Could the EQ-5D-3L predict all-cause mortality in older Chinese? Evidence from a 5-year longitudinal study in eastern China.

PURPOSE: To assess the ability of the 3-level EQ-5D (i.e., EQ-5D-3L) in predicting all-cause mortality in older Chinese adults. METHODS: The data were from a 5-year longitudinal study, Weitang Geriatric Diseases Study, including 4579 community-dwelling older people in eastern China, with the mean age of 72.5 years at baseline and female being 52.0%. Three multivariable logistic regression models were adopted to assess the associations of the baseline EQ-5D data [i.e., the EQ-5D problems, EQ-5D-3L index score, and EQ-5D visual analog scale (VAS) score] with the 5-year all-cause mortality, adjusting for socio-demographic characteristics, and subsequently, health conditions and lifestyle habits. RESULTS: A total of 183 participants died over the 5-year study period. A larger proportion of the dead reported problems in physical dimensions (i.e., including three dimensions: mobility, self-care, and usual activities, p < 0.05 for all). The mean EQ-5D index score (0.928) and EQ-VAS score (79.7) of the living were higher than those of the dead (0.915 and 73.2, p < 0.05 for both). In multivariable logistic analyses, the EQ-5D health problems in the physical-related dimensions [odds ratio (OR) 2.16, p < 0.05] and the EQ-VAS score (OR: 0.97, p < 0.001) were associated with the 5-year all-cause mortality when adjusting for socio-demographic characteristics, health conditions, and lifestyle habits. CONCLUSIONS: It appears that the EQ-5D-3L could predict mortality in general older Chinese, which could be used to detect high-risk older individuals in China.

Identification of a 3,3-difluorinated tetrahydropyridinol compound as a novel antitumor agent for hepatocellular carcinoma acting via cell cycle arrest through disturbing CDK7-mediated phosphorylation of Cdc2.

Tetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21.25 and 29.07 µM, respectively). We also found that this compound mediated cell cycle arrest in the G0/G1 phase at 30-40 µM. Western blot analysis demonstrated that the cell cycle arrest induced by this compound in HepG2 and HMCCLM3 cells was associated with a significant decrease in Cdc2 and cyclin B1, which led to the accumulation of the phosphorylated-Tyr15 (inactive) form of Cdc2 and low expression of M phase-promoting factor (cyclin B1/Cdc2). Moreover, cells treated with this compound exhibited decreased expression of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H). This compound also induced cell apoptosis via activation of caspase-3. A xenograft model in nude mice demonstrated anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the anticancer effect of this compound was partially due to G0/G1 cell cycle arrest via inhibition of CDK7-mediated expression of Cdc2, and this compound may be a promising anticancer candidate for further investigation.

How the EQ-5D utilities are derived matters in Chinese diabetes patients: a comparison based on different EQ-5D scoring functions for China.

OBJECTIVES: In China, multiple approaches to calculating EQ-5D utilities are available, including the two EQ-5D-3L (3L2014 and 3L2018) scoring functions, the EQ-5D-5L (5L) scoring function, and the crosswalk function linking the 3L utilities and 5L health states. The study compared utilities derived from them in terms of agreement and discriminative power; and assessed whether the use of different approaches may affect QALY estimation in Chinese type 2 diabetes (T2D) patients. METHODS: Cross-sectional data of 289 T2D patients who self-completed both the 5L and 3L questions were used. Agreement were examined using intraclass correlation coefficient (ICC) and Bland-Altman plots. The ability of the EQ-5D utilities in differentiating the patients with and without clinical conditions was evaluated using F-statistics. Their influence on QALY estimation was assessed adopting mean absolute difference (MAD) in utility values between the patients. RESULTS: The ICC values were 0.881 (3L2014-3L2018), 0.958 (5L-c5L2014), and 0.806 (5L-c5L2018). The two 3L utilities and the three 5L utilities had poor agreement at the lower end of utility scale according to Bland-Altman plots. The 3L2018 utilities had lower F-statistics compared to the 3L2014 utilities; the two c5L utilities had larger or similar F-statistics compared to the 5L utilities. The mean MADs were 0.138 (5L), 0.116 (3L2014), 0.115 (c5L2014), 0.055 (c5L2018), and 0.055 (3L2018). CONCLUSION: The 3L2014 utilities is more discriminative than the 3L2018 utilities; and the two c5L utilities have no worse discriminative power compared with the 5L utilities. The choice of the approach to calculating the EQ-5D utilities is likely to affect QALY estimates.

STAT3 rs4796793 contributes to lung cancer risk and clinical outcomes of platinum-based chemotherapy.

BACKGROUND: Signal transducer and activator of transcription (STAT) 3 plays a vital role in carcinogenesis and drug response. Platinum-based chemotherapy is the first-line treatment for lung cancer patients, especially those in advanced stages. In the present study, we investigated the association of STAT3 polymorphism rs4796793 with lung cancer susceptibility, platinum-based chemotherapy response, and toxicity. METHODS: A total of 498 lung cancer patients and 213 healthy controls were enrolled in the study. 467 of them received at least 2-cycle platinum-based chemotherapy. Unconditional logistical regression analysis was used to assess the associations. RESULTS: STAT3 rs4769793 G allele carriers had an increased susceptibility of lung cancer [additive model: adjusted OR (95% CI) 1.376 (1.058-1.789), P = 0.017; recessive model: adjusted OR (95% CI) 1.734 (1.007-2.985), P = 0.047]. Rs4769793 was not significantly associated with platinum-based chemotherapy response in lung cancer patients. STAT3 rs4796793 was associated with an increased risk of severe overall toxicity [additive model: adjusted OR (95% CI) 1.410 (1.076-1.850), P = 0.013; dominant model: adjusted OR (95% CI) 1.638 (1.091-2.459), P = 0.017], especially hematological toxicity [additive model: adjusted OR (95% CI) 1.352 (1.001-1.826), P = 0.049]. CONCLUSIONS: STAT3 rs4796793 may be considered as a potential candidate biomarker for the prediction of susceptibility and prognosis in Chinese lung cancer patients. However, well-designed studies with larger sample sizes are required to verify the results.

Resistin facilitates metastasis of lung adenocarcinoma through the TLR4/Src/EGFR/PI3K/NF-κB pathway.

Metastasis is the main cause of lung cancer-related death. The tumor microenvironment greatly contributes to tumor metastasis. Resistin, mainly secreted by tumor-associated macrophages in tumor tissues, is a 12.5-kDa cysteine-rich secretory protein that is found at significantly higher levels in the serum or plasma of cancer patients compared with healthy controls. In this study, we explored the expression and role of resistin in lung adenocarcinoma. Our study showed that resistin was strongly expressed in lung adenocarcinoma tissues and promoted the migration and invasion of lung adenocarcinoma cells in a dose-dependent manner. Toll-like receptor 4 (TLR4) was the functional receptor of resistin for migration and invasion in A549 cells. Src/epidermal growth factor receptor (EGFR) was involved in resistin-induced migration and invasion. Resistin increased the phosphorylation of EGFR through the TLR4/Src pathway. We also found that PI3K/nuclear factor (NF)-κB were the intracellular downstream effectors mediating resistin-induced migration and invasion. Taken together, our results suggested that resistin promoted lung adenocarcinoma metastasis through the TLR4/Src/EGFR/PI3K/NF-κB pathway.

Molecular characteristics of rhesus macaque interferon-lambda receptor 1 (mmuIFNLR1): Sequence identity, distribution and alteration after simian-human immunodeficiency virus infection in the skin and buccal mucosa.

Interferon-lambda receptor 1 (IFNLR1) is the key to interferon-lambda's biological activities. Rhesus macaques (Macaca mulatta) are supposedly more suitable for translational studies on interferon lambda-associated human diseases, yet little is known about their IFNLR1 (mmuIFNLR1). In this study, we cloned the coding sequence of mmuIFNLR1, examined its variants, and determined the distribution of mmuIFNLR1 mRNA and immunoreactivity in the buccal mucosa and arm skin of normal and immunodeficiency virus (SHIV/SIV) infected rhesus macaques. It was found that mmuIFNLR1 has 93.1% amino acid sequence identity to that of humans; all the amino acid residues of mmuIFNLR1 signal peptide, transmembrane region, PxxLxF motif and those essential for ligand binding are identical to that of humans; 6 variants of mmuIFNLR1, including the ones corresponding to that of humans were detected; IFNLR1 immunoreactivity was localized in primarily the epithelia of buccal mucosa and arm skin; SHIV/SIV infection could affect the levels of mmuIFNLR1 mRNA and immunoreactivity. These data expanded our knowledge on mmuIFNLR1 and provided a scientific basis for rational use of rhesus macaques in studies of IFN-λ associated human diseases like AIDS. Future studies testing IFNLR1-targeting therapeutics in rhesus macaques were warranted.

Flower colour and essential oil compositions, antibacterial activities in Lagerstroemia indica L.

Compositions of volatile oil from Lagerstroemia indica L. were reported for the first time. Out of 114 components where 58, 63, 67 and 61 compounds were identified from the white, pink, mauve, carmine flower with yields of 0.92%, 1.15%, 1.12% and 1.08%, respectively. Main compounds of white flower were 2-methyl-cyclopentanone (9.41%), m-xylene (7.53%) while the pink, carmine flower contained octacosane (19.81% and 13.91%) and heneicosane (18.02% and 7.98%), respectively, and mauve flower contained cyclohexanone (8.13%), 1-octacosanol (7.87%). Only 23 components were common in four oils, representing 16.57-32.72% of the total oils. Composition classification of four oils included mainly alkanes, benzenes, ketones with 52.98-73.03% of the total oils. The results revealed the different characteristics in quality of these oils. The pink, mauve, carmine flower oils were found active against S. aureus and A. niger, P. aeruginosa and S. aureus, E. coli and B. subtilis with MIC value of 0.078 mg/mL.

Physical Stability, Oxidative Stability, and Bioactivity of Nanoemulsion Delivery Systems Incorporating Lipophilic Ingredients: Impact of Oil Saturation Degree.

There is great interest in the application of a lipid-based delivery system (like nanoemulsion) to improve the bioavailability of lipophilic components. Although emulsion characteristics are believed to be influenced by oil types, there is still a lack of systematic research concentrating on the effect of oil saturation degree on the nanoemulsion quality, especially for evaluation of the bioactivity. Here, we aimed to test the effect of oil saturation degree on the physical stability, oxidative stability, and bioactivity of the designed nanoemulision system. Our findings suggest that the oxidative stability and bioactivity of a nanoemulsion incorporating tocopherol and sesamol highly depend on the oil saturation. A nanoemulsion with an oil with a high degree of unsaturation was more susceptible to oxidation, and addition of tocopherol and sesamol could retard the lipid oxidation. Sesamol exhibited better bioactivity during the experiment compared with tocopherol in the Caenorhabditis elegans (C. elegans) model. The lipid-lowering effect of tocopherol and sesamol increased with lower saturation oil groups. The antioxidant activity of tocopherol and sesamol was higher in the high saturation oil groups. Overall, the obtained data is meaningful for applications using the designed systems to deliver lipophilic ingredients.

Ginnalin A from Kujin tea (Acer tataricum subsp. ginnala) exhibits a colorectal cancer chemoprevention effect via activation of the Nrf2/HO-1 signaling pathway.

Ginnalin A (also known as acertannin) is one of the most important phenolic compounds of several beverage Acer plants. In this study, it is reported for the first time that ginnalin A is an activator of the Nrf2 signaling pathway in human colon cancer cells. Ginnalin A, isolated from the leaves of Acer tataricum subsp. ginnala, exhibited promising preventive activity against colon cancer cells (HCT116, SW480 and SW620) with IC50 values of 24.8 µM, 22.0 µM and 39.7 µM, respectively. In addition, it significantly reduced the colony formation of these cells. Flow cytometry analysis indicated that ginnalin A suppressed cancer proliferation via the induction of cell cycle arrest at the S-phase. Real time PCR analysis demonstrated that ginnalin A can upregulate the mRNA expression levels of Nrf2-related antioxidant genes Nrf2, HO-1 and NQO1. Western blotting analysis revealed that ginnalin A promoted the Nrf2 nuclear translocation and upregulated the proteins Nrf2, HO-1 and NQO1. Moreover, the upregulation of p62 and the inhibition of Keap1 were also found by Western blotting analysis. Therefore, the activation of the Nrf2 signaling pathway was probably induced through the upregulation of p62 and the inhibition of Keap1.

Analysis of Differential Expressions of Long Non-coding RNAs in Nasopharyngeal Carcinoma Using Next-generation Deep Sequencing.

Background: Little knowledge about long non-coding RNAs(lncRNAs) in nasopharyngeal carcinoma (NPC) has been acquired. Methods: Next-generation sequencing was applied in 7 cases of NPC tissues and 7 cases of normal tissues in nasopharynx. PLEX, CNCI and CPAT soft-wares were used to predict novel lncRNAs. Real-time Quantitative PCR (qPCR) further validated the data in 20 cases of NPC tissues and 14 cases of normal tissues. Then the cis-regulators and trans-regulators and potential biological functions together with pathways were predicted by Bioinformatics. Results: Totally, 4248 novel lncRNAs were found to be expressed in our samples. And 2192 lncRNAs and 23342 mRNAs were considered to be differentially expressed in NPC. Among the results, 306 lncRNAs and 4599 mRNAs were significantly up-regulated, whereas 204 lncRNAs and 2059 mRNAs were significantly down-regulated, respectively. Moreover, 62 lncRNAs trans-regulated genes were involved in Epstein-Barr virus (EBV) infection pathway in our study. Jun proto-oncogene (JUN), which was related to a cis-regulator lncRNA RP4-794H19.1, was enriched in cancers and involved in Tumor Necrosis Factor (TNF) signaling pathway, might play a key role in NPC. Conclusion: These findings broadened the lncRNAs landscape of NPC tissues and shed light on the roles of these lncRNAs, which might be conducive to the comprehensive management of NPC.

A new biphenyl derivative from the mangrove endophytic fungus Phomopsis longicolla HL-2232.

A new biphenyl derivative 5,5'-dimethoxybiphenyl-2,2'-diol (1), together with five known compounds (2-5), was isolated from the mangrove endophytic fungus Phomopsis longicolla HL-2232. The structures of these compounds were elucidated using comprehensive spectroscopic methods. The absolute configuration of 4 was determined by single-crystal X-ray diffraction for the first time. The inhibitory activities of all compounds against two Vibrio bacteria were evaluated.

Flotilin-1 promotes the tumorigenicity and progression of malignant phenotype in human lung adenocarcinoma.

Lung adenocarcinoma (LUAD) accounts for the most common histological subtype of lung cancer which remains the leading cause of cancer death worldwide. The discovery of more sensitive and specific novel target biomarkers for predicting the development and progression of LUAD is imperative. Flotillin-1 (Flot-1) has been reported to have important roles in the progression of several tumor types but not been reported in the progression of LUAD. Here, we demonstrated that the expression of flotillin-1 was upregulated in 5 LUAD cells. Moreover, multiple approaches were used to explore the tumorigenicity of flotillin-1 in LUAD cell lines. The expression levels of flotillin-1 were analyzed by immunoblotting after overexpression and siRNA-based knockdown. Cell proliferation, scratch wound healing, transwell migration and matrigel invasion and xenograft tumor growth assays were used to determine the role of flotillin-1 in LUAD progression. Downregulation of flotillin-1 reversed, whereas upregulation of flotillin-1 enhanced, the malignant phenotype of LUAD cells in vitro. Consistently, cells with flotillin-1 knockdown formed smaller tumors in nude mice than cells transfected with the empty vector. Furthermore, the control group demonstrated significantly more tumorigenic effects compared to the flotillin-1-silenced group in the xenograft model of LUAD. In all, there draws a conclusion that flotillin-1 is a tumorigenic protein that plays an important role in promoting the proliferation and tumorigenicity of LUAD, suggesting that flotillin-1 may represent a novel the therapeutic target to LUAD.

Increased atherosclerotic lesions in apoE mice with plasma phospholipid transfer protein overexpression.

OBJECTIVE: Plasma phospholipid transfer protein (PLTP) is involved in the metabolism of HDL and apolipoprotein B (apoB)-containing lipoproteins. Atherosclerosis susceptibility is decreased in mice with PLTP deficiency that is associated with decreased liver production of apoB-containing lipoproteins and increase in their antioxidant. To investigate additionally the effect of PLTP on the development of atherosclerosis, we overexpressed PLTP in mice. METHODS AND RESULTS: PLTP was overexpressed in apoE knockout mice using an adenovirus-associated virus (AAV)-mediated system. Plasma PLTP activity was 1.3- to 2-fold higher in mice injected with AAV-PLTP than in mice injected with control AAV-GFP, and PLTP levels were sustained during the experiment period (4 months). We show that 2-fold increased PLTP activity results in (1) a decrease in HDL cholesterol, HDL phospholipid, and apoAI levels; (2) a decrease in vitamin E contents in total plasma and in individual lipoprotein fractions; (3) an increase in lipoprotein oxidizability as assessed by copper-induced formation of conjugated dienes; (4) an increase in autoantibodies against oxidized apoB-containing particles; and (5) an increase in atherosclerosis lesions in proximal aorta. CONCLUSIONS: These observations indicate that elevated plasma PLTP levels constitute a novel, long-term risk factor for atherosclerosis.

[Construction of fused osmoregulation proBA gene from a salt-tolerant mutant of Bacillus subtilis and its influence on the osmotolerance of Escherichia coli].

The osmoregulation proB and proA genes from Bacillus subtilis 93151 are overlapping genes, which encode two proteins ProB and ProA. A restriction enzyme site was inserted in the overlapping region of proB and proA genes from a salt-tolerant mutant of B. subtilis 93151, and a fusion gene was constructed by cloning proB and proA genes respectively. SDS-PAGE analysis showed that a novel protein with molecular mass of 85 kD was observed. When expressed in E. coli, enhanced intracellular concentrations of free proline and osmotolerance of the strain carrying the fusion gene were observed, compared with the control host cell harbouring a plasmid encoding the separate ProB and ProA.

Two new stemphol sulfates from the mangrove endophytic fungus Stemphylium sp. 33231.

Two new stemphol sulfates, stemphol A (1) and stemphol B (2), along with known compound stemphol (3) were isolated from the EtOAc extract of the fermentation of an endophytic Stemphylium sp. 33231. The structures of these compounds were elucidated on the basis of spectroscopic analysis. The isolated compounds exhibited potent antibacterial activities against six terrestrial pathogenic bacteria with MIC values of 0.6-10 µg ml(-1). The inhibitory activities of all compounds against five cancer cell lines were evaluated.

[Cloning and sequencing of the proBA gene from the selected mutant resistant to proline analogue from Bacillus subtilis].

NTG was used to make chemical mutation for Bacillus subtilis 93151. An enhanced osmotolerant mutant was obtained, which could grow in minimal medium containing 14% NaCl (w/v) and was not subject to proline-mediated feedback repression. The content of the intracellular free proline from the mutant increased rapidly with the rising of NaCl concentration. A 2.3 kb DNA fragment from the mutant was amplified using PCR method. Sequence analysis indicated that three bases changed within the proB gene, compared with the wild-type strain. One of the mutations was substitution of an A for a T at nt position 781, leading to a change of a Ser to a Thr at amino acid residue 261 of the deduced protein product, while other two were silent mutations. The recombinant vector pBE2-proB could functionally complement the proline auxotrophy E. coli 1.1252. Sequence analysis of proA showed that proA and proB overlapped by 4 nt, and there was a SD sequence at nt 14 upstream of the start codon of proA. The deduced amino acid of proA gene shared a high similarity with that of Bacillus subtilis 168 (77%).

Epidermal growth factor-like domain-containing protein 7 (EGFL7) enhances EGF receptor-AKT signaling, epithelial-mesenchymal transition, and metastasis of gastric cancer cells.

Epidermal growth factor-like domain-containing protein 7 (EGFL7) is upregulated in human epithelial tumors and so is a potential biomarker for malignancy. Indeed, previous studies have shown that high EGFL7 expression promotes infiltration and metastasis of gastric carcinoma. The epithelial-mesenchymal transition (EMT) initiates the metastatic cascade and endows cancer cells with invasive and migratory capacity; however, it is not known if EGFL7 promotes metastasis by triggering EMT. We found that EGFL7 was overexpressed in multiple human gastric cancer (GC) cell lines and that overexpression promoted cell invasion and migration as revealed by scratch wound and transwell migration assays. Conversely, shRNA-mediated EGFL7 knockdown reduced invasion and migration. Furthermore, EGFL7-overexpressing cells grew into larger tumors and were more likely to metastasize to the liver compared to underexpressing CG cells following subcutaneous injection in mice. EGFL7 overexpression protected GC cell lines against anoikis, providing a plausible mechanism for this enhanced metastatic capacity. In excised human gastric tumors, expression of EGFL7 was positively correlated with expression levels of the mesenchymal marker vimentin and the EMT-associated transcription repressor Snail, and negatively correlated with expression of the epithelial cell marker E-cadherin. In GC cell lines, EGFL7 knockdown reversed morphological signs of EMT and decreased both vimentin and Snail expression. In addition, EGFL7 overexpression promoted EGF receptor (EGFR) and protein kinase B (AKT) phospho-activation, effects markedly suppressed by the EGFR tyrosine kinase inhibitor AG1478. Moreover, AG1478 also reduced the elevated invasive and migratory capacity of GC cell lines overexpressing EGFL7. Collectively, these results strongly suggest that EGFL7 promotes metastasis by activating EMT through an EGFR-AKT-Snail signaling pathway. Disruption of EGFL7-EGFR-AKT-Snail signaling may a promising therapeutic strategy for gastric cancer.