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1.
Pharmacogenomics ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32397904

RESUMO

Aim: We aimed to identify genetic variants associated with ACE inhibitor (ACEI)-induced cough. Materials & methods: A nested case-control study was performed among hypertensive Chinese patients receiving enalapril-only therapy. Whole-exome sequencing and genome-wide association analysis were performed. Results: We identified that PNPT1 rs13015243 (odds ratio [OR]: 0.47; 95% CI: 0.34-0.66; p = 7.45 × 10-6), PNPT1 rs13009649 (OR: 0.48; 95% CI: 0.35-0.67; p = 9.96 × 10-6) and PCGF3 rs1044147 (OR: 2.67; 95% CI: 1.71-4.17; p = 9.91 × 10-6) were significantly associated with ACEI-induced cough. Nearly genome-wide significant associations in previously reported candidate risk genes CLASP1, ACE, CES1, CPN1, XPNPEP1, PDE11A or SLC38A were detected in our dataset. Conclusion: Our results suggest that ACEI-induced cough is associated with noncoding SNPs of PNPT1 and PCGF3, all of which are independent of the bradykinin pathway. Study registration: NCT03259399.

2.
Artigo em Inglês | MEDLINE | ID: mdl-32374907

RESUMO

The present study compared performances of the 3 major methods used for assessing platelet reactivity (PR)-VerifyNow, light-transmission aggregometry (LTA), and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EmBase and the Cochrane library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices including sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio, and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA, and TEG, respectively. A total of 26 prospective studies involving 22,185 subjects were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA, and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other 2 methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR, and NLR. Despite a lack of studies that directly compared the 3 methods, our findings suggest that TEG should be recommended.

4.
Int J Mol Med ; 45(6): 1783-1792, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32236608

RESUMO

Cluster of differentiation 44 (CD44) as a transmembrane glycoprotein is found to be expressed in non­small cell lung cancer (NSCLC), is significantly associated with NSLC progression, metastasis and drug resistance. This study aimed to explore whether CD44 inhibition improves the sensitivity of epidermal growth factor receptor (EGFR) wild­type NSCLC cells to cisplatin and how it affects wild­type EGFR in NSCLC cells. Small interfering RNA was used to knockdown CD44 expression in EGFR wild­type NSCLC cell line H460. Results suggested that CD44 downregulation reduced cell growth, promoted G0/G1 cell cycle arrest and induced cell apoptosis in H460 cells and these effects were evidently enhanced when in combination with cisplatin. Deactivation of EGFR signaling pathway including EGFR phosphorylation and its downstream molecules, targets ERK, AKT1 and SRC which were also observed in CD44­silenced H460 cells with or without EGF stimulation. Furthermore, the CD44 expression level was positively correlated with wild­type EGFR level in human lung adenocarcinoma tissues and CD44 inhibition significantly accelerated the degradation of EGFR, indicating that enhanced sensitivity of H460 cells to cisplatin by downregulation of CD44 might be due to EGFR degradation. This study demonstrated that suppression of CD44 deactivated EGFR signals in NSCLC cells with wild­type EGFR, thereby contributing to the inhibition of cell proliferation and the reinforcement of cisplatin sensitivity. It is suggested that downregulation of CD44 could be a novel potential therapeutic strategy for the treatment of EGFR wild­type NSCLC.

5.
Bioorg Med Chem Lett ; 30(12): 127167, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32317208

RESUMO

Epidermal growth factor receptor (EGFR) is one of the important and valuable drug targets. Overexpression of EGFR is associated with the development of many types of cancer. In this study, three PROTACs small molecules (16a-16c) were designed, synthesized and evaluated for their cytotoxicity against the growth in different NSCLC cell line and the degradation effect. The bioassay results indicated that 16c has a good inhibition in PC9 cells and H1975 cells, and the corresponding IC50 value was 0.413 µM and 0.657 µM, respectively. Western blotting results demonstrated that compound 16c could serve as an effective EGFRdel19-targeting degrader in PC9 cells.

6.
Chem Commun (Camb) ; 56(39): 5315-5318, 2020 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-32282006

RESUMO

We report thermo-responsive gels of polyacrylamide (PAAm) with ionic surfactants in mixed water and ethylene glycol (W-EG) solvents as smart windows to solubilize ultraviolet absorbents for UV shielding materials. The Krafft point (TK) of the ionic surfactants determines the phase transition that switches the transparency and opacity of the gels. The TK can be flexibly tuned within a wide temperature range (6-75 °C) with high predictability by changing the surfactant or adjusting the ratio of W-EG solvents.

7.
Artigo em Inglês | MEDLINE | ID: mdl-32230705

RESUMO

The purpose of this article is to promote an increase in the number of enterprises that will disclose corporate social responsibility (CSR) information, and to improve on their quality of CSR information disclosure. Using the theory of organizational ecology, we propose that the density of companies that disclose CSR information in a region has an impact on both the quality and the performance of CSR disclosures. The study results suggest that an increase in the density of CSR information disclosing enterprises in a region will increase the number of enterprises with disclosure intentions. A density increase has a nonlinear influence on the quality of CSR information disclosure and on corporate performance, where the influence of disclosing enterprises' density on corporate performance is partly mediated by the quality of CSR information disclosure. Our research also shows that the impact of density change of disclosing enterprises on the quality of CSR information disclosure is mediated by corporate capital structure.

8.
Disaster Med Public Health Prep ; : 1-4, 2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32284090

RESUMO

The recent outbreak of coronavirus in Wuhan, China, has imposed challenges on the Chinese medical system. Not only the dramatically increasing number of infected cases and insufficient medical resources, but also the peoples' panic throughout the whole country have made medical services extremely difficult. To respond to these challenges effectively, our hospital implemented an urgent response strategy, including human resources and medical resources preparation and re-allocation, immediate fever screening, strict patient-visiting flow management, and reasonable information communication. Our experience and response measures could provide a reference for other hospitals in the current situation.

9.
Cell Death Dis ; 11(3): 207, 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32231200

RESUMO

This study aimed to evaluate treatment response, survival, safety profiles, and predictive factors to chimeric antigen receptor T cell (CAR-T) therapy in Chinese patients with relapsed or refractory B cell acute lymphoblast leukemia (R/R B-ALL). 39R/R B-ALL patients who underwent CAR-T therapy were included. Baseline data were collected from patients' electronic medical records. Patients' peripheral bloods, bone marrow aspirates, and biopsies were obtained for routine examination, and treatment response and survival profiles as well as adverse events were evaluated. The rates of complete remission (CR), CR with minimal residual disease (MRD) negative/positive, and bridging to hematopoietic stem-cell transplantation (HSCT) were 92.3%, 76.9%, 15.4%, and 43.6%, respectively. The median event-free survival (EFS) was 11.6 months (95% confidence interval (CI): 4.0-19.2 months) and median overall survival (OS) was 14.0 months (95% CI: 10.9-17.1 months). Bridging to HSCT independently predicted better EFS and OS, while high bone marrow blasts level independently predicted worse EFS. The incidence of cytokine release syndrome (CRS) was 97.4%, and refractory disease as well as decreased white blood cell independently predicted higher risk of severe CRS. Other common adverse events included hematologic toxicities (grade I: 5.1%, grade II: 7.7%, grade III: 17.9%, grade IV: 69.2%), neurotoxicity (28.2%), infection (38.5%), and admission for intensive care unit (10.3%). In conclusion, CAR-T therapy presents with promising treatment response, survival and safety profiles, and higher disease burden predicts worse survival as well as increased risk of severe CRS in Chinese R/R B-ALL patients.

10.
Expert Opin Ther Targets ; : 1-11, 2020 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-32308059

RESUMO

Background: Adenosine 2A receptor (A2AR) is involved in many physiological and pathological functions and serves as an important drug target. Inhibition of A2AR may alleviate symptoms associated with a variety of neuropsychiatric disorders. However, the currently used A2AR antagonists have specificity limitations.Research design and methods: A Fab fragment (Fab2838) of an A2AR mouse monoclonal antibody can specifically bind to A2AR to form a complex and inhibit the activity of its receptor. We constructed the vector AntiA2AR, a small-molecule peptide that binds to and inhibits A2AR based on Fab2838.Results: Experiments in HEK293T cells showed that peptide AntiA2AR of 29 peptides was the most effective among the synthesized peptides in inhibiting the A2AR downstream signal cAMP/PKA/CREB. In neurons, the AntiA2AR reversed the calcium flow change induced by the A2AR agonist CGS21680 (1 µM). Furthermore, AntiA2AR expression in the mice striatum weakened the p-PKA/p-CREB signal, enhanced locomotor abilities and increased time spent in the center area in the home-cage observation experiment and increased anxiolytic behavior in the elevated-plus maze test.Conclusions: Antagonistic peptide AntiA2AR can effectively block the A2AR signaling pathway. This provides a new strategy for the specific inhibition of A2AR and provides information needed for drug development.

11.
Artigo em Inglês | MEDLINE | ID: mdl-32253693

RESUMO

Heavy metal pollution is a global ecological safety issue, especially in crops, where it directly threatens regional ecological security and human health. Selecting scientific evaluation methods is an important prerequisite for understanding the distribution of heavy metals in a region. To evaluate the distribution characteristics of arsenic (As), cadmium (Cd), copper (Cu), and zinc (Zn) in farmland soil-rice system in Doumen District of Zhuhai City, Pearl River Delta, we analyzed the high geological background area and heavy metal contents in soil by inverse distance-weighted interpolation and single-factor pollution index. Bioconcentration factor (BCF) was used to study the migration and accumulation characteristics of heavy metals. Then, the soil-rice system was evaluated comprehensively with a novel evaluation method, i.e., the influence index of comprehensive quality (IICQ). Results showed that As, Cd, Cu, and Zn in the soil of the study area followed normal distribution. Cd and Cu were the main pollutants whose point contamination rates were 50% and 22.86%, respectively. A total of 2.86% of the soil were contaminated by As, and no Zn contamination was observed in the soil. At the same time, As and Cd in rice were partially polluted, and the Cu and Zn were not polluted. The order of bioaccumulation coefficient was Cd > Zn > Cu > As, and no evident enrichment was observed. According to the impact index of IICQ to evaluate the pollution of heavy metals in the soil-rice system, 96.98% of the soil in study area was in a state of moderate, heavy, and extreme pollution, which were concentrated in the northern and central parts of the study area. The soil-rice system in the high geological background area was in a subhealthy state. A total of 90.69% of the soil were polluted, but the rice met the national food safety standards.

12.
Thyroid ; 2020 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-32188373

RESUMO

Background: Iodine is important in both thyroid function and human metabolism. Studies have explored the effect of iodine on metabolic disorders through thyroid function. This study aimed to investigate the relationship between iodine status and metabolic disorders, such as metabolic syndrome (MetS), hypertension, impaired glucose metabolism, central obesity, and dyslipidemia. Methods: A total of 51,795 subjects aged ≥18 years from the TIDE (Thyroid Disorders, Iodine Status and Diabetes, a national epidemiological cross-sectional study) program were included. The prevalence of metabolic disorders and its related diseases was calculated based on the level of urinary iodine concentrations (UICs) using the chi-square method. To further explore whether the prevalence was associated with UIC, quadratic and UIC-stratified logistic regression models were used. Results: The prevalence of metabolic disorders as a function of UIC was found to be U-shaped with a lower prevalence of 76.0% at an UIC of 300-499 µg/L. Participants with an UIC of 300-499 µg/L showed an association with metabolic disorders (odds ratio [OR] = 0.857, 95% confidence interval [CI 0.796-0.922]) and hypertension (OR = 0.873 [CI 0.814-0.936]). An UIC of 300-799 µg/L was found to be associated with the occurrence of MetS and impaired glucose tolerance. An UIC of 500-799 µg/L was associated with the occurrence of prediabetes (OR = 0.883 [CI 0.797-0.978]). An UIC of ≥300 µg/L was associated with the occurrence of hypertriglyceridemia, hypercholesterolemia, and high levels of low-density lipoprotein cholesterol. Furthermore, an UIC of <100 µg/L showed an association with hypertension (OR = 1.097 [CI 1.035-1.162]) and hypercholesterolemia (OR = 1.178 [CI 1.117-1.242]). Conclusions: The association between UICs in adults and metabolic disorders and its related diseases is U-shaped. The association between UIC and metabolic disorders disappears in cases of iodine deficiency (<100 µg/L) or excess (≥500 µg/L).

14.
Dev Cell ; 53(2): 240-252.e7, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197067

RESUMO

Understanding of NAD+ metabolism provides many critical insights into health and diseases, yet highly sensitive and specific detection of NAD+ metabolism in live cells and in vivo remains difficult. Here, we present ratiometric, highly responsive genetically encoded fluorescent indicators, FiNad, for monitoring NAD+ dynamics in living cells and animals. FiNad sensors cover physiologically relevant NAD+ concentrations and sensitively respond to increases and decreases in NAD+. Utilizing FiNad, we performed a head-to-head comparison study of common NAD+ precursors in various organisms and mapped their biochemical roles in enhancing NAD+ levels. Moreover, we showed that increased NAD+ synthesis controls morphofunctional changes of activated macrophages, and directly imaged NAD+ declines during aging in situ. The broad utility of the FiNad sensors will expand our mechanistic understanding of numerous NAD+-associated physiological and pathological processes and facilitate screening for drug or gene candidates that affect uptake, efflux, and metabolism of this important cofactor.

15.
J Clin Lab Anal ; : e23308, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32185826

RESUMO

BACKGROUND: Recent reports have indicated that circular RNA (circRNA) may regulate tumorigenesis development. However, the function of circRNAs in esophageal squamous cell carcinoma (ESCC) is unclear. MATERIAL AND METHOD: The RT-qPCR assay was performed to detect hsa_circ_0012563 expression in ESCC tissues and cell lines. Then, the MTT assay, colony formation assay, flow cytometric assay, and cell migration and invasion assay were performed to examine the function of hsa_circ_0012563. In addition, the RT-PCR and Western blot were used to detect XRCC1 and epithelial-to-mesenchymal transition (EMT) related gene expression. RESULTS: The RT-qPCR revealed that the hsa_circ_0012563 expression was remarkably upregulated in ESCC tissue and ESCC cell lines. Functionally, downregulation of hsa_circ_0012563 suppressed cell proliferation, migration, and invasion and promoted cell apoptosis. Mechanically, the knockdown of hsa_circ_0012563 inhibited XRCC1-mediated EMT pathway to suppress cell migration and invasion. CONCLUSIONS: Therefore, these results reveal hsa_circ_0012563 is a critical oncogene and may be a novel biomarker in ESCC.

16.
Comput Biol Med ; 118: 103634, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32174312

RESUMO

Pharmacokinetic parameters estimated from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) time course data enable the physio-biological interpretation of tissue angiogenesis. This study aims to develop machine learning approaches for cervical carcinoma prediction based on pharmacokinetic parameters. The performance of individual parameters was assessed in terms of their efficacy in differentiating cancerous tissue from normal cervix tissue. The effect of combining parameters was evaluated using the following two approaches: the first approach was based on support vector machines (SVMs) to combine the parameters from one pharmacokinetic model or across several models; the second approach was based on a novel method called APITL (artificial pharmacokinetic images for transfer learning), which was designed to fully utilize the comprehensive pharmacokinetic information acquired from DCE-MRI data. A "winner-takes-all" strategy was employed to consolidate the slice-wise prediction into subject-wise prediction. Experiments were carried out with a dataset comprising 36 patients with cervical cancer and 17 healthy subjects. The results demonstrated that parameter Ve, representing volume fraction of the extracellular extravascular space (EES), attained high discriminative power regardless of the pharmacokinetic model used for estimation. An approximately 10% improvement in the accuracy was achieved with the SVM approach. The APITL method further outperformed SVM and attained a subject-wise prediction accuracy of 94.3%. Our experiment demonstrated that APITL could predict cervical carcinoma with high accuracy and had potential in clinical applications.

17.
Spectrochim Acta A Mol Biomol Spectrosc ; 233: 118191, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135501

RESUMO

A well-designed naphthopyran-diaminomaleonitrile dyad (sensor 1) has been synthesized successfully, its molecular structure was well characterized by NMR and mass spectrometry. Sensor 1 exhibits excellent photochromic and photochromic fluorescence switch performance with reversible color change and good fatigue resistance upon alternating ultraviolet irradiation and thermal bleaching. In addition, sensor 1 displayed excellent fluorescent and colorimetric sensing ability towards Cu2+ ions with high selectivity and sensitivity. The addition of 5.0 equiv. of Cu2+ ions into sensor 1 (1 × 10-5) in CH3CN solution significantly quenched the fluorescence of sensor 1 by 80.0%. Furthermore, the addition of Cu2+ ions also caused the complete disappearance of the absorbance band at 350-450 nm in absorbance spectra of sensor 1 and accompanied by the distinct color change form yellow to colorless. Job's plot, mass spectrometry, 1H NMR titration and DFT calculations proved that sensing performance was attributed to the formation of 1:1 sensor 1-Cu2+complexes. Sensor 1 can monitor the existence of Cu2+ ions in living cells via the fluorescence images. Sensor 1 showed great potential applications as chemosensor and photochromic materials.

18.
Artigo em Inglês | MEDLINE | ID: mdl-32119572

RESUMO

As the core component of cell metabolism, central carbon metabolism, consisting of glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle converts nutrients into metabolic precursors for biomass and energy to sustain the life of virtually all extant species. The metabolite levels or distributions in central carbon metabolism often change dynamically with cell fates, development, and disease progression. However, traditional biochemical methods require cell lysis, making it challenging to obtain spatiotemporal information about metabolites in living cells and in vivo. Genetically encoded fluorescent sensors allow the rapid, sensitive, specific, and real-time readout of metabolite dynamics in living organisms, thereby offering the potential to fill the gap in current techniques. In this review, we introduce recent progress made in the development of genetically encoded fluorescent sensors for central carbon metabolism and discuss their advantages, disadvantages, and applications. Moreover, several future directions of metabolite sensors are also proposed. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 13 is June 12, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

19.
Artigo em Inglês | MEDLINE | ID: mdl-32123110

RESUMO

Vibrational modes in mechanical resonators provide a promising candidate to interface and manipulate classical and quantum information. The observation of coherent dynamics between distant mechanical resonators can be a key step toward scalable phonon-based applications. Here we report tunable coherent phonon dynamics with an architecture comprising three graphene mechanical resonators coupled in series, where all resonators can be manipulated by electrical signals on control gates. We demonstrate coherent Rabi oscillations between spatially separated resonators indirectly coupled via an intermediate resonator serving as a phonon cavity. The Rabi frequency fits well with the microwave burst power on the control gate. We also observe Ramsey interference, where the oscillation frequency corresponds to the indirect coupling strength between these resonators. Such coherent processes indicate that information encoded in vibrational modes can be transferred and stored between spatially separated resonators, which can open the venue of on-demand phonon-based information processing.

20.
Food Chem ; 319: 126568, 2020 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169768

RESUMO

Penthorum chinense Pursh is a dietary medicinal plant widely distributed in Asia-Pacific countries. The present study aims to profile the chemical constituents of P. chinense and investigate its prebiotic role in modulating gut microbiota. Fifty polyphenolic compounds were rapidly identified using UPLC-HR-MS. Total flavonoid and phenolic contents of P. chinense were 46.6% and 61.3% (w/w), respectively. Thirteen individual polyphenols were quantified, which accounted for 33.1% (w/w). P. chinense induced structural arrangement of microbial community in mice, showing increased microbiota diversity, elevated Bacteroidetes/Firmicutes ratio and enriched gut health-promoting bacteria. After a one-week drug-free wash, most of these changes were recovered, but the abundance of some beneficial bacteria was further increased. The altered composition of gut microbiota enriched several metabolic pathways. Moreover, P. chinense increased antioxidant capacity in vivo. The results suggest that polyphenol-enriched P. chinense modulates gut microbiota and enhances antioxidant capacity in mice toward a beneficial environment for host health.

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