-NKX2-1/high-LKB1 tumors. In summary, losses of LKB1 at the transcriptional level by altered activity of the NKX2-1/p53 pathway may promote tumor malignancy and poor patient outcome.
MicroRNAs (miRNAs) are endogenous non-coding RNAs that are known to be involved in the pathogenesis of tumors. Gastric carcinoma (GC) is a common malignancy worldwide. The aim of this study was the ...identification of the expression signature and functional roles of aberrant miRNAs in GC. Initial screening established a profile of aberrantly expressed miRNAs in tumors. miR-370 was confirmed to be overexpressed in GC tissues. Higher expression of miR-370 in GC tissues was associated with more advanced nodal metastasis and a higher clinical stage compared with controls. In addition, significantly higher level of miR-370 was noted in the plasma of GC patients compared with controls. Patients having more invasive or advanced tumors also exhibited a higher plasma level of miR-370. In vitro assays indicated that exogenous miR-370 expression enhanced the oncogenic potential of GC cells. The AGS-GFPM2 cells with exogenous miR-370 expression also exhibited enhanced abdominal metastatic dissemination in nude mice. Reporter assays confirmed that miR-370 targeted predicted sites in 3'UTR of transforming growth factor-β receptor II (TGFβ-RII) gene. The exogenous miR-370 expression decreased TGFβ-RII expression and the phosphorylation of Smad3 elicited by TGFβ1. The TGFβ1-mediated repression in cell migration was reverted by exogenous miR-370 expression. A reverse correlation between miR-370 and TGFβ-RII expression was noted in GC tissues. This study concludes that miR-370 is a miRNA that is associated with GC progression by downregulating TGFβ-RII. The miRNA expression profile described in this study should contribute to future studies on the role of miRNAs in GC.
Previous studies on the relationship between corporate social responsibility (CSR) and firm value generally belong to one of the two opposing schools of thought: the social impact hypothesis and the ...shift of focus hypothesis. This study, however, proposes that the relationship between CSR and company value is non-linear and neither wholly positive nor negative. We employed the corporate social responsibility index (CRSI) to test this hypothesis. The panel smooth transition regression (PSTR) model was used to analyse listed Taiwanese firms from 2010 to 2012 and calculate the value transition threshold of CSR, using CSRI as the transition variable. We then applied PSTR to determine whether CSRI shows a two-regime, non-linear relationship, as inferred by our model. Empirical findings show that the threshold value of CSRI is 13.082, thus, we concluded that investment in CSR does not contribute to enhancing company value until it exceeds the value transition threshold.
Summary Background Itch is the cardinal symptom of atopic dermatitis (AD). β‐Endorphin, a neuropeptide, is increased in both AD skin and sera. Interleukin (IL)‐31, an itch‐relevant cytokine, ...activates IL‐31 receptors in keratinocytes. However, how IL‐31 and β‐endorphin interact in AD skin remains elusive.
Objectives To investigate the mechanistic interaction of IL‐31 and β‐endorphin in AD.
Methods This was a prospective cross‐sectional study. We recruited adult patients with AD and controls according to Hanifin’s AD criteria. Serum levels of IL‐31 and β‐endorphin were measured by enzyme‐linked immunosorbent assay. Expressions of IL‐31 receptor A (IL‐31RA) and β‐endorphin in the skin were assessed by immunohistochemistry. Their expression in the skin and blood was compared and correlated in patients with AD and in controls. We also treated primary keratinocytes with IL‐31 and measured calcium influx, β‐endorphin production and signalling pathways to define their mechanistic interactions.
Results β‐Endorphin was increased in the supernatant from IL‐31‐treated keratinocytes. IL‐31 receptor activation resulted in calcium influx and STAT3 activation; pretreatment with STAT3 inhibitor stopped the increase of β‐endorphin. Notably, either replacement of extracellular calcium or treatment with 2‐aminoethoxydiphenyl borate, an inhibitor for the store‐operated channel, blocked STAT3 activation. We found higher levels of blood β‐endorphin and IL‐31, which were significantly correlated, in patients with AD. Moreover, IL‐31RA and β‐endorphin were increased and colocalized both in AD human skin and TPA‐painted mouse skin.
Conclusions IL‐31 receptor activation in keratinocytes induces calcium influx and STAT3‐dependent production of β‐endorphin. These results might contribute to an understanding of the regulatory mechanisms underlying peripheral itch.
The mechanical properties and fracture characteristics of stainless steel clad plates by vacuum hot rolling at different rolling temperature of 1100°C (S1), 1200°C (S2) and 1300°C (S3) are ...investigated in detail. The carburized layer thickness and grain size is gradually increased with the increasing rolling temperature. The sufficient alloy element diffusion, recovery and recrystallization at the bonding temperature of 1300°C lead to the highest interfacial shear strength and the lowest longitudinal tensile strength among the three clad plates. However, the tensile ductility is increased with the increasing rolling temperature, which is attributed to the increased interfacial bonding strength. The strong interface can effectively delay the formation of interfacial delamination crack and premature localized necking, resulting into a prolong uniform plastic deformation stage with a low stress triaxiality. In addition, there are many intergranular tunnel cracks with the length of 50–150µm presented in the carburized layer due to Cr23C6 carbides on the grain boundary, which can effectively toughen the stainless steel clad plates.
Although 1H-nuclear magnetic resonance (NMR)-based lipid/metabolomics has been used to detect atherosclerosis, data regarding lipid/metabolomic signature in rheumatoid arthritis (RA)-related ...atherosclerosis are scarce. We aimed to identify the distinct lipid/metabolomic profiling and develop a prediction score model for RA patients with subclinical atherosclerosis (SA).
Serum levels of lipid metabolites were determined using 1H-NMR-based lipid/metabolomics in 65 RA patients and 12 healthy controls (HCs). The occurrence of SA was defined as the presence of carotid plaques revealed in ultrasound images.
Compared with HC, RA patients had significantly higher levels of phenylalanine and glycoprotein acetyls (GlycA) and lower levels of leucine and isoleucine. RA patients with SA had significantly higher levels of phenylalanine, creatinine, and glycolysis_total and lower levels of total lipid in HDL(HDL_L) than RA patients without SA. The Lasso logistic regression analysis revealed that age, creatinine, HDL_L, and glycolysis_total were significant predictors for the presence of SA. The prediction scoring algorithm was built as ( -0.657 + 0.011*Age + 0.004*Creatinine -0.120*HDL_L + 0.056*glycolysis-related measures), with AUC 0.90, sensitivity 83.3%, and specificity 87.2%. Serum phenylalanine levels were significantly decreased, and the levels of HDL_L and HDL_Particle were significantly increased in 20 RA patients, paralleling the decrease in disease activity score for 28-joints.
With 1H-NMR-based lipid/metabolomics, distinct profiling of lipid metabolites was identified between RA patients and HC or between RA patients with and without SA. We further developed a scoring model based on lipid/metabolomics profiling for predicting RA-associated SA.
Summary
The association between Parkinson’s disease and fracture was not completely understood. This nationwide study investigated increased risk of fracture in patients with Parkinson’s disease. In ...the nested cohort study, Parkinson’s disease was associated with pneumonia, septicemia, stroke, urinary tract infection, and mortality after fracture admission.
Introduction
Falls are a common complication in people with Parkinson’s disease (PD). This study evaluated fracture risk and post-fracture outcomes in patients with PD.
Methods
We identified 1,423 adults aged 40 years and older newly diagnosed with PD using the Taiwan National Health Insurance Research Database from 2000 to 2003. Comparison cohort consisted of 5,692 adults without PD randomly selected from the same dataset, frequency matched in age and sex. Followed-up events of fracture from January 1, 2000, until December 31, 2008, were ascertained from medical claims. Adjusted hazard ratios (HR) and 95 % confidence interval (CI) of fracture associated with PD were evaluated. Another nested cohort study of 397,766 hospitalized fracture patients analyzed for adjusted odds ratios (ORs) and 95 % CIs of adverse events after fracture among patients with and without PD between 2004 and 2010.
Results
The incidences of fracture for people with and without PD were 39.5 and 23.9 per 1,000 person-years, respectively (
p
< 0.0001). Compared with control, the adjusted HR of fracture was 2.25 (95 % CI 1.97–2.58) for PD patients. Previous PD was associated with risks of pneumonia (OR 1.44, 95 % CI 1.36–1.52), septicemia (OR 1.41, 95 % CI 1.33–1.49), stroke (OR 1.40, 95 % CI 1.32–1.50), urinary tract infection (OR 1.53, 95 % CI 1.46–1.61), and mortality (OR 1.25, 95 % CI 1.15–1.35) after fracture.
Conclusions
PD was associated with higher risk of fracture. Patients with PD had more complications and mortality after fracture. Fracture prevention and attention to post-fracture adverse events are needed for this susceptible population.
Conventional teacher-led instruction remains dominant in most elementary mathematics classrooms in Taiwan. Under such instruction, the teacher can rarely take care of all students. Many students may ...then continue to fall behind the standard of mathematics achievement and lose their interest in mathematics; they eventually give up on learning mathematics. In fact, students in Taiwan generally have lower interest in learning mathematics compared to many other regions/countries. Thus, how to enhance students’ mathematics achievement and interest are two major problems, especially for those low-achieving students. This paper describes how we designed a game-based learning environment, called
Math-Island
, by incorporating the mechanisms of a construction management game into the knowledge map of the elementary mathematics curriculum. We also report an experiment conducted with 215 elementary students for 2 years, from grade 2 to grade 3. In this experiment, in addition to teacher-led instruction in the classroom, students were directed to learn with Math-Island by using their own tablets at school and at home. As a result of this experiment, we found that there is an increase in students’ mathematics achievement, especially in the calculation and word problems. Moreover, the achievements of low-achieving students in the experimental school outperformed the low-achieving students in the control school (a control group in another school) in word problems. Moreover, both the low-achieving students and the high-achieving students in the experimental school maintained a rather high level of interest in mathematics and in the system.
Grape pomace (GP) is a polyphenolic-rich byproduct of wine production. As most polyphenolics are either bound to cellular matrices or present as free polymeric forms, treatment with hydrolytic ...enzymes may act to increase GP functionalities. The aim of this study was to examine the impact of tannase alone (T), pectinase plus cellulase (PC) or a mixture of them (TPC) on the hydrolysis of polyphenolics in red GP (RGP), white GP (WGP), and mixed GP (MGP) from Brazilian wine production, as well as antioxidant activity of the products. T was the most potent in increasing total polyphenols in GP by liberating gallic acid, caffeic acid, quercetin, and trans-resveratrol. PC increased the catechin content in RGP and TPC increased the procyanidin B2 in WGP. T treatment of GP was most effective in increasing antioxidant activity. In conclusion, the enzymatic treatment, particularly with T, increases the polyphenolic content and antioxidant activity of GP.
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•Enzymatic treatments increase total polyphenolics and antioxidant activity of grape pomace.•Tannase displays the largest hydrolytic efficacy.•Enzymes release phenolic acids and aglycones from grape pomace.•The increase in gallic acid and resveratrol highly correlates with the increase in antioxidant activity.
All hepatitis E virus (HEV) variants reported to infect humans belong to the species Orthohepevirus A (HEV-A). The zoonotic potential of the species Orthohepevirus C (HEV-C), which circulates in rats ...and is highly divergent from HEV-A, is unknown. We report a liver transplant recipient with hepatitis caused by HEV-C infection. We detected HEV-C RNA in multiple clinical samples and HEV-C antigen in the liver. The complete genome of the HEV-C isolate had 93.7% nt similarity to an HEV-C strain from Vietnam. The patient had preexisting HEV antibodies, which were not protective against HEV-C infection. Ribavirin was an effective treatment, resulting in resolution of hepatitis and clearance of HEV-C viremia. Testing for this zoonotic virus should be performed for immunocompromised and immunocompetent patients with unexplained hepatitis because routine hepatitis E diagnostic tests may miss HEV-C infection. HEV-C is also a potential threat to the blood product supply.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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