Search

Currently, cancer is still a leading cause of human death globally. Tumor deterioration comprises multiple events including metastasis, therapeutic resistance and immune evasion, all of which are tightly related to the phenotypic plasticity especially epithelial–mesenchymal plasticity (EMP). Tumor cells with EMP are manifest in three states as epithelial–mesenchymal transition (EMT), partial EMT, and mesenchymal–epithelial transition, which orchestrate the phenotypic switch and heterogeneity of tumor cells via transcriptional regulation and a series of signaling pathways, including transforming growth factor‐β, Wnt/β‐catenin, and Notch. However, due to the complicated nature of EMP, the diverse process of EMP is still not fully understood. In this review, we systematically conclude the biological background, regulating mechanisms of EMP as well as the role of EMP in therapy response. We also summarize a range of small molecule inhibitors, immune‐related therapeutic approaches, and combination therapies that have been developed to target EMP for the outstanding role of EMP‐driven tumor deterioration. Additionally, we explore the potential technique for EMP‐based tumor mechanistic investigation and therapeutic research, which may burst vigorous prospects. Overall, we elucidate the multifaceted aspects of EMP in tumor progression and suggest a promising direction of cancer treatment based on targeting EMP. [ABSTRACT FROM AUTHOR]

Alcohol consumption significantly impacts disease burden and has been linked to various diseases in observational studies. However, comprehensive meta-analyses using Mendelian randomization (MR) to examine drinking patterns are limited. We aimed to evaluate the health risks of alcohol use by integrating findings from MR studies. A thorough search was conducted for MR studies focused on alcohol exposure. We utilized two sets of instrumental variables—alcohol consumption and problematic alcohol use—and summary statistics from the FinnGen consortium R9 release to perform de novo MR analyses. Our meta-analysis encompassed 64 published and 151 de novo MR analyses across 76 distinct primary outcomes. Results show that a genetic predisposition to alcohol consumption, independent of smoking, significantly correlates with a decreased risk of Parkinson's disease, prostate hyperplasia, and rheumatoid arthritis. It was also associated with an increased risk of chronic pancreatitis, colorectal cancer, and head and neck cancers. Additionally, a genetic predisposition to problematic alcohol use is strongly associated with increased risks of alcoholic liver disease, cirrhosis, both acute and chronic pancreatitis, and pneumonia. Evidence from our MR study supports the notion that alcohol consumption and problematic alcohol use are causally associated with a range of diseases, predominantly by increasing the risk. [ABSTRACT FROM AUTHOR]

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development. [ABSTRACT FROM AUTHOR]

Tumors desmoplastic microenvironments are characterized by abundant stromal cells and extracellular matrix (ECM) deposition. Cancer-associated fibroblasts (CAFs), as the most abundant of all stromal cells, play significant role in mediating microenvironments, which not only remodel ECM to establish unique pathological barriers to hinder drug delivery in desmoplastic tumors, but also talk with immune cells and cancer cells to promote immunosuppression and cancer stem cells-mediated drug resistance. Thus, CAFs mediated desmoplastic microenvironments will be emerging as promising strategy to treat desmoplastic tumors. However, due to the complexity of microenvironments and the heterogeneity of CAFs in such tumors, an effective deliver system should be fully considered when designing the strategy of targeting CAFs mediated microenvironments. Engineered exosomes own powerful intercellular communication, cargoes delivery, penetration and targeted property of desired sites, which endow them with powerful theranostic potential in desmoplastic tumors. Here, we illustrate the significance of CAFs in tumors desmoplastic microenvironments and the theranostic potential of engineered exosomes targeting CAFs mediated desmoplastic microenvironments in next generation personalized nano-drugs development. [ABSTRACT FROM AUTHOR]

In the tumor microenvironment, tumor-associated macrophages (TAMs) interact with cancer cells and contribute to the progression of solid tumors. Nonetheless, the clinical significance of TAM-related biomarkers in prostate cancer (PCa) is largely unexplored. The present study aimed to construct a macrophage-related signature (MRS) for predicting PCa patient prognosis based on macrophage marker genes. Six cohorts comprising 1056 PCa patients with RNA-Seq and follow-up data were enrolled. Based on macrophage marker genes identified by single-cell RNA-sequencing (scRNA-seq) analysis, univariate analysis, least absolute shrinkage and selection operator (Lasso)-Cox regression, and machine learning procedures were performed to derive a consensus MRS. Receiver operating characteristic curve (ROC), concordance index, and decision curve analyses were used to confirm the predictive capacity of the MRS. The predictive performance of the MRS for recurrence-free survival (RFS) was stable and robust, and the MRS outperformed traditional clinical variables. Furthermore, high-MRS-score patients presented abundant macrophage infiltration and high-expression levels of immune checkpoints (CTLA4, HAVCR2, and CD86). The frequency of mutations was relatively high in the high-MRS-score subgroup. However, the low-MRS-score patients had a better response to immune checkpoint blockade (ICB) and leuprolide-based adjuvant chemotherapy. Notably, abnormal ATF3 expression may be associated with docetaxel and cabazitaxel resistance in PCa cells, T stage, and the Gleason score. In this study, a novel MRS was first developed and validated to accurately predict patient survival outcomes, evaluate immune characteristics, infer therapeutic benefits, and provide an auxiliary tool for personalized therapy. [ABSTRACT FROM AUTHOR]

Background: It is essential to identify the chemical components for the quality control methods establishment of Chinese Classical Formula (CCF). However, CCF are complex mixture of several herbal medicines with huge number of different compounds and they are not equal to the combination of chemical components from each herb due to particular formula ratio and preparation techniques. Therefore, it is time-consuming to identify compounds in a CCF by analyzing the LC–MS/MS data one by one, especially for unknown components. Methods: An ultra-high pressure liquid chromatography-linear ion trap-orbitrap high resolution mass spectrometry (UHPLC-LTQ-Orbitrap-MS/MS) approach was developed to comprehensively profile and characterize multi-components in CCF with Erdong decoction composed of eight herbal medicines as an example. Then the MS data of Erdong decoction was analyzed by MS/MS-based molecular networking and these compounds with similar structures were connected to each other into a cluster in the network map. Then the unknown compounds connected to known compounds in a cluster of the network map were identified due to their similar structures. Results: Based on the clusters of the molecular networking, 113 compounds were rapidly tentative identification from Erdong decoction for the first time in the negative mode, which including steroidal saponins, triterpenoid saponins, flavonoid O-glycosides and flavonoid C-glycosides. In addition, 10 alkaloids were tentatively identified in the positive mode from Nelumbinis folium by comparison with literatures. Conclusion: MS/MS-based molecular networking technique is very useful for the rapid identification of components in CCF. In Erdong decoction, this method was very suitable for the identification of major steroidal saponins, triterpenoid saponins, and flavonoid C-glycosides. [ABSTRACT FROM AUTHOR]

Background: Angiogenesis is important for the progression of gastric cancer (GC). Y-box binding protein 1 (YB-1) predicts advanced disease and indicates neovasculature formation in GC tissues, while the related mechanisms remain elusive. Exosomes mediate intercellular communications via transferring various molecules including proteins, lipids, mRNAs, and microRNAs, while the cargos of GC exosomes and the related mechanisms in GC angiogenesis were rarely reported except for several microRNAs.Methods: In this study, human umbilical vein endothelial cells (HUVECs) were, respectively, treated by the exosomes isolated from the YB-1 transfected and the control SGC-7901 cells (SGC-7901-OE-Exo and SGC-7901-NC-Exo), and their apoptosis, proliferation, migration, invasion, and angiogenesis were, sequentially, compared. The levels of angiogenic factors including VEGF, Ang-1, MMP-9 and IL-8 in the exosome-treated HUVECs and the GC-derived exosomes were, separately, detected using PCR and Western blotting as well as RNA sequencing assays.Results: We observed the consistent level of YB-1 in the exosomes and their originated GC cells, and the internalization of exosomes into HUVECs. Comparing with SGC-7901-NC-Exo, SGC-7901-OE-Exo significantly inhibited the apoptosis but promoted the proliferation, migration, invasion, and angiogenesis of HUVECs, within which the increased mRNA and protein levels of VEGF, Ang-1, MMP-9 and IL-8 were demonstrated. Meanwhile, mRNA levels of VEGF, Ang-1, MMP-9 and IL-8 showed no significant difference between SGC-7901-NC-Exo and SGC-7901-OE-Exo, although statistically higher mRNA of YB-1 was detected in the SGC-7901-OE-Exo.Conclusions: Our findings illustrate YB-1 as the key component of exosome to promote GC angiogenesis by upregulating specific angiogenic factors in the exosome-treated endothelial cells but not in the exosomes themselves. [ABSTRACT FROM AUTHOR]

Xue, X.; Wang, X., and Li, L., 2019. Employment absorption capacity of e-commerce service industry. In: Guido-Aldana, P.A. and Mulahasan, S. (eds.), Advances in Water Resources and Exploration. Journal of Coastal Research, Special Issue No. 93, pp. 879–882. Coconut Creek (Florida), ISSN 0749-0208. E-commerce service industry will play an important role in promoting national economic growth, increasing employment, adjusting industrial structure and improving resource utilization efficiency. With the rapid development of e-commerce and the increasingly serious employment situation, how to promote the employment potential of e-commerce service industry? In this paper, the development of China's e-commerce service industry is analyzed and the methods of employment elasticity analysis and industrial structure deviation are used to study the employment absorption capacity of e-commerce service industry. The research shows that there is a positive correlation between the development of e-commerce service industry and its employment growth. Although their development has not quite matched, e-commerce service industry still has a strong employment absorption capacity. Finally, some suggestions on how to promote and enhance the employment potential of e-commerce service industry are put forward. [ABSTRACT FROM AUTHOR]

There is insufficient evidence on the relationship between air pollution and mortality from cardiovascular disease (CVD) in northeast China. Here, we explored the short-term effects of air pollution on CVD mortality and preliminarily investigated differences in population susceptibility to air pollution in Shenyang, China. CVD mortality, air pollution, and meteorological data during 2013–2016 were obtained. Time-series analysis was applied to evaluate the association between air pollution and daily CVD mortality with different lag structures. In the single-pollutant model, each 10 μg/m3 increase in PM2.5, PM10, SO2, NO2, and O3 concentrations and 1 mg/m3 increase in CO concentrations at lag0 (same day) was significantly associated with an increase of 0.40% (95% confidence interval, 0.22–0.59%), 0.26% (0.12–0.40%), 0.43% (0.16–0.70%), 0.90% (0.14–1.67%), 0.76% (0.21–1.32%), and 3.33% (0.97–5.75%), respectively, in overall CVD mortality. Susceptibility to air pollutants was higher among females, elderly people, and ischemic heart disease patients. Furthermore, air pollution effects on CVD mortality were 2–8 times greater during the non-heating period. In conclusion, the air pollutants PM2.5, PM10, SO2, NO2, O3, and CO showed significant positive effects on CVD mortality in Shenyang, China. These findings highlight the adverse effects of air pollution and suggest the need for personal protective equipment and reduction of air pollution sources. [ABSTRACT FROM AUTHOR]

Short-term exposures to air pollution are associated with acute effects on respiratory health. This study aimed to describe 10-year temporal trends in respiratory mortality in the urban areas of Shenyang, China, according to gender and age and estimate the effects of air pollution on respiratory diseases (ICD-10J00-J99) and lung cancer (ICD-10 C33-C34) using a case-crossover design. During the study period 2013-2015, the exposure-response relationship between ambient air pollutants and mortality data was fitted by a quasi-Poisson model. Age-standardized mortality rates for a combined number of respiratory diseases and for lung cancer declined in Shenyang; however, death counts increased with aging. Deaths from respiratory diseases increased by 4.7% (95% CI, 0.00-9.9), and lung cancer mortality increased by 6.5% (95% CI, 1.2-12.0), both associated with a 10 μg/m3 increase in exposure to particulate matter < 2.5 μg in diameter (PM2.5). Moreover, males in Shenyang’s urban areas were more susceptible to the acute effects of PM2.5 and SO2 exposure; people aged ≥ 65 years had a high susceptibility to ozone, and those aged < 65 years were more susceptible to other air pollutants. These results provided an updated estimate of the short-term effects of air pollution in Shenyang. Since population aging is also associated with increasing mortality from respiratory diseases and lung cancer, reinforcing air quality control measures and health-promoting behaviors is urgent and necessary in Shenyang. [ABSTRACT FROM AUTHOR]

Xue, X.; Wang, X., and Li, L., 2019. Employment absorption capacity of e-commerce service industry. In: Guido-Aldana, P.A. and Mulahasan, S. (eds.), Advances in Water Resources and Exploration. Journal of Coastal Research, Special Issue No. 93, pp. 879–882. Coconut Creek (Florida), ISSN 0749-0208. E-commerce service industry will play an important role in promoting national economic growth, increasing employment, adjusting industrial structure and improving resource utilization efficiency. With the rapid development of e-commerce and the increasingly serious employment situation, how to promote the employment potential of e-commerce service industry? In this paper, the development of China's e-commerce service industry is analyzed and the methods of employment elasticity analysis and industrial structure deviation are used to study the employment absorption capacity of e-commerce service industry. The research shows that there is a positive correlation between the development of e-commerce service industry and its employment growth. Although their development has not quite matched, e-commerce service industry still has a strong employment absorption capacity. Finally, some suggestions on how to promote and enhance the employment potential of e-commerce service industry are put forward. [ABSTRACT FROM AUTHOR]

Background: The human 8-oxoguanine DNA glycosylase 1 (hOGG1), apurinic/apyrimidinic endonuclease 1 (APE1), and adenosine diphosphate ribosyl transferase (ADPRT) genes play an important role in the DNA base excision repair pathway. Single nucleotide polymorphisms (SNPs) in critical genes are suspected to be associated with the risk of lung cancer. This study aimed to identify the association between the polymorphisms of hOGG1 Ser326Cys, APE1 Asp148Glu, and ADPRT Val762Ala, and the risk of lung adenocarcinoma in the non-smoking female population, and investigated the interaction between genetic polymorphisms and environmental exposure in lung adenocarcinoma. Methods: We performed a hospital-based case-control study, including 410 lung adenocarcinoma patients and 410 cancer-free hospital control subjects who were matched for age. Each case and control was interviewed to collect information by well-trained interviewers. A total of 10 ml of venous blood was collected for genotype testing. Three polymorphisms were analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique. Results: We found that individuals who were homozygous for the variant hOGG1 326Cys/Cys showed a significantly increased risk of lung adenocarcinoma (OR = 1.54; 95% CI: 1.01–2.36; P = 0.045). When the combined effect of variant alleles was analyzed, we found an increased OR of 1.89 (95% CI: 1.24–2.88, P = 0.003) for lung adenocarcinoma individuals with more than one homozygous variant allele. In stratified analyses, we found that the OR for the gene-environment interaction between Ser/Cys and Cys/Cys genotypes of hOGG1 codon 326 and cooking oil fumes for the risk of lung adenocarcinoma was 1.37 (95% CI: 0.77–2.44; P = 0.279) and 2.79 (95% CI: 1.50–5.18; P = 0.001), respectively. Conclusions: The hOGG1 Ser326Cys polymorphism might be associated with the risk of lung adenocarcinoma in Chinese non-smoking females. Furthermore, there is a significant gene-environment association between cooking oil fumes and hOGG1 326 Cys/Cys genotype in lung adenocarcinoma among female non-smokers. [ABSTRACT FROM AUTHOR]

A series of oral prodrugs based on the structure of gemcitabine (2′,2′-difluorodeoxycytidine) were synthesised by introducing an amide group at the N4-position of the cytidine ring. A total of 16 compounds were obtained, and their chemical and biological characteristics were evaluated. The half-maximal inhibitory concentrations (IC50s) for most of these compounds were higher than that of gemcitabine in vitro. Compounds 5d and 5m, the representative compounds, were examined in terms of their physiological stabilities and pharmacokinetics. Compound 5d showed good stability in PBS and simulated intestinal fluid, and an analysis of its pharmacokinetics in mice suggested that the introduction of an amide group to gemcitabine could greatly improve its bioavailability. Further evaluation of compound 5d in vivo showed that this compound possesses higher activity than gemcitabine against the growth of HepG2 human hepatocellular carcinoma cells and HCT-116 colon adenocarcinoma cells with less toxicity to animals. These results suggest that compound 5d could be further developed as a potential oral anticancer agent for clinical applications in which gemcitabine is currently used. [ABSTRACT FROM AUTHOR]

Background: Aberrant activations of Wnt and Notch signaling pathways are individually reported to be associated with the pathogenesis of non-small-cell lung cancer (NSCLC). However, the data about the cross talk between the two signaling pathways are still limited. To elucidate potential Wnt/Notch cross talk within NSCLC, we examined the impact of Notch3 activity on LiCl-induced cell cycle changes. Methods: The lung cancer cell lines were treated with LiCl, a Wnt activator, in the absence or presence of Notch3-siRNA. Cell cycles and the expression of the regulators of cell cycle, c-MYC, p21 and Skp2 (S phase kinase-associated protein 2) were measured after treatment. Results: The treatment with LiCl increased the percent of cells at S phase and G phase and the expression of c-MYC and Skp2 and decreased the expression of p21. Moreover, the expression of Notch3 and its down-stream genes, HES-1 and HEYL, was up-regulated by LiCl. Notch3-siRNA weakened the effect of LiCl on the cell cycle and resulted in attenuation of the LiCl-induced increment of c-MYC and Skp2 and the LiCl-induced decrement of p21. Conclusions: These data suggest that Notch3 activation cooperatively takes part in the LiCl-induced cell cycle changes, at least partially, associated with c-MYC, Skp2 and p21. [ABSTRACT FROM AUTHOR]

Background: Lung adenocarcinoma is a heterogernous disease that creates challenges for classification and management. The purpose of this study is to identify specific miRNA markers closely associated with the survival of LUAD patients from a large dataset of significantly altered miRNAs, and to assess the prognostic value of this miRNA expression profile for OS in patients with LUAD.Methods: We obtained miRNA expression profiles and corresponding clinical information for 372 LUAD patients from The Cancer Genome Atlas (TCGA), and identified the most significantly altered miRNAs between tumor and normal samples. Using survival analysis and supervised principal components method, we identified an eight-miRNA signature for the prediction of overall survival (OS) of LUAD patients. The relationship between OS and the identified miRNA signature was self-validated in the TCGA cohort (randomly classified into two subgroups: n = 186 for the training set and n = 186 for the testing set). Survival receiver operating characteristic (ROC) analysis was used to assess the performance of survival prediction. The biological relevance of putative miRNA targets was also analyzed using bioinformatics.Results: Sixteen of the 111 most significantly altered miRNAs were associated with OS across different clinical subclasses of the TCGA-derived LUAD cohort. A linear prognostic model of eight miRNAs (miR-31, miR-196b, miR-766, miR-519a-1, miR-375, miR-187, miR-331 and miR-101-1) was constructed and weighted by the importance scores from the supervised principal component method to divide patients into high- and low-risk groups. Patients assigned to the high-risk group exhibited poor OS compared with patients in the low-risk group (hazard ratio [HR] = 1.99, P <0.001). The eight-miRNA signature is an independent prognostic marker of OS of LUAD patients and demonstrates good performance for predicting 5-year OS (Area Under the respective ROC Curves [AUC] = 0.626, P = 0.003), especially for non-smokers (AUC = 0.686, P = 0.023).Conclusions: We identified an eight-miRNA signature that is prognostic of LUAD. The miRNA signature, if validated in other prospective studies, may have important implications in clinical practice, in particular identifying a subgroup of patients with LUAD who are at high risk of mortality. [ABSTRACT FROM AUTHOR]