PD-L1 up-regulation in cancer contributes to immune evasion by tumor cells. Here, we show that Wnt ligand and activated EGFR induce the binding of the β-catenin/TCF/LEF complex to the CD274 gene promoter region to induce PD-L1 expression, in which AKT activation plays an important role. β-Catenin depletion, AKT inhibition, or PTEN expression reduces PD-L1 expression in tumor cells, enhances activation and tumor infiltration of CD8+ T cells, and reduces tumor growth, accompanied by prolonged mouse survival. Combined treatment with a clinically available AKT inhibitor and an anti–PD-1 antibody overcomes tumor immune evasion and greatly inhibits tumor growth. In addition, AKT-mediated β-catenin S552 phosphorylation and nuclear β-catenin are positively correlated with PD-L1 expression and inversely correlated with the tumor infiltration of CD8+ T cells in human glioblastoma specimens, highlighting the clinical significance of β-catenin activation in tumor immune evasion.

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Photodynamic therapy (PDT) and photothermal therapies (PTTs) are both promising strategies for effective tumor therapy. However, the absence of O 2 at tumor sites hinders the sustained response of photosensitizers. Here, we develop a recycled cerium oxide (CeO 2 ) catalase nanozyme-loaded hyaluronic acid nanovesicle to address the hypoxic tumor microenvironments and targeted delivery of the photosensitizers [indocyanine green (ICG)] to tumors. A polysaccharide complex effectively modifies the surface of a polyethylenimine phenylboronic acid nanostructure to achieve the CeO 2 nanozyme-loading nanovesicles that exhibit both tumor-targeted enhancement and an improved hypoxic microenvironment. Also, the hydrogen peroxide responsiveness and acid-sensitive cleavage of phenylboronic acid specifically disintegrate the ICG/nanozyme coloaded nanovesicles in the tumor microenvironment. The in vitro synergistic tests and tumor suppression rate tests indicated that the cerium oxide nanozyme significantly improves the outcomes of PDT via ceriumelement valence state recycling and hypoxia improvement, thus enhancing the tumor suppression efficiency. This pH/H 2 O 2responsive nanozyme/ICG codelivery system provides a good carrier model for improving the tumor microenvironment and increasing the efficiency of tumor-targeted PTT and PDT therapies.

Bromodomain-containing 4 (Brd4) is a histone modification reader and transcriptional regulator that has been reported to interact with acetylated lysine histone motifs transcription factors (TFs), transcription co-activators and rna polymerase ii. The selective small molecule inhibitor JQ1, which binds competitively to bromodomains, has been reported to exhibit anti-proliferative effects in various types of cancer. Previous studies on the mechanism of action of JQ1 mostly focused on a specific tumor type or disease; however, the general mechanism through which JQ1 affects various tumors remains to be determined. in the present study, chromatin immunoprecipitation sequencing data for BRD4 and its expression profiles in six cancer cell lines were integrated and analyzed systematically. The results indicated that Brd4 binds to enhancers with histone H3 acetylated at lysine 27 (H3K27ac) and mediator complex subunit 1 in a cell type-specific manner, as well as binds to promoter regions with the oncogenic TFs MYc and e2F1 in a cell type-common manner. The cell type-common sites across the six cell types investigated were found to be functionally important for tumorigenesis, whereas the cell type-specific sites were functionally enriched with the cell identity, all of which were sensitive to JQ1 treatment. Furthermore, a core set of JQ1-regulated Brd4 binding genes were obtained, which were significantly inhibited by JQ1 in various cancer cell lines and contributed to hallmarks of cancer. These results implied a common mechanism underlying the therapeutic effects of JQ1 and suggested its potential suitability as an anti-cancer drug targeting Brd4-mediated transcriptional regulation.

Crown profile models were developed for Chinese fir (Cunninghamia lanceolata) in Shunchang County, Fujian Province. We used data from 360 trees located in 65 pure, even-aged, and unthinned temporary plots. The data was divided into three groups according to site index. Nine models, including models for upper crown, lower crown, and entire crown, were fit; the optimal ones in each group were validated and chosen to estimate crown shape. The optimal models explained at least 70% variability in crown radius. In addition, models for crown width, height above ground to crown base, and height above ground to largest crown radius were also developed to facilitate the convenient simulation of crown profile models. These three models explained 85.4%, 85.1%, and 86.9%variability. All models also passed the F-test and residual test. The 3D images of a single tree and stands were presented by OpenGL technology on visual c++ platform based on the proposed models. Tree growth was compared and analyzed using crown profile curves under constrained conditions. The analysis results accorded with plant growth.

BackgroundIt has been reported that D1 receptor (D1R) activation reduces GABAA receptor (GABAAR) current, and baicalin (BAI) displays therapeutic efficacy in diseases involving cognitive impairment.MethodsWe investigated the mechanisms by which BAI could improve DA-induced minimal hepatic encephalopathy (MHE) using immunoblotting, immunofluorescence, and co-immunoprecipitation.ResultsBAI did not induce toxicity on the primary cultured neurons. And no obvious toxicity of BAI to the brain was found in rats. DA activated D1R/dopamine and adenosine 3′5′-monophosphate-regulated phospho-protein (DARPP32) to reduce the GABAAR current; BAI treatment did not change the D1R/DARPP32 levels but blocked DA-induced reduction of GABAAR levels in primary cultured neurons. DA decreased the interaction of GABAAR with TrkB and the expression of downstream AKT, which was blocked by BAI treatment. Moreover, BAI reversed the decrease in the expression of GABAAR/TrkB/AKT and prevented the impairment of synaptogenesis and memory deficits in MHE rats.ConclusionsThese results suggest that BAI has neuroprotective and synaptoprotective effects on MHE which are not related to upstream D1R/DARPP32 signaling, but to the targeting of downstream GABAAR signaling to TrkB.

BackgroundMalignant glioma is the most devastating and aggressive tumour in the brain and is characterised by high morbidity, high mortality and extremely poor prognosis. The main purpose of the present study was to investigate the effects of schisandrin B (Sch B) on glioma cells both in vitro and in vivo and to explore the possible anticancer mechanism underlying Sch B-induced apoptosis and cell cycle arrest.MethodsThe anti-proliferative ability of Sch B on glioma cells were assessed by MTT and clony formation assays. Flow cytometric analysis was used to detect cell cycle changes. Apoptosis was determined by Hoechst 33342 staining and annexin V/PI double-staining assays. The mitochondrial membrane potential was detected by Rhodamine 123 staining. The in vivo efficacy of Sch B was measured using a U87 xenograft model in nude mice. The expressions of the apoptosis-related and cell cycle-related proteins were analysed by western blot. Student’s t-test was used to compare differences between treated groups and their controls.ResultsWe found that Sch B inhibited growth in a dose- and time-dependent manner as assessed by MTT assay. In U87 and U251 cells, the number of clones was strongly suppressed by Sch B. Flow cytometric analysis revealed that Sch B induced cell cycle arrest in glioma cells at the G0/G1 phase. In addition, Sch B induced glioma cell apoptosis and reduced mitochondrial membrane potential (ΔΨm) in a dose-dependent manner. Mechanically, western blot analysis indicated that Sch B induced apoptosis by caspase-3, caspase-9, PARP, and Bcl-2 activation. Moreover, Sch B significantly inhibited tumour growth in vivo following the subcutaneous inoculation of U87 cells in athymic nude mice.CoclusionsIn summary, Sch B can reduce cell proliferation and induce apoptosis in glioma cells and has potential as a novel anti-tumour therapy to treat gliomas.

Background:Esophageal cancer is one of the worst malignant digestive neoplasms with poor treatment outcomes. Esophagectomy plays an important role and offers a potential curable chance to these patients. However, esophagectomy with radical lymphadenectomy is known as one of the most invasive digestive surgeries which are associated with high morbidity and mortality. The enhanced recovery after surgery (ERAS) protocol is a patient-centered, surgeon-led system combining anesthesia, nursing, nutrition, and psychology, which is designed for reducing complications, promoting recovery, and improving treatment outcomes. This systematic review and meta-analysis is aiming at how beneficial, and to what extent ERAS really will be.Methods:A systematic literature search will be performed through January 2018 using MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and Google Scholar for relevant articles published in any language. Randomized controlled trials, prospective cohort studies, and propensity-matched comparative studies will be included. All meta-analyses will be performed using Review Manager software. The quality of the studies will be evaluated using the guidelines listed in the Cochrane Handbook. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements will be followed until the findings of the systematic review and meta-analysis are reported.Results:The results of this systematic review and meta-analysis will be published in a peer-reviewed journal.Conclusion:Our study will draw an objective conclusion of the comparisons between ERAS and conventional care in aspects of perioperative outcomes and provide level I evidences for clinical decision makings.