Search

Objective The Immunoscore method has proved fruitful for predicting prognosis in patients with colon cancer. However, there is still room for improvement in this scoring method to achieve further advances in its clinical translation. This study aimed to develop and validate a modified Immunoscore (IS-mod) system for predicting overall survival (OS) in patients with stage I−III colon cancer. Methods The IS-mod was proposed by counting CD3+ and CD8+ immune cells in regions of the tumor core and its invasive margin by drawing two lines of interest. A discovery cohort (N=212) and validation cohort (N=103) from two centers were used to evaluate the prognostic value of the IS-mod. Results In the discovery cohort, 5-year survival rates were 88.6% in the high IS-mod group and 60.7% in the low IS-mod group. Multivariate analysis confirmed that the IS-mod was an independent prognostic factor for OS [adjusted hazard ratio (HR)=0.36, 95% confidence interval (95% CI): 0.20−0.63]. With less annotation and computation cost, the IS-mod achieved performance comparable to that of the Immunoscore-like (IS-like) system (C-index, 0.676 vs. 0.661, P=0.231). The 2-category IS-mod using 47.5% as the threshold had a better prognostic value than that using a fixed threshold of 25% (C-index, 0.653 vs. 0.573, P=0.004). Similar results were confirmed in the validation cohort. Conclusions Our method simplifies the annotation and accelerates the calculation of Immunoscore method, thus making it easier for clinical implementation. The IS-mod achieved comparable prognostic performance when compared to the IS-like system in both cohorts. Besides, we further found that even with a small reference set (N≥120), the IS-mod still demonstrated a stable prognostic value. This finding may inspire other institutions to develop a local reference set of an IS-mod system for more accurate risk stratification of colon cancer.

Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer, which is the malignant tumor with the highest mortality and morbidity in the world. Herein, ZNF280A, a member of the zinc finger protein family carrying two consecutive Cys2His2 zinc finger domains, was shown by us to act as a tumor driver in LUAD. The immunohistochemical analysis of ZNF280A in LUAD indicated its positive correlation with tumor grade, pathological stage and lymphatic metastasis, and negative relationship with patients’ survival. A loss-of-function study revealed the inhibition of LUAD development by ZNF280A in vitro and in vivo, whereas ZNF280A overexpression induced opposite effects. Statistical analysis of gene expression profiling in LUAD cells with or without ZNF280A knockdown identified EIF3C as a potential downstream of ZNF280A, which possesses similar regulatory effects on phenotypes of LUAD cells with ZNF280A. Moreover, downregulation of EIF3C in ZNF280A-overexpressed cells could attenuate neutralize the ZNF280A-induced promotion of LUAD. In summary, our study demonstrated that ZNF280A may promote the development of LUAD by regulating cell proliferation, apoptosis, cell cycle, and cell migration and probably via interacting EIF3C.

Background: About 1/3 of all brain tumors are gliomas. Previous glioma studies have reported increased expression of Periostin (POSTN) in these cancerous tissues, but its role and mechanism in gliomas development remain unknown. Methods: Nanoscale liquid chromatography coupled to tandem mass spectrometry (Nano LC-MS/MS) and RNA sequencing were used to identify differential protein and mRNA expression in glioma samples from the clinic. Quantitative real-time PCR (qRT-PCR) was used to detect the expression of POSTN in tissues and cells. The effects of POSTN on glioma cell migration and invasion were examined using wound-healing, transwell, and three-dimensional spheroid assays in vitro, and a xenograft nude-mouse model in vivo. POSTN’s effect on the stability, endocytosis, and degradation of EGFR was examined by immunoblotting and immunofluorescence. Truncated mutation analysis was performed to interrogate any direct interactions between POSTN and EGFR. Immunohistochemical staining was carried out to confirm the clinical significance of POSTN. Findings: In this study, POSTN was upregulated in gliomas and was associated with poor prognosis. POSTN depletion inhibited glioma epithelial-to-mesenchymal transition (EMT) both in vitro and in vivo. Furthermore, POSTN downregulation dampened EGFR signaling via promotion of EGFR endocytosis and degradation. In addition, POSTN was found to bind to EGFR and RIN1, inhibiting EGFR endocytosis and degradation, thus promoting the activation of the PI3K-AKT signaling pathway. Interpretation: These findings indicate the POSTN/EGFR/RIN1 axis inhibits EGFR endocytosis and degradation. Targeting POSTN/EGFR/RIN1 interactions may prove beneficial the treatment of gliomas. Funding Information: This work was supported by grants from National Natural Science Foundation of China (81772682), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). Declaration of Interests: The authors have declared that no competing interest exists. Ethics Approval Statement: Our study protocol was approved by the Research Ethics Committee of Nanjing Medical University (Nanjing, Jiangsu, China).

Purpose：We focus on adverse events in colorectal cancer patients with advanced age, high Eastern Cooperative Oncology Group scores and comorbidities. Methods：408 Chinese colorectal cancer patients undergoing adjuvant chemotherapy at Peking Union Medical College Hospital were included. The cumulative incidences of different adverse events and mediation analyses were analyzed with respect to age, Eastern Cooperative Oncology Group status and comorbidities. Results：Young patients and patients with Eastern Cooperative Oncology Group score 1 had a significantly higher incidence of digestive adverse events related to adjuvant therapy. There were no significant mediation effects of adverse events on survival. Conclusion：Advanced age did not directly lead to poor survival outcomes and adverse events. Although higher Eastern Cooperative Oncology Group scores and comorbidity led to impaired survival and higher incidence of adverse events, the latter had no mediation effects on survival outcomes.

Designing of fast, inexpensive and sensitive furfural determination methods for dairy milk is crucial in analytical and food chemistry. In this study, an electrochemical sensor was developed for the cathodic determination of furfural using a one-step electrochemically reduced graphene oxide (ErGO) modified glassy carbon electrode (GCE). The morphology and chemical constituents of the obtained ErGO/GCE were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), and Raman and X-ray photoelectron spectroscopy (XPS). The results showed that the fast and green electrochemical reduction process effectively eliminated the oxygen-containing groups in GO and produced reduced graphene with a high surface area and improved electron transfer kinetics. In addition, the ErGO based sensor displayed excellent responses for furfural in a Na2HPO4-NaH2PO4 solution (pH = 9.18) with a wide linear range from 2 to 2015 μM and a low detection limit of 0.4 μM (S/N = 3). The reduction mechanism of furfural was also discussed. Furthermore, the feasibility of the sensor was confirmed by the determination of furfural in three milk samples which generated acceptable outputs.

The detection of intracellular nitroreductase (NTR) activity is important for the study of hypoxia in organisms. In the present study, a Rhodol-derived fluorescent chemosensor (Rhod-NO

Uremic toxins are a class of toxins that accumulate in patients with chronic kidney disease (CKD). Indoxyl sulfate (IS), a typical uremic toxin, is not efficiently removed by hemodialysis. Modulation of IS production in the gut microbiota may be a promising strategy for decreasing IS concentration, thus, delaying CKD progression. In the present study, we identified isoquercitrin (ISO) as a natural product that can perturb microbiota-mediated indole production without directly inhibiting the growth of microbes or the indole-synthesizing enzyme TnaA. ISO inhibits the establishment of H proton potential by regulating the gut bacteria electron transport chain, thereby inhibiting the transport of tryptophan and further reducing indole biosynthesis. This non-microbiocidal mechanism may enable ISO to be used as a therapeutic tool, specifically against pathologies triggered by the accumulation of the microbial-produced toxin IS, as in CKD. Herein, we have shown that it is possible to inhibit gut microbial indole production using natural components. Therefore, targeting the uremic toxin metabolic pathway in gut bacteria may be a promising strategy to control host uremic toxin production., Graphical abstract

Background An artificial intelligence method could accelerate the clinical implementation of tumour-stroma ratio (TSR), which has prognostic relevance in colorectal cancer (CRC). We, therefore, developed a deep learning model for the fully automated TSR quantification on routine haematoxylin and eosin (HE) stained whole-slide images (WSI) and further investigated its prognostic validity for patient stratification. Methods We trained a convolutional neural network (CNN) model using transfer learning, with its nine-class tissue classification performance evaluated in two independent test sets. Patch-level segmentation on WSI HE slides was performed using the model, with TSR subsequently derived. A discovery (N=499) and validation cohort (N=315) were used to evaluate the prognostic value of TSR for overall survival (OS). Findings The CNN-quantified TSR was a prognostic factor, independently of other clinicopathologic characteristics, with stroma-high associated with reduced OS in the discovery (HR 1.72, 95% CI 1.24-2.37, P=0.001) and validation cohort (2.08, 1.26-3.42, 0.004). Integrating TSR into a Cox model with other risk factors showed improved prognostic capability. Interpretation We developed a deep learning model to quantify TSR based on histologic WSI of CRC and demonstrated its prognostic validity for patient stratification for OS in two independent CRC patient cohorts. This fully automatic approach allows for the objective and standardised application while reducing pathologists' workload. Thus, it can potentially be of significant aid in clinical prognosis prediction and decision-making. Funding National Key Research and Development Program of China, National Science Fund for Distinguished Young Scholar, and National Science Foundation for Young Scientists of China.

Flammulina velutipes polysaccharides (FVP) can improve gut health through gut microbiota and metabolism regulation. In this study, the 28-days fed experiment was used to investigate gut microbime and metabolic profiling induced by FVP. After treatment, intestinal tissue section showed the higher villus height and villus height/crypt depth (V/C) value in FVP-treated group. The 16 s rRNA gene sequencing revealed microbiota composition alteration caused by FVP, as the Firmicutes phylum increased while Bacteroidetes phylum slightly decreased. The metabolic profiling was detected by LC/MS and results showed 56 and 99 compounds were dramatically changed after FVP treatment in positive and negative ion mode, respectively. Annotation in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways displayed the adjustment of energy metabolism, amino acid metabolism, nucleotide metabolism and other related basic pathways after FVP treatment. Our study suggested that FVP can be developed as a dietary supplement for intestine health promotion.

Background Our previous studies have indicated that miR-198 reduces cellular methylguanine DNA methyltransferase (MGMT) levels to enhance temozolomide sensitivity. Transforming growth factor beta 1 (TGF-β1) switches off miR-198 expression by repressing K-homology splicing regulatory protein (KSRP) expression in epidermal keratinocytes. However, the underlying role of TGF-β1 in temozolomide resistance has remained unknown. Methods The distribution of KSRP was detected by western blotting and immunofluorescence. Microarray analysis was used to compare the levels of long noncoding RNAs (lncRNAs) between TGF-β1–treated and untreated cells. RNA immunoprecipitation was performed to verify the relationship between RNAs and KSRP. Flow cytometry and orthotopic and subcutaneous xenograft tumor models were used to determine the function of TGF-β1 in temozolomide resistance. Results Overexpression of TGF-β1 contributed to temozolomide resistance in MGMT promoter hypomethylated glioblastoma cells in vitro and in vivo. TGF-β1 treatment reduced cellular MGMT levels through suppressing the expression of miR-198. However, TGF-β1 upregulation did not affect KSRP expression in glioma cells. We identified and characterized 2 lncRNAs (H19 and HOXD-AS2) that were upregulated by TGF-β1 through Smad signaling. H19 and HOXD-AS2 exhibited competitive binding to KSRP and prevented KSRP from binding to primary miR-198, thus decreasing miR-198 expression. HOXD-AS2 or H19 upregulation strongly promoted temozolomide resistance and MGMT expression. Moreover, KSRP depletion abrogated the effects of TGF-β1 and lncRNAs on miR-198 and MGMT. Finally, we found that patients with low levels of TGF-β1 or lncRNA expression benefited from temozolomide therapy. Conclusions Our results reveal an underlying mechanism by which TGF-β1 confers temozolomide resistance. Furthermore, our findings suggest that a novel combination of temozolomide with a TGF-β inhibitor may serve as an effective therapy for glioblastomas.

Sintilimab, an anti-programmed death 1 antibody, plus pemetrexed and platinum had revealed promising efficacy for nonsquamous NSCLC in a phase 1b study. We conducted a randomized, double-blind, phase 3 study to compare the efficacy and safety of sintilimab with placebo, both in combination with such chemotherapy (ClinicalTrials.gov: NCT03607539).A total of 397 patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC without sensitizing EGFR or anaplastic lymphoma kinase genomic aberration were randomized (2:1 ratio) to receive either sintilimab 200 mg or placebo plus pemetrexed and platinum once every 3 weeks for four cycles, followed by sintilimab or placebo plus pemetrexed therapy. Crossover or treatment beyond disease progression was allowed. The primary end point was progression-free survival (PFS) as judged by an independent radiographic review committee.As of November 15, 2019, the median follow-up was 8.9 months. The median PFS was significantly longer in the sintilimab-combination group than that in the placebo-combination group (8.9 versus 5.0 mo; hazard ratio, 0.482, 95% confidence interval [CI]: 0.362-0.643; p0.00001). The confirmed objective response rate was 51.9% (95% CI: 45.7%-58.0%) in the sintilimab-combination group and 29.8% (95% CI: 22.1%-38.4%) in placebo-combination group. The incidence of grade 3 or higher adverse events was 61.7% in sintilimab-combination group and 58.8% in placebo-combination group.In Chinese patients with previously untreated, locally advanced or metastatic nonsquamous NSCLC, the addition of sintilimab to chemotherapy with pemetrexed and platinum resulted in considerably longer PFS than with chemotherapy alone with manageable safety profiles.

Objective The aim of this study was to explore the association between the expression of a long non-coding RNA (lncRNA), cancer susceptibility candidate 8 (CASC8), and pancreatic adenocarcinoma (PAAD). Materials and methods starBase database was used to perform differential expression, survival, and competing endogenous RNA (ceRNA) network and H19/miR-671 correlation analyses for CASC8 in 178 PAAD samples. Using the cBioPortal database website, we analyzed the alteration in CASC8 expression and its correlation with the overall survival in PAAD. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed using the circlncRNAnet database. Analysis of CASC8 polymorphisms was performed using the UCSC Xena database. Finally, the expression of CASC8 in Chinese PAAD tissues was validated by qPCR. Results The expression of CASC8 was observed to be high in 178 PAAD samples [fold change = 8.71, P = 0.0014, false discovery rate (FDR) = 0.04] and was related with poor prognosis, but not in pancreatic neuroendocrine tumor (pNET). CASC8 amplification was noted in 6% of the PAAD patients; however, the gene amplification did not affect the expression of CASC8 but was involved with the overall survival time of PAAD patients. Network analysis indicated that H19 is the ceRNA pair of CASC8 and that CASC8 competitively binds to miR-671 and might participate in the process of epithelial-to-mesenchymal transition (EMT). The correlation analysis showed that CASC8 was significantly negatively correlated with SMAD7. The analysis of CASC8 polymorphism showed that high copy number segment (CNS) of CASC8 is associated with low survival. Validation using PAAD tissues from Chinese patients was consistent with the in silico findings. Conclusion CASC8 is specifically expressed at a high level in PAAD and associated with poor prognosis, which might be through its interaction with H19, miR-671, and SMAD7. These results indicate that CASC8 could serve as a novel marker for predicting the prognosis and as a potential target for the therapy of PAAD.

Objective To evaluate the human epidermal growth factor receptor 2 (HER2) status in patients with breast cancer using multidetector computed tomography (MDCT)-based handcrafted and deep radiomics features. Methods This retrospective study enrolled 339 female patients (primary cohort, n=177; validation cohort, n=162) with pathologically confirmed invasive breast cancer. Handcrafted and deep radiomics features were extracted from the MDCT images during the arterial phase. After the feature selection procedures, handcrafted and deep radiomics signatures and the combined model were built using multivariate logistic regression analysis. Performance was assessed by measures of discrimination, calibration, and clinical usefulness in the primary cohort and validated in the validation cohort. Results The handcrafted radiomics signature had a discriminative ability with a C-index of 0.739 [95% confidence interval (95% CI): 0.661-0.818] in the primary cohort and 0.695 (95% CI: 0.609-0.781) in the validation cohort. The deep radiomics signature also had a discriminative ability with a C-index of 0.760 (95% CI: 0.690-0.831) in the primary cohort and 0.777 (95% CI: 0.696-0.857) in the validation cohort. The combined model, which incorporated both the handcrafted and deep radiomics signatures, showed good discriminative ability with a C-index of 0.829 (95% CI: 0.767-0.890) in the primary cohort and 0.809 (95% CI: 0.740-0.879) in the validation cohort. Conclusions Handcrafted and deep radiomics features from MDCT images were associated with HER2 status in patients with breast cancer. Thus, these features could provide complementary aid for the radiological evaluation of HER2 status in breast cancer.

Background: Lung cancer is the most commonly diagnosed malignant tumor worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer (NSCLC). The relationship between ZNF280A and LUAD has not been demonstrated and remains unclear. Methods: In this study, it was demonstrated that ZNF280A was upregulated in LUAD tissues compared with the normal tissues. Further investigations indicated that the overexpression/knockdown of ZNF280A could promote/inhibit proliferation, colony formation and migration of LUAD cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of ZNF280A could also suppress tumorigenicity of LUAD cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of ZNF280A and identified EIF3C as the potential target. Results: Furthermore, our study revealed that knockdown of EIF3C could inhibit development of LUAD in vitro, and alleviate the ZNF280A overexpression induced promotion of LUAD. Conclusions: In conclusion, our study showed, as the first time, ZNF280A as a tumor promotor for LUAD, whose function was carried out probably through the regulation of EIF3C.

Background: Neoantigens are newly formed antigens that have not been previously recognized by the immune system. They may arise from altered tumor proteins that form as a result of mutations. Although neoantigens have recently been linked to antitumor immunity in long-term survivors of cancers, such as melanoma and colorectal cancer, their prognostic and immune-modulatory role in many cancer types remains undefined. Objective: The purpose of this study is to identify prognostic markers for long-term extrahepatic cholangiocarcinoma (EHCC) survival. Methods: We investigated neoantigens in EHCC, a rare, aggressive cancer with a 5-year overall survival rate lower than 10%, using a combination of whole-exome sequencing (WES), RNA sequencing (RNA-seq), computational biophysics, and immunohistochemistry. Results: Our analysis revealed a decreased neutrophil infiltration-related trend of high-quality neoantigen load with IC50 Conclusion: We suggest that the WDFY3 neoantigens may affect prognosis by regulating antitumor immunity and that the WDFY3 neoantigens may be harnessed as potential targets for immunotherapy of EHCC.

Shida Yan,1,* Yingyi Wang,2,* Xiao Chen,1,* Yefan Zhang,1 Zhen Huang,1 Jianjun Zhao,1 Jianguo Zhou,1 Zhiyu Li,1 Xinyu Bi,1 Zhiwen Luo,1 Jianqiang Cai,1 Hong Zhao1 1Department of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Medical Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianqiang Cai; Hong ZhaoDepartment of Hepatobiliary Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 17 Panjiayuan Nanli, Chaoyang District, Beijing 100021, People’s Republic of ChinaEmail caijianqiang188@sina.com; zhaohong@cicams.ac.cnPurpose: This study aimed to investigate the clinicopathological features and prognosis of gallbladder neuroendocrine carcinoma (GB-NEC).Patients and Methods: Fifteen patients with GB-NEC and 171 patients with gallbladder adenocarcinoma (GB-ADC) treated in two tertiary medical centers between 2009 and 2015 were included. The clinicopathological features and prognostic risk factors of GB-NEC were analyzed retrospectively. A propensity score matching in a 1:2 ratio was used to compare the prognosis of GB-NEC and GB-ADC.Results: For patients with GB-NEC, the median age of patients was 58.4 years (range 26– 75), with a M:F ratio of 7:8. Based on 2010 WHO classification, ten cases were pathologically confirmed as NECs and five cases as MANECs. For TNM staging, eleven patients were stage III or above; while for Nevin staging, seven patients were stage IV or above. The 1-, 2-, and 3-year overall survival (OS) of GB-NEC were 60.0%, 38.8% and 31.1%, respectively, and the median survival time was 20.4 months. Patients with lymph node metastasis had significantly shorter survival than those without (OS: 10.4 vs 26.0 months, p< 0.05). Accordingly, patients of Nevin stage III had better OS than those of Nevin stage IV (p< 0.05), but other potential risk factors including gender, age, clinical symptoms, TNM stage, histopathologic subtype and treatment showed no significance. After the propensity score matching, the baseline variables had no significant difference between 15 patients with GB-NEC and 30 patients with GB-ADC, survival analysis showed GB-NEC had worse prognosis (3-year overall survival rate: 31.1% vs 63.8%, p< 0.01).Conclusion: Nevin staging helps classify patients of GB-NEC with different prognosis and the lymph node metastasis is a strong negative prognostic factor for OS. The propensity score analysis revealed even with the similar stage and treatment, GB-NEC still had worse OS than GB-ADC.Keywords: gallbladder, neuroendocrine carcinoma, adenocarcinoma, survival, propensity score matching

Concussion is a widely recognized environmental risk factor for neurodegenerative diseases, including Parkinson's disease (PD). Small-vessel disease of the brain has been reported to contribute to neurodegenerative diseases. In this study, we observed BBB disruption in wild-type (WT) mice, but not in matrix metalloproteinase 9 (MMP-9) knockout mice, subjected to single severe traumatic brain injury (ssTBI). Furthermore, treating ssTBI mice with the MMP-9 inhibitor GM6001 effectively maintained BBB integrity, promoted the elimination of damaged mitochondria via mitophagy, and then prevented neuronal death and progressive neurodegeneration. However, we did not observe this neuroprotective effect of MMP-9 inhibition in beclin-1-/+ mice. Collectively, these findings revealed that concussion led to BBB disruption via MMP-9, and that GM6001 prevented the development of PD via the autophagy pathway.

Huawei Corporation has made outstanding contributions to the economy, environment and industry of China. At the same time it inevitably faces some difficulties and challenges. This article will conduct the following related research discussions. a. Huawei's enterprise outlook, staff situation and main operation projects. b. Two challenge cases from 2018 to 2021 and specific analysis of Huawei's corporate social responsibility: the social performance of employees and the protection of their rights and interests, as well as the challenges in the negotiation between Huawei and government agencies. c. The stakeholders' corresponding quadrant and salience diagrams.

Considering the urgent demands of consumers for more all-natural food alternatives and the development trend of healthy times, seeking for new types foam and foam-forming healthcare food biomacromolecules is highly required to food valorization and industry. Herein, the enhanced foaming properties of bovine lactoferrin (LF) after forming complexes with ginsenoside Re (Re) and ginsenoside Rb1 (Rb1) was confirmed, while the interaction mechanism between LF and Re/Rb1 was also revealed. Detailly, multi-spectroscopy (absorption, fluorescence/3D fluorescence, CD spectroscopy), thermodynamic analysis and molecular docking results indicated that the interaction between LF and Re/Rb1 is mainly driven by hydrogen bonds and van der Walls forces accompanied by a conformational change of LF, forming LF-Re and LF-Rb1 complexes with a ratio of 1:1. Moreover, the foamability of LF (141%, LF: Re = 1 : 0, molar ratio) increased to be 172% (LF: Re = 1 : 10) and 200.67% (LF: Re = 1 : 20) after forming complexes with Re, while the foamability of LF (150%, LF: Rb1 = 1 : 0) increased to be 171.67% (LF: Rb1 = 1 : 10) and 189.5% (LF: Rb1 = 1 : 20) after forming complexes with Rb1. This work laid the groundwork for promoting the development of all-natural foam agents, also provided a feasible strategy to improve the applications of functional molecules in food valorization and industry.

The glioma-astrocyte interaction plays an important role in tumor microenvironment remodeling; however, the underlying mechanism has not been completely clarified. In this study, we show that glioma cells stimulate normal human astrocyte (NHA) into reactive astrocyte (RAS) in a non-contact manner. Additionally, the amount of O6-alkylguanine DNA alkyltransferase (MGMT) mRNA in exosomes (EXOs) released by RAS was significantly increased compared with that in non-reactive NHA. Importantly, MGMT-negative glioma cells can take up RAS-EXOs and acquire a temozolomide (TMZ)-resistant phenotype via the translation of exogenous exosomal MGMT mRNA both in vitro and in vivo. Our findings illuminate a novel phenomenon that may be a potent mechanism underlying glioma recurrence in which glioma-associated NHAs protect MGMT-negative glioma cells from TMZ-induced apoptosis by the functional intercellular transfer of exosomal MGMT mRNA.

Although there have existed kinds of gold nanoclusters (AuNCs) employed for various sensing purposes, scarce studies were proposed for systematically exploring their multiple routes of the sensing mechanism since that plays the critical role for broadening their analysis applications. Herein, casein-directed gold nanoclusters (AuNCs@casein) have been successfully raised for identifying their multiple routes towards the sensing mechanism. Initially, the current nanoclusters were synthesized in aqueous solution with a quantum yield of nearly 2.1%, which obviously showed the red fluorescence at 600 nm. Subsequently, we have explored three routes of quenching the fluorescence of AuNCs@casein by introducing thiourea, bromelain, and graphene oxide with amino groups (GO-NH2) as the representatives. To be specific, the formed bonds of Au-S between thiourea and AuNCs@casein achieved to quench their fluorescence, and the templates of AuNCs@casein destroyed by bromelain also showed the dramatically decreased fluorescence, and the energy transferring from the current AuNCs to GO-NH2 indeed lead to the fluorescent variations of AuNCs@casein. On the basis of these phenomena, AuNCs@casein was further applied for simply sensing thiourea, bromelain and GO-NH2 through the standard formats. Significantly, this study elaborated three quenching routes of AuNCs@casein and may provide more sensing strategies for other types of nanoclusters.

MicroRNAs have been found ectopically expressed in many cancers and play essential roles in tumor EMT progress. Recent studies identified decreased miR-940 expression in glioma cells and may serve as a tumor-suppressor. However, whether miR-940 involve in glioma EMT remain poorly understood. Here we confirmed that miR-940 was significantly reduced in glioma cells and tissues. Introduction of miR-940 dramatically suppressed invasion and migration of glioma cells. Gain-of-function experiments showed ZEB2 as a direct target of miR-940, knockdown of ZEB2 evidently repressed invasive capacity of glioma cells through EMT. Moreover, reintroduction of ZEB2 effectively reversed the tumor suppressive effect of miR-940 treatment. In vivo study showed reduced tumor cell motion in miR-940-injected groups. Spearman's correlation analysis indicated inversely correlated expression of ZEB2 and miR-940 in gliomas and NBTs. Altogether, miR-940-ZEB2 cascade may play important roles in glioma cells invasion and EMT progression, and might provide new therapeutic approaches for better outcomes of GBM patients.

Malignant tumors posed severe threat to human health, and various efforts have been contributed towards assaying tumor markers, howbeit, achieving to identify the multiple targets by one single analytical mode is in demand. Hereby, three kinds of aptamer-functionalized silver and silver/gold nanoclusters (DNA-AgNCs and DNA-Ag/AuNCs) were originally synthesized, and possessed the specific recognition ability for their corresponding targets. Specifically, the fluorescence of AgNCs or Ag/AuNCs was quenched by introducing graphene oxide (GO), and more competitive interactions between tumor markers and their aptamers occurred with the targets added, thus facilitating their fluorescence recovered. Based on AgNCs or Ag/AuNCs cooperating with GO, this sensing mode was subsequently employed for detecting mucin 1 in a linear range of 1.33–200 ng/mL with a detection limit of 0.18 ng/mL. Meanwhile, this method was also applied to examine carcinoembryonic antigen and cancer antigen 125, and showed the linear range of 6.7 ng/mL–13.3 μg/mL with a detection limit of 3.18 ng/mL for CEA, while CA125 sensing acquired a linear range of 2 ng/mL–6.7 μg/mL accompanied by a detection limit of 1.26 ng/mL. Besides, this strategy provided the potential ways to identify other tumor markers by designing their corresponding nanoclusters with the aptamers.

Hereby, one type of facile-green copper nanoclusters (CuNCs) derived from ovalbumin (CuNCs@OVA) has been innovatively synthesized with a quantum yield of 5.8%. Meaningfully, this nanoclusters exhibited the multiple advantages including satisfactory photostability, low-toxicity and satisfactory stability. By the characterizations in detail, there existed –COOH, –OH, –NH2 and C˭O groups on their surfaces of the prepared CuNCs@OVA, providing their possible applications for sensing. Significantly, the fluorescence of the as-prepared CuNCs@OVA could be quenched by introducing Vitamin B1, while they exhibited the enhanced fluorescence by adding into doxycycline. On the basis of both the fluorescence quenching and enhancement, CuNCs were further employed as the fluorescent probe for assaying both Vitamin B1 and doxycycline. Consequently, it displayed a linear range of 1–1000 nM with the detection limit of 380 pM for assaying VB1, as well as a linear range from 1 to 1000 μM with the detection limit of 270 nM for detecting doxycycline, which indicates the potential applications of CuNCs@OVA for the actual-sample detections.

Chronic kidney disease (CKD) is a worldwide public health problem. Uremic retention solutes such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) are accumulated in CKD patients and are associated with the incidence of CKD progression. Amino acids are the major precursors of uremic retention solutes in gut. The dynamic change of amino acid metabolism in the gut during CKD progression has not been reported previously. In this paper, we studied the dynamic change of gut IS/PCS precursor and amino acid metabolism profile during CKD progression in 5/6 nephrectomized (5/6Nx) rats model. The related gut microbiota and metagenome profile was also studied. Rat plasma, urine and feces were collected at different time points after nephrectomization. Plasma IS and PCS, fecal indole (the precursor of IS), p-cresol (the precursor of PCS) and 19 kinds of amino acids were analyzed by LC-MS. During CKD progression, 5/6 Nx rats showed increased plasma IS, PCS concentration and increased fecal indole, p-cresol concentration. 5/6 Nx rats also showed disordered gut amino acids metabolism profile which became more significant along with the progession of CKD. The abundance of some specific gut bacteria also changed significantly in 5/6 Nx rats. The 16S rDNA sequencing data of gut microbiota was further analyzed by an online tool PICRUSt, a large-scale computational method for metagenomes prediction with 16S rDNA sequencing data. The content of each gene was compared between the two groups by Mann-Whitney U test, and then the significantly regulated genes in 5/6 Nx group were subjected to KEGG website. The amino acid metabolism related genes were picked out. Most of these genes are more abundant in 5/6 Nx groups. Our study showed that gut amino acids metabolism profile was disordered with CKD progression, which was highly related to the gut microbiota dysbiosis and metagenome change. And that regulation of gut amino acids metabolism pathway may be a possible way to intervene the progression of CKD.

Herein, blue-fluorescence carbon dots (CDs) derived from carboxymethylcellulose have been innovatively synthesized with well-distributed sizes. Subsequently, a sensitive assay of isoniazid and H2O2 has been further proposed based on the hydrogen bond formation between CDs and isoniazid and the further oxidation of isoniazid by H2O2. To be specific, the richness of carboxyl groups and hydroxyl groups on the CDs enables isoniazid to be adsorbed on the surface of CDs, resulting in effective fluorescence quenching through aggregation. Moreover, we have taken the advantage of the oxidation reaction between isoniazid and H2O2 to achieve the immediate recovery of the fluorescence of CDs. Consequently, quantitative evaluation of H2O2 in a linear range from 4 nM to 800 nM has been proposed along with the range from 20 nM to 6 μM for isoniazid, and its practicability is subsequently validated by detecting actual samples, suggesting that the current strategy may broaden the avenues for sensing both isoniazid and H2O2.

Metastasis significantly reduces the survival rate of osteosarcoma (OS) patients. Therefore, identification of novel targets remains extremely important to prevent metastasis and treat OS. In this report, we show that SPARCL1 is downregulated in OS by epigenetic methylation of promoter DNA. In vitro and in vivo experiments revealed that SPARCL1 inhibits OS metastasis. We further demonstrated that SPARCL1-activated WNT/β-catenin signaling by physical interaction with various frizzled receptors and lipoprotein receptor-related protein 5/6, leading to WNT-receptor complex stabilization. Activation of WNT/β-catenin signaling contributes to the SPARCL1-mediated inhibitory effects on OS metastasis. Furthermore, we uncovered a paracrine effect of SPARCL1 on macrophage recruitment through activated WNT/β-catenin signaling-mediated secretion of chemokine ligand5 from OS cells. These findings suggest that the targeting of SPARCL1 as a new anti-metastatic strategy for OS patients.

Hereby, one kind of facile carbon dots (CDs) from hydroxypropylmethyl cellulose (HPMC) has been successfully provided, which obviously emitted blue fluorescence. With the related characterizations in detail, the CDs prepared here mainly consisted of C and O, owing to the functional groups of -OH and C=O on their surfaces. Likewise, the CDs also showed multiple advantages, including excellent photostability, superior dispersity and desirable stability. Moreover, the CDs were applied for sensing ciprofloxacin due to forming complexes with ciprofloxacin, thus leading to the fluorescence quenching of CDs. This proposed method was permitted to sense ciprofloxacin in a linear range of 10 nM L-1 - 90 μM L-1, suggesting that it may broaden the sensing ways for assaying ciprofloxacin.

// Tongle Zhi 1, * , Tianfu Yu 1, * , Minhong Pan 2, * , Er Nie 1 , Weining Wu 1 , Xiefeng Wang 1 , Ning Liu 1 , Yongping You 1 , Yingyi Wang 1 and Junxia Zhang 1 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China * These authors have contributed equally to this work Correspondence to: Yingyi Wang, email: lindsay_wang3431@126.com Junxia Zhang, email: zjx232@njmu.edu.cn Keywords: EZH2; miRNA; prognosis; TMZ; glioma Received: June 28, 2017 Accepted: August 27, 2017 Published: October 24, 2017 ABSTRACT Recent data have been shown that EZH2 is a critical oncogene via the repression of tumor suppressor genes in human cancers. In our study, we performed a genome-wide miRNA screen with a bioinformatics analysis to identify EZH2 specific miRNAs. Of these miRNAs, miR-524-5p and miR-324-5p were decreased in glioma tissues, and confered poor prognosis for glioma patients. Upregulation of miR-524-5p and miR-324-5p reduced glioma cell proliferation and increased temozolomide (TMZ) chemosensitivity by targeting EZH2. Importantly, the effection of miR-524-5p and miR-324-5p on cell proliferation and TMZ chemosensitivity in glioma were reversed by expression of EZH2 cDNA. Further, miR-524-5p and miR-324-5p overexpression suppressed glioma growth and prolonged survival in an intracranial xenograft model. Multivariate Cox regression analysis revealed that miR-524-5p was an independent prognostic factor in gliobalstoma patients. Taken together, these data indicate that miRNA-driven EZH2 repression may provide evidence of the molecular mechanism for gliomagenesis and the novel therapeutic targets for glioma.

// Tianfu Yu 1, * , Yingyi Wang 1, * , Qi Hu 1, * , WeiNing Wu 1, * , Youzhi Wu 2 , Wenjin Wei 3 , Dongfeng Han 4 , Yongping You 1 , Ning Lin 5 and Ning Liu 1 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China 2 Department of Neurosurgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China 3 Department of Neurosurgery, The Affiliated Ganzhou Hospital of Nanchang University, Ganzhou, Jiangxi Province, China 4 Department of Neurosurgery, Xuzhou Central Hospital, Xuzhou, China 5 Department of Neurosurgery, The First People’s Hospital Chuzhou, Chuzhou, China * These authors have contributed equally to this work Correspondence to: Ning Lin, email: lin2007512@vip.163.com Ning Liu, email: liuning0853@126.com Keywords: EZH2; EZH2 inhibitor; epigenetics; glioma; glioma stem cell Received: April 18, 2017 Accepted: August 04, 2017 Published: September 27, 2017 ABSTRACT Enhancer of zeste homolog 2 (EZH2) is the catalytic unit of polycomb repressive complex 2 (PRC2) which epigenetically silences many genes involved in tumor-suppressive mechanisms via the trimethylation of lysine 27 of histone H3 (H3K27me3). We recently found that overexpression of EZH2 was associated with poor outcome of glioblastoma (GBM). In this study, we examined the antitumor effects of the EZH2 inhibitor GSK343 on glioma cells in vitro and in vivo . The proliferation and cell cycle of glioma cells was measured. Wound healing assay and transwell invasion assay were performed to evaluate the capacity of migration and invasion of glioma cells. Western blot, qPCR, immunoprecipitation and fluorescent staining were used to test the levels of EZH2 and associated proteins. Spheroid formation assay and clonogenic assays were conducted to assess the stemness of glioma stem cells. Finally, the effect of GSK343 was measured through a nude mice model with intracranially xenotransplanted glioma. We found that GSK343 reduced proliferation, attenuated cell motility and reversed epithelial-mesenchymal transition in U87 and LN229 glioma cells. GSK343 also suppressed the stemness of cell lines and patient derived glioma stem cells. Further, GSK343 inhibited histone H3K27 methylation and upregulated the expression of EZH2 target genes thereby regulating the levels of markers involved in epithelial-mesenchymal transition and stemness. Taken together, our results indicate that GSK343 could be a potential drug against glioblastoma.

// Xu Zhou 1, * , Weining Wu 1, * , Ailiang Zeng 1 , Er Nie 1 , Xin Jin 1 , Tianfu Yu 1 , Tongle Zhi 1 , Kuan Jiang 1 , Yingyi Wang 1 , Junxia Zhang 1 and Yongping You 1 1 Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China * These authors have contributed equally to this work Correspondence to: Yongping You, email: yypl9@njmu.edu.cn Keywords: glioblastoma, proliferation, TMZ resistance, microRNA, p53 Abbreviations: GBM, glioblastoma multiforme; miRNAs, microRNAs; TMZ, temozolomide; CCK-8, Cell Counting Kit-8; EdU, 5-ethynyl-2′-deoxyuridine Received: February 18, 2017 Accepted: July 29, 2017 Published: August 24, 2017 ABSTRACT Glioblastoma multiforme is the most common primary malignancy in the brain and confers a uniformly poor prognosis. MicroRNAs have been shown to activate or inhibit tumorigenesis. Abnormalities in the p53 signaling pathway are found in various cancers and correlate with tumor formation. We examined the expression of microRNA-141-3p (miR-141-3p) in glioma of different grades by analysis of expression profiling databases and clinical specimens. Cell proliferation and flow cytometry assays were performed to evaluate the promotion of miR-141-3p in proliferation, cell cycle, apoptosis, and temozolomide resistance of glioblastoma cells in vitro . Bioinformatics analyses, luciferase reporter assays, and immunoblotting showed that p53 is a target gene of miR-141-3p. A significant inverse correlation was observed between expression of miR-141-3p and p53 in glioma and normal brain tissues (R 2 =0.506, P

Herein, carbon dots (CD@Papain) from papain have been originally synthesized in aqueous solution along with a quantum yield of 6.2%, and showed cyan fluorescence at 435 nm. Meanwhile, papain-templated Au nanoclusters (AuNCs@Papain) were prepared with the same precursor. On the basis of the two types of nanomaterials, CD@Papain and AuNCs@Papain have been designed to assemble as one nanosensor (termed as CD-AuNCs@Papain) through a typical cross-linking reaction. Significantly, it not only emitted the dual-emission fluorescent signals with the same excitation, but also can assay multiple targets through exhibiting cyan, yellow, and red emission respectively. Thereby, H 2 O 2 , doxycycline and I - can be detected by CD-AuNCs@Papain. The mechanism of the fluorescence variations of CD-AuNCs@Papain: Au(0) of CD-AuNCs@Papain oxidized as Au(I) by H 2 O 2 , the formation of hydrogen bonds between the CD-AuNCs@Papain and I - , the inner filter effect (IFE) occurring caused by tetracyclines. Meanwhile, the detection limits of H 2 O 2 , doxycycline and I - were obtained as 0.3 nM, 0.2 nM, and 0.6 nM at a signal-to-ratio of 3, respectively. These results suggested that the nanoprobe here has provided the possibility for rapidly assaying multiple targets with the acceptable selectivity.

Background MIR155 host gene (MIR155HG) is a long noncoding RNA that has been considered as the primary micro (mi)RNA of miR-155. MIR155HG plays an essential role in hematopoiesis, inflammation, and tumorigenesis. Our study investigated the clinical significance, biological function, mechanisms, and small-molecule inhibitors of the MIR155HG/miR-155 axis in glioma. Methods We analyzed the expression of the MIR155HG/miR-155 axis and the correlation with glioma grade and patient survival using 2 different glioma gene expression datasets. Biological significance was elucidated through a series of in vitro and in vivo experiments. Furthermore, we conducted a high-throughput screening for small molecules to identify a potential inhibitor of the MIR155HG/miR-155 axis. Results Increased MIR155HG was associated with glioma grade, mesenchymal transition, and poor prognosis. Functionally, MIR155HG reduction by small interfering RNA inhibited cell proliferation, migration, invasion, and orthotopic glioma growth by repressing the generation of its derivatives miR-155-5p and miR-155-3p. Bioinformatics and luciferase reporter assays revealed that protocadherin 9 and protocadherin 7, which act as tumor suppressors by inhibiting the Wnt/β-catenin pathway, were direct targets of miR-155-5p and miR-155-3p, respectively. Finally, we identified NSC141562 as a potent small-molecule inhibitor of the MIR155HG/miR-155 axis. Conclusions Our results demonstrate that the MIR155HG/miR-155 axis plays a critical role in facilitating glioma progression and serves as a prognostic factor for patient survival in glioblastoma. High-throughput screening indicated that the MIR155HG/miR-155 axis inhibitor NSC141562 may be a useful candidate anti-glioma drug.

We present a novel photovoltaic self-powered gas sensor based on a p-type single-walled carbon nanotube (SWNT) and n-type silicon (n-Si) heterojunction. The energy from visible light suffices to drive the device owing to a built-in electric field (BEF) induced by the differences between the Fermi levels of SWNTs and n-Si.

Rationale and Objectives Ki-67 is one of the most important biomarkers of breast cancer traditionally measured invasively via immunohistochemistry. In this study, deep learning based radiomics models were established for preoperative prediction of Ki-67 status using multiparametric magnetic resonance imaging (mp-MRI). Materials and Methods Total of 328 eligible patients were retrospectively reviewed [training dataset (n = 230) and a temporal validation dataset (n = 98)]. Deep learning imaging features were extracted from T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and contrast enhanced T1-weighted imaging (T1+C). Transfer learning techniques constructed four feature sets based on the individual three MR sequences and their combination (i.e., mp-MRI). Multilayer perceptron classifiers were trained for final prediction of Ki-67 status. Mann-Whitney U test compared the predictive performance of individual models. Results The area under curve (AUC) of models based on T2WI,T1+C,DWI and mp-MRI were 0.727, 0.873, 0.674, and 0.888 in the training dataset, respectively, and 0.706, 0.829, 0.643, and 0.875 in the validation dataset, respectively. The predictive performance of mp-MRI classification model in the AUC value was significantly better than that of the individual sequence model (all p Conclusion In clinical practice, a noninvasive approach to improve the performance of radiomics in preoperative prediction of Ki-67 status can be provided by extracting breast cancer specific structural and functional features from mp-MRI images obtained from conventional scanning sequences using the advanced deep learning methods. This could further personalize medicine and computer aided diagnosis.

Heterostructured metal oxides with large specific surface area are crucial for constructing gas sensors with high performance. However, using slurry-coating and screen-printing methods to fabricate gas sensors cannot result in high uniformity and reproducibility of the sensors. Here, NiO nanowalls decorated by SnO

Glioma is one of the most frequent primary malignant brain tumours in adults and accumulating evidence has shown that microRNAs (miRNAs) are associated with various types of tumours, including glioma. It is essential to acquire a better understanding of the roles and mechanisms of miRNAs in WNT-driven glioblastoma (GBM). Here, we report that miR-206 inhibited the WNT/β-catenin pathway by directly targeting Frizzled 7 (FZD7) and functioned as a tumour-suppressor in glioma. The expression of miR-206 in human samples and glioma cells was assessed by real-time quantitative PCR (RT-qPCR), fluorescence in situ hybridization (FISH), and histological analysis. Cell Counting Kit-8 (CCK-8), colony formation, EdU, flow cytometry, wound healing, transwell invasion, and three-dimensional migration were performed to observe cellular proliferation, migration, and invasion in vitro. The effects of miR-206 in vivo were investigated using a xenograft nude mouse model. miR-206 expression was significantly downregulated in glioma specimens. FZD7 was confirmed as a direct target of miR-206. GBM cell proliferation, migration, and invasion were blocked by restoring the expression of miR-206. Moreover, intracranial glioma models demonstrated an inhibitory effect of miR-206 on intracranial glioma tumour growth. Our results suggested that miR-206 plays a key role in blocking the WNT/β-catenin signalling pathway by suppressing FZD7 and provides a prospective therapeutic strategy for the treatment of malignant glioma and other WNT-driven tumours.

Objectives: This is the first study to investigate the oxidative stress (OxS) levels in drug-free bipolar disorder (BD) patients and their association with lithium response.Methods: A total...

Alzheimer’s disease (AD) is the most common neurodegenerative disorder worldwide and causes severe financial and social burdens. Despite much research on the pathogenesis of AD, the neuropathological mechanisms remain obscure and current treatments have proven ineffective. In the past decades, transgenic rodent models have been used to try to unravel this disease, which is crucial for early diagnosis and the assessment of disease-modifying compounds. In this review, we focus on transgenic rodent models used to study amyloid-beta pathology in AD. We also discuss their possible use as promising tools for AD research. There is still no effective treatment for AD and the development of potent therapeutics are urgently needed. Many molecular pathways are susceptible to AD, ranging from neuroinflammation, immune response, and neuroplasticity to neurotrophic factors. Studying these pathways may shed light on AD pathophysiology as well as provide potential targets for the development of more effective treatments. This review discusses the advantages and limitations of these models and their potential therapeutic implications for AD.

Pulmonary lymphoepithelioma-like carcinoma (LELC) is a rare type of non-small cell lung cancer. The clinical course and prognosis of advanced LELC are largely unknown. Few reports have discussed multimodality treatment for LELC.This retrospective study identified records from 2007 to 2018 of pulmonary LELCs and other lung cancer subtypes from hospital information systems and collected demographic, treatment, and survival data.In this cohort of 69 LELCs (median age: 55.4), more female, non-smokers, and fewer right upper lobe tumors (4.3%) were observed in the LELC subgroup compared with others. The median overall survival (OS) of LELCs was 40 months, superior to other subtypes (p 0.05), except adenocarcinoma (p = 0.062). Patients with early stage disease and primary tumor resection tended to have better OS in univariate analysis, but surgery was the independent predictor in multivariate analysis (0.042). The median OS of 52 advanced LELCs was 22.7 months. Platinum-based chemotherapy and radiotherapy with curative purpose were independent predictors for OS of advanced LELCs (p = 0.004 and 0.003, respectively). For patients who received multimodality treatment in advanced setting, the median line of treatments was two. The overall response and disease-control rates were 61.8% and 80.6%, respectively. There were no differences in response or survival between patients receiving taxane-combined and non-taxane-combined chemotherapy. However, patients treated with radiotherapy in upfront settings had significantly favorable response and progression-free survival compared with those without. One case with PD-L1 positivity had pembrolizumab in the 4Patients who underwent radical resection of primary tumors had better prognoses. Patients with advanced LELC could achieve satisfactory survival by receiving multimodality treatment, including platinum-based chemotherapy and/or radiotherapy. Immune checkpoint inhibitors may be part of future therapies. A well-organized clinical trial should be performed to determine the optimal treatment regimen.

The natural compound Zerumbone (hereinafter referred to as ZER), a monocyclic sesquiterpenoid, has been reported to possess many pharmacological properties, including antioxidant and anti-inflammatory properties. This study aimed to investigate the underlying mechanism of ZER against acute liver injury (ALI) in CCl4-induced mice models. ICR mice were pretreated intraperitoneally with ZER for five days, then received a CCl4 injection two hours after the last ZER administration and were sacrificed 24 h later. Examination of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities and the histopathological analysis confirmed the hepatoprotective effect of ZER. Biochemical assays revealed that ZER pretreatment recovered the activities of antioxidant enzymes superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), restored the glutathione (GSH) reservoir, and reduced the production of malondialdehyde (MDA), all in a dose-dependent manner. Furthermore, administration of ZER in vivo reduced the release amounts of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-&alpha, ) and inhibited the increased protein levels of Toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-&kappa, B) p-p65, and cyclooxygenase (COX-2). Further studies in lipopolysaccharide (LPS)-induced Raw264.7 inflammatory cellular models verified that ZER could inhibit inflammation via inactivating the TLR4/NF-&kappa, B/COX-2 pathway. Thus, our study indicated that ZER exhibited a hepatoprotective effect against ALI through its antioxidant and anti-inflammatory activities and the possible mechanism might be mediated by the TLR4/NF-&kappa, B/COX-2 pathway. Collectively, our studies indicate ZER could be a potential candidate for chemical liver injury treatment.

Background Glioblastoma multiforme (GBM) is the most common and aggressive form of astrocytoma among adult brain tumors. Multiple studies have shown that long non-coding RNAs (lncRNAs) play important roles in acting as molecular sponge for competing with microRNAs (miRNAs) to regulate downstream molecules in tumor progression. We previously reported that miR155 host gene (miR155HG), an lncRNA, and its derivative miR-155 promote epithelial-to-mesenchymal transition in glioma. However, the other biological functions and mechanisms of miR155HG sponging miRNAs have been unknown. Considering ANXA2 has been generally accepted as oncogene overexpressed in a vast of cancers correlated with tumorigenesis, which might be the target molecule of miR155HG sponging miRNA via bioinformatics analysis. We designed this study to explore the interaction of miR155HG and ANXA2 to reveal the malignancy of them in GBM development. Methods The expression of miR155HG was analyzed in three independent databases and clinical GBM specimens. Bioinformatics analysis was performed to assess the potential tumor-related functions of miR155HG. The interaction of miR155HG and miR-185 and the inhibition of ANXA2 by miR-185 were analyzed by luciferase reporter experiments, and biological effects in GBM were explored by colony formation assays, EDU cell proliferation assays, flow cytometric analysis and intracranial GBM mouse model. Changes in protein expression were analyzed using western blot. We examined the regulatory mechanism of ANXA2 on miR155HG in GBM by gene expression profiling analysis, double immunofluorescence staining, chromatin immunoprecipitation and luciferase reporter assays. Results We found that miR155HG was upregulated in GBM tissues and cell lines. Bioinformatic analyses of three GBM databases showed that miR155HG expression levels were closely associated with genes involved in cell proliferation and apoptosis. Knocking down miR155HG suppressed GBM cell proliferation in vitro, induced a G1/S-phase cell cycle arrest, and increased apoptosis. We also found that miR155HG functions as a competing endogenous RNA for miR-185. Moreover, miR-185 directly targets and inhibits ANXA2, which exhibits oncogenic functions in GBM. We also found that ANXA2 promoted miR155HG expression via STAT3 phosphorylation. Conclusion Our results demonstrated that overexpressed miR155HG in GBM can sponge miR-185 to promote ANXA2 expression, and ANXA2 stimulates miR155HG level through phosphorylated STAT3 binding to the miR155HG promoter. We establish the miR155HG/miR185/ANXA2 loop as a mechanism that underlies the biological functions of miR155HG and ANXA2 in GBM and further suggest this loop may serve as a therapeutic target and/or prognostic biomarker for GBM. Electronic supplementary material The online version of this article (10.1186/s13046-019-1132-0) contains supplementary material, which is available to authorized users.

Glioma is one of the most prevalent primary malignant brain tumours among adults, and accumulating evidence has shown that dysregulation of microRNAs (miRNAs) is associated with various types of cancers, including glioma. It is necessary to gain a better understanding of the roles and mechanisms of action of miRNAs in WNT-driven glioblastoma multiforme (GBM). Here, we report that miR-206 inhibits the WNT/β-catenin pathway by directly targeting Frizzled 7 (FZD7) mRNA and functions as a tumour suppressor in glioma. The expression of miR-206 in human glioma samples and glioma cells was assessed by reverse-transcription quantitative PCR, fluorescence in situ hybridisation, and histological analysis. Cell Counting Kit-8, colony formation, 5-ethynyl-2’-deoxyuridine incorporation, flow-cytometric, wound healing, Transwell invasion, and three-dimensional migration assays were performed to examine glioma cell proliferation, migration, and invasion in vitro. The effects of miR-206 in vivo were investigated in a xenograft nude-mouse model. MiR-206 expression was significantly lower in glioma specimens than in normal control samples. FZD7 was confirmed as a direct target gene of miR-206. GBM cell proliferation, migration, and invasion were blocked after restoration of miR-206 expression. Moreover, intracranial glioma models revealed an inhibitory effect of miR-206 on intracranial glioma tumour growth. Our results suggest that miR-206 plays a key role in the blockade of the WNT/β-catenin signalling pathway by down-regulating FZD7 and may be a promising therapeutic agent against malignant glioma and other WNT-driven tumours.

Integrating kinds of bactericides as one entirety shows prospect for improving antibacterial efficiency, thus a new type of nanoclusters based on bactericide-directed herein emerged as a combination for achieving a higher antibacterial effect. Specifically, an easily operated approach for preparing bacitracin-directed silver, gold, and copper nanoclusters (AgNCs, AuNCs, and CuNCs, respectively) was proposed. Meanwhile, AgNCs@Bacitracin, AuNCs@Bacitracin, and CuNCs@Bacitracin emitted cyan, yellow, and red colors of fluorescence, respectively, and different sizes and nitrogen contents of these nanoclusters played a critical role for their fluorescence alterations. Significantly, AgNCs@Bacitracin exhibited robust bacteria-killing efficiency than other nanoclusters, owing to its marked damage on the bacterial membrane. Additionally, propidium iodide (PI) staining indicated the bacterial membrane damage of 72.3% to the bacteria population followed by the treatment with AgNCs@Bacitracin, and the introduction of AgNCs@Bacitracin lead to the higher reactive oxygen species (ROS) production, facilitating their attractive antibacterial activity. Moreover, this strategy of developing new nanoclusters broadened the avenues for designing the improved antibacterial materials.

Background Epithelial cell transformation sequence 2 (ECT2) is upregulated in glioma and promotes glioma cell proliferation. A preliminary experiment showed a positive correlation between ECT2 and pituitary tumor-transforming gene 1 (PTTG1). The aim of this study was to explore how ECT2 affects PTTG1 to influence the proliferation of glioma cells. Methods The expression of ECT2 in glioma was detected by western blot and reverse transcription PCR. The effect of ECT2 on glioma proliferation was examined using cell proliferation-related assays and in vivo experiments. The effect of ECT2 on the stability of E2F transcription factor 1 (E2F1) and the expression of PTTG1 were examined by western blot, co-immunoprecipitation, and in vivo ubiquitination assays. Results ECT2 was upregulated in gliomas and was negatively correlated with prognosis; its downregulation inhibited glioma cell proliferation. Furthermore, ECT2 regulated PTTG1 expression by affecting the stability of E2F1, thereby affecting the glioma cell proliferation. In addition, the deubiquitinating enzyme proteasome 26S subunit, non-ATPase 14 (PSMD14) affected the degradation of E2F1 and regulated the stability of E2F1. Interestingly, ECT2 regulated the expression of PSMD14. Conclusion In this study, we clarify a new mechanism by which ECT2 regulates the expression of PTTG1 and thus affects the proliferation of glioma cells: ECT2 influences the stability of E2F1 by regulating the expression of the deubiquitinating enzyme PSMD14, thereby affecting the expression of PTTG1. Intensive and extensive understanding of the mechanism of ECT2 in glioma proliferation may provide an opportunity for the development of new molecular therapeutic targets for glioma treatment.