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1.
Mar Drugs ; 18(3)2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32210159

RESUMO

Jahanyne, a lipopeptide with a unique terminal alkynyl and OEP (2-(1-oxo-ethyl)-pyrrolidine) moiety, exhibits anticancer activity. We synthesized jahanyne and analogs modified at the OEP moiety, employing an α-fluoromethyl ketone (FMK) strategy. Preliminary bioassays indicated that compound 1b (FMK-jahanyne) exhibited decreased activities to varying degrees against most of the cancer cells tested, whereas the introduction of a fluorine atom to the α-position of a hydroxyl group (2b) enhanced activities against all lung cancer cells. Moreover, jahanyne and 2b could induce G0/G1 cell cycle arrest in a concentration-dependent manner.

4.
J Transl Med ; 18(1): 108, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32122370

RESUMO

BACKGROUND: Commonly used miRNA detection methods cannot be applied for high-throughput analyses. However, this study was aimed to performed a liquid bead array detection system (LBAS) to detect tissue 6 miRNAs in non-small cell lung cancer (NSCLC). METHODS: In this study, evaluation of LBAS was performed to observe the precision, specificity, limitation and stability. Then, a total of 52 primary NSCLC patients who received resection operation without preoperative radiotherapy and chemotherapy between June 2013 and March 2014 were selected, and then the total RNA of the tissues were extracted. We prepared six NSCLC-related miRNAs for LBAS. After optimization and evaluation, LBAS was verified by detecting the relative expression levels of 6 microRNAs in the pathological tissues and corresponding normal tissues of 52 NSCLC patients. RESULTS: The results of evaluation of LBAS showed that the Mean Fluorescence Intensity (MFI) of the reaction only added with chimeric probes and beads showed no significant change after 180 days (P > 0.05). And the intra-assay Coefficient of Variation (CV) was between 1.57 and 3.5%, while the inter-assay CV was between 4.24 and 11.27%, indicating this system was ideal for diagnostic reagents. In addition, only the beads corresponding to the additional miRNAs showed high MFIs from 8426 to 18,769, whereas the fluorescence values of the other beads were under background levels (MFIs = 20 to 55) in each reaction, indicating no cross reactivity among the miRNAs. The limit of detection of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 were 5.27, 1.39, 1.85, 2.01, 1.34, and 2.73 amol/µL, respectively, showing that the lowest detection limit of miRNA by this system was under pM level. Then, the relative expression levels of miR-21, miR-210, miR-125b, miR-155, miR-375, and miR-31 by using this system were significantly correlated with NSCLC (P < 0.05). And the results of AUC method indicated that specific of the LBAS system was 94.2%. CONCLUSIONS: Our findings suggest that LBAS was simple, high-throughput, and freely combined with absolute quantification. Thus, this system could be applied for tumor miRNAs detection.

5.
Cancer Cell ; 37(3): 387-402.e7, 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32142667

RESUMO

We report that neurofibromin, a tumor suppressor and Ras-GAP (GTPase-activating protein), is also an estrogen receptor-α (ER) transcriptional co-repressor through leucine/isoleucine-rich motifs that are functionally independent of GAP activity. GAP activity, in turn, does not affect ER binding. Consequently, neurofibromin depletion causes estradiol hypersensitivity and tamoxifen agonism, explaining the poor prognosis associated with neurofibromin loss in endocrine therapy-treated ER+ breast cancer. Neurofibromin-deficient ER+ breast cancer cells initially retain sensitivity to selective ER degraders (SERDs). However, Ras activation does play a role in acquired SERD resistance, which can be reversed upon MEK inhibitor addition, and SERD/MEK inhibitor combinations induce tumor regression. Thus, neurofibromin is a dual repressor for both Ras and ER signaling, and co-targeting may treat neurofibromin-deficient ER+ breast tumors.

6.
Cancer ; 2020 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-32125701

RESUMO

BACKGROUND: The current study was performed to investigate whether circulating cell-free Epstein-Barr virus DNA (cfEBV DNA) would be useful for posttreatment surveillance in patients with nasopharyngeal carcinoma (NPC). METHODS: The authors identified a total of 1984 nondisseminated NPC patients from an institutional big-data research platform. Blood samples were collected within 3 months of the completion of radiotherapy and every 3 to 12 months thereafter for cfEBV DNA analysis. Patients were followed until disease recurrence was detected or for a median of 60 months. Diagnostic performance was assessed by calculating the sensitivity, specificity, and accuracy based on the clinical detection of disease recurrence by conventional surveillance modalities (imaging scans and pathological examination). RESULTS: During follow-up, a total of 767 patients (38.7%) had detectable cfEBV DNA. The recurrence rate among these patients was 63.8% (489 of 767 patients), which was significantly higher than that in patients with undetectable cfEBV DNA (8.6%; 105 of 1217 patients). cfEBV DNA sensitivity, specificity, and accuracy were 68.8%, 80.0%, and 78.2%, respectively, for local recurrence; 80.2%, 80.0%, and 85.9%, respectively, for regional recurrence; and 91.1%, 80.0%, and 92.8%, respectively, for distant metastasis. cfEBV DNA was found to have higher sensitivity for the detection of extrapulmonary metastases (94.9%-96.5%) compared with pulmonary metastases (78.4%). It is interesting to note that among the patients with disease recurrence with detectable cfEBV DNA, positive cfEBV DNA results preceded radiological and/or clinical evidence of disease recurrence by a median of 2.3 months (interquartile range, 0.1-9.5 months). In addition, of the 278 cfEBV DNA-positive patients who did not develop disease recurrence, 227 (81.7%) had transiently positive cfEBV DNA that fell to undetectable levels during long-term monitoring. CONCLUSIONS: Plasma cfEBV DNA in patients with NPC appears to be an early sign of tumor recurrence, especially extrapulmonary metastases.

7.
PLoS Negl Trop Dis ; 14(3): e0008070, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150558

RESUMO

Hand, foot, and mouth disease (HFMD) has become a major public health issue in China. The disease incidence varies substantially over time and across space. To understand the heterogeneity of HFMD transmission, we compare the spatiotemporal dynamics of HFMD in Qinghai and Shanghai by conducting combined analysis of epidemiological, wavelet time series, and mathematical methods to county-level data from 2009 to 2016. We observe hierarchical epidemic waves in Qinghai, emanating from Huangzhong and in Shanghai from Fengxian. Besides population, we also find that the traveling waves are significantly associated with socio-economic and geographical factors. The population mobility also varies between the two regions: long-distance movement in Qinghai and between-neighbor commuting in Shanghai. Our findings provide important evidence for characterizing the heterogeneity of HFMD transmission and for the design and implementation of interventions, such as deploying optimal vaccine and changing local driving factors in the transmission center, to prevent or limit disease spread in these areas.

8.
Int J Nanomedicine ; 15: 1457-1468, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32184598

RESUMO

Purpose: Zinc oxide nanoparticles (nZnO) have been widely used in the medicine field. Numerous mechanistic studies for nZnO's anticancer effects are merely performed under high concentration exposure. However, possible anticancer mechanisms of epigenetic dysregulation induced by low doses of nZnO are unclear. Methods: nZnO were characterized and bladder cancer T24 cells were treated with nZnO for 48 hrs at different exposure concentrations. Cell cycle, apoptosis, cell migration and invasion were determined. We performed qRT-PCR, Western blot and chromatin immunoprecipitation to detect the mRNA and protein levels of signaling pathway cascades for histone modification. Results: In this study, we investigated the potential anticancer effects and mechanisms of nZnO on histone modifications in bladder cancer T24 cells upon low-dose exposure. Our findings showed that low concentrations of nZnO resulted in cell cycle arrest at S phase, facilitated cellular late apoptosis, repressed cell invasion and migration after 48 hrs exposure. These anticancer effects could be attributed to increased RUNX3 levels resulting from reduced H3K27me3 occupancy on the RUNX3 promoter, as well as decreased contents of histone methyltransferase EZH2 and the trimethylation of histone H3K27. Our findings reveal that nZnO are able to enter into the cytoplasm and nucleus of T24 cells. Additionally, both particles and ions from nZnO may jointly contribute to the alteration of histone methylation. Moreover, sublethal nZnO-conducted anticancer effects and epigenetic mechanisms were not associated with oxidative stress or DNA damage. Conclusion: We reveal a novel epigenetic mechanism for anticancer effects of nZnO in bladder cancer cells under low-dose exposure. This study will provide experimental basis for the toxicology and cancer therapy of nanomaterials.

9.
Breast Cancer Res Treat ; 180(2): 379-384, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034579

RESUMO

PURPOSE: Protease-activated receptor 1 (PAR1) is a signaling protein ubiquitously present on the surface of tumor cells, and its homologous protein fragment, PAR1-activating peptide (P1AP), can inhibit protein signal transduction of PAR1/G in tumor cells. pH (Low) insertion peptide (pHLIP) can target the acidic tumor microenvironment (TME) and can be used as an excellent carrier to deliver P1AP to tumor cells for therapeutic purposes. METHODS: PAR1 expression on the surface of MDA-MB-231 cells and human MCF10A mammary epithelial cells was observed. The binding between fluorescent-labeled pHLIP(Var7)-P1AP and MDA-MB-231 cells under different pH values was analyzed. The effect of pHLIP(Var7)-P1AP on the proliferation of MDA-MB-231 cells was analyzed under the conditions of pH 7.4 and 6.0. RESULTS: PAR1 was highly expressed on the surface of MDA-MB-231 cells. In an acidic environment (pH 6.0 and 5.0), fluorescent-labeled pHLIP(Var7)-P1AP and MDA-MB-231 cells had a high binding ability, and the binding ability increased with the decrease in pH. In an acidic environment (pH 6.0), pHLIP(Var7)-P1AP significantly inhibited MDA-MB-231 cell proliferation. With 0.5 µg, 1 µg, 2 µg, 4 µg, and 8 µg of pHLIP(Var7)-P1AP, the cell proliferation inhibition rates were 3.39%, 5.27%, 14.29%, 22.14%, and 35.69%, respectively. CONCLUSION: PAR1 was highly expressed on the surface of MDA-MB-231 cells. pHLIP(Var7)-P1AP can effectively target MDA-MB-231 cells in an acidic environment and inhibit the growth of MDA-MB-231 cells by inhibiting the signal transduction of PAR1/G protein.

10.
J Chem Inf Model ; 60(3): 1540-1550, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32097559

RESUMO

The farnesoid X receptor (FXR) is a bile acid-sensing transcription factor with indispensable roles in regulating metabolic processes. Nowadays, FXR has become a highly promising drug target for severe liver disorders, especially nonalcoholic steatohepatitis (NASH). A recent study showed that imatinib and its analogues were able to allosterically enhance agonist-induced FXR activation and its target gene expression. However, the allosteric modulation mechanism of FXR by these compounds remains unclear. In this work, the most effective imatinib analogue, P16, was used as a probe to explore this issue by computational approaches. Our results identified one potential allosteric site surrounded by residues Ile335, Phe336, Lys338, Glu339, Leu340, and Leu348, which could efficiently accommodate P16. In addition, the long-time molecular dynamics simulations indicated that the binding of P16 could significantly decrease the fluctuation of the co-activator and enhance the communications between the endogenous ligand chenodeoxycholic acid (CDCA) and FXR. By analyzing the residue interaction network, we observed two unique communication pathways connecting P16 and CDCA through three key residues, Arg331, Ser332, and Phe336. The communications of network organization in the P16-bound complex may allow the synergistic effect of the two compounds via robust signal transmission between the binding sites and global network bridges, which coordinate allosteric transitions and modulate the receptor activity. Our study offers insights into the allosteric modulation occurring in FXR and would be helpful for discovery of new allosteric modulators targeting FXR for further clinical research.

11.
Aging (Albany NY) ; 12(4): 3486-3501, 2020 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-32039832

RESUMO

This work aimed to investigate tumor-infiltrating immune cells (TIICs) and immune-associated genes in the tumor microenvironment of osteosarcoma. An algorithm known as ESTIMATE was applied for immune score assessment, and osteosarcoma cases were assigned to the high and low immune score groups. Immune-associated genes between these groups were compared, and an optimal immune-related risk model was built by Cox regression analyses. The deconvolution algorithm (referred to as CIBERSORT) was applied to assess 22 TIICs for their amounts in the osteosarcoma microenvironment. Osteosarcoma cases with high immune score had significantly improved outcome (P<0.01). The proportions of naive B cells and M0 macrophages were significantly lower in high immune score tissues compared with the low immune score group (P<0.05), while the amounts of M1 macrophages, M2 macrophages, and resting dendritic cells were significantly higher (P<0.05). Important immune-associated genes were determined to generate a prognostic model by Cox regression analysis. Interestingly, cases with high risk score had poor outcome (P<0.01). The areas under the curve (AUC) for the risk model in predicting 1, 3 and 5-year survival were 0.634, 0.781, and 0.809, respectively. Gene set enrichment analysis suggested immunosuppression in high-risk osteosarcoma patients, in association with poor outcome.

12.
Genes (Basel) ; 11(2)2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32041281

RESUMO

Cucumber is one of the most important vegetables in the world. The C2H2 zinc finger protein (C2H2-ZFP) family plays an important role in the growth development and abiotic stress responses of plants. However, there have been no systematic studies on cucumber. In this study, we performed a genome-wide study of C2H2-ZFP genes and analyzed their chromosomal location, gene structure, conservation motif, and transcriptional expression. In total, 101 putative cucumber C2H2-ZFP genes were identified and divided into six groups (I-VI). RNA-seq transcriptome data on different organs revealed temporal and spatial expression specificity of the C2H2-ZFP genes. Expression analysis of sixteen selected C2H2-ZFP genes in response to cold, drought, salt, and abscisic acid (ABA) treatments by real-time quantitative polymerase chain reaction showed that C2H2-ZFP genes may be involved in different signaling pathways. These results provide valuable information for studying the function of cucumber C2H2-ZFP genes in the future.

13.
ChemSusChem ; 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-32057185

RESUMO

An organic Na-ion battery is reported with a polyanionic 9,10-anthraquinone-2,6-disulfonate (Na2 AQ26DS, 130 mAh g-1 ) cathode and the Na-intercalated state (Na4 TP) of sodium terephthalate (Na2 TP, 255 mAh g-1 ) as the anode. The resulting full cells deliver the maximum discharge capacity of 131 mAh g-1 cathode in 0.5-3.2 V, simultaneously maintaining the average value of ≈62 mAh g-1 cathode during 1200 cycles (0.5 A g-1 , ≈4 C). These results are among the best performing organic sodium-ion full cells reported to date.

14.
Artigo em Inglês | MEDLINE | ID: mdl-32099347

RESUMO

Purpose: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) has published three classifications of COPD from 2007 to 2017. No studies have investigated the ability of these classifications to predict COPD-related hospitalizations. We aimed to compare the discrimination ability of the GOLD 2007, 2011, and 2017 classifications to predict COPD hospitalization and all-cause mortality. Patients and Methods: We followed 1300 participants with COPD aged ≥40 years who participated in the HUNT Study (1995-1997) through to December 31, 2015. Survival analysis and time-dependent area under receiver operating characteristics curves (AUC) were used to compare the discrimination abilities of the GOLD classifications. Results: Of the 1300 participants, 522 were hospitalized due to COPD and 896 died over 20.4 years of follow-up. In adjusted models, worsening GOLD 2007, GOLD 2011, or GOLD 2017 categories were associated with higher hazards for COPD hospitalization and all-cause mortality, except for the GOLD 2017 classification and all-cause mortality (ptrend=0.114). In crude models, the AUCs (95% CI) for the GOLD 2007, GOLD 2011, and GOLD 2017 for COPD hospitalization were 63.1 (58.7-66.9), 60.9 (56.1-64.4), and 56.1 (54.0-58.1), respectively, at 20-years' follow-up. Corresponding estimates for all-cause mortality were 57.0 (54.8-59.1), 54.1 (52.1-56.0), and 52.6 (51.0-54.3). The differences in AUCs between the GOLD classifications to predict COPD hospitalization and all-cause mortality were constant over the follow-up time. Conclusion: The GOLD 2007 classification was better than the GOLD 2011 and 2017 classifications at predicting COPD hospitalization and all-cause mortality.

15.
Future Oncol ; 16(9): 427-437, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32102557

RESUMO

Aim: This study aimed to assess the nutritional status of patients with locoregionally advanced nasopharyngeal cancer, for whom intensity-modulated radiotherapy (IMRT) was planned using their pre- or post-induction chemotherapy (IC) nasopharyngeal gross tumor volume. Materials & methods: 212 cases of stage III-IVb nasopharyngeal cancer were randomized into groups A (n = 97) and B (n = 115). IMRT was planned for groups A and B using pre-IC and post-IC images, respectively. Results: There was a significant decrease in the nutritional parameters of group B compared with those of group A during radiotherapy. Multivariate analysis indicated that the T stage and nasopharyngeal gross tumor volume IMRT-planning protocol were prognostic factors of poor nutritional status. Conclusion: Decreasing the IMRT target volume through IC can improve nutritional status.

16.
Carbohydr Polym ; 234: 115907, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32070526

RESUMO

Current developments of lithium-ion batteries (LIBs) are mainly focused on improving security and cycle performance. Herein, a novel polyvinylidene fluoride (PVDF)/triphenyl phosphate (TPP)/cellulose acetate (CA) nanofiber membrane was fabricated by one-step electrospinning and used as separator in lithium-ion batteries. Compared to traditional polyethylene membrane, the obtained composite showed higher porosity, elevated thermal stability, superior electrolyte wettability, and improved flame resistance. In addition, batteries assembled with PVDF/TPP/CA membrane exhibited excellent electrochemical properties and cycle stability. The enhanced performances were attributed to the porous structure and presence of CA and TPP. Overall, the proposed hybrid organic cellulose-based composite polymer membranes look promising as separators for advanced LIBs.

17.
J Biochem Mol Toxicol ; : e22474, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32043710

RESUMO

With the rapid development of nanotechnology, nanomaterials are now being used for cancer treatment. Although studies on the application of silver nanoparticles in cancer treatment are burgeoning, few studies have investigated the toxicology mechanisms of autophagy in cancer cells under exposure to sublethal silver nanoparticles. Here, we clarified the distinct mechanisms of silver nanoparticles for the regulation of autophagy in prostate cancer PC-3 cells under sublethal exposure. Silver nanoparticle treatment caused lysosome injury, including the decline of lysosomal membrane integrity, decrease of lysosomal quantity, and attenuation of lysosomal protease activity, which resulted in blockage of autophagic flux. In addition, sublethal silver nanoparticle exposure activated AMP-activated protein kinase/mammalian target of rapamycin-dependent signaling pathway to modulate autophagy, which resulted from silver nanoparticles-induced cell hypoxia and energy deficiency. Taken together, the results show that silver nanoparticles could regulate autophagy via lysosome injury and cell hypoxia in PC-3 cells under sublethal dose exposure. This study will provide an experimental basis for the cancer therapy of nanomaterials.

18.
Br J Neurosurg ; : 1-5, 2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32031020

RESUMO

Background: Few data are available on the risk factors involved in nosocomial meningitis from multi-drug-resistant Gram-negative bacteria (MDR-GNB). Our aim was to identify the risk factors of prognosis for MDR-GNB nosocomial meningitis.Methods: Retrospective study of patients undergoing neurosurgery and with positive cerebrospinal fluid culture results post operation between January 2012 and January 2017 in a tertiary hospital in China.Results: In total, 3533 patients were screened. Forty patients with meningitis and completed data were included and divided into two groups, 29 who survived in the successful group (SG) and 11 who died in the failed group (FG). Statistically significant different factors involved in treating successful and failed were pathogen types, highest body temperature in the first 24h of symptoms, CSF glucose content and meropenem susceptibility (for Acinetobacter baumannii). The most common pathogen in the failed ones is Acinetobacter baumannii with meropenem MIC ≥ 16mg/L.Conclusions: Treatment of MDR-GNB nosocomial meningitis is more likely to fail in patients with severe condition when symptoms occur and infected by Acinetobacter baumannii. Researches with larger population are needed to find more factors to improve patient outcome.

19.
Food Res Int ; 129: 108870, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32036882

RESUMO

Aimed to evaluate the changes of three soluble dietary fibers from Lentinula edodes by-products (LESDF) with different molecular weights in the digestive system and their effects on large intestinal fermentation, fermentation products and the types of gut microbiota were determined. The 1D/2D NMR results showed that main form of glucose in LESDF-1 was methyl glycopyranosides and LESDF-3 had distinct branching structures in possible repetitive unit. LESDF-2 showed the beneficial fermentation performance with the slower changes of total carbohydrate consumption and highest production of propionic acid and butyric acid. Results suggested that branched chain structure could increase the consumption rate of LESDF, but not affect the concentration of total SCFAs produced. LESDF-3 was found to promote the production of Bacteroides, which indicated LESDF was one of the nutritional components with the influence on the composition and relative abundance of intestinal microbial community.

20.
Mol Psychiatry ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959849

RESUMO

Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of L-acetylcarnitine, creatinine, L-asparagine, L-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, L-serine, oleic acid, myo-inositol, dodecanoic acid, L-methionine, hypoxanthine, palmitic acid, L-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. L-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of L-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan-kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased L-tryptophan and kynurenic acid levels, and alterations in the tryptophan-kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.

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