Osteoarthritis (OA), the most prevalent age-related joint disorder, is characterized by chronic inflammation, progressive articular cartilage destruction, and subchondral bone sclerosis. Accumulating ...evidences indicate that circular RNAs (circRNAs) play a critical role in various diseases, but the function of circRNAs in OA remains largely unknown. Here we showed that circRNA.33186 was significantly upregulated in IL-1β)-treated chondrocytes and in cartilage tissues of a destabilized medial meniscus (DMM)-induced OA mouse model. Knockdown of circRNA.33186 increased anabolic factor (type II collagen) expression and decreased catabolic factor (MMP-13) expression. Knockdown of circRNA.33186 also promoted proliferation and inhibited apoptosis in IL-1β-treated chondrocytes. Silencing of circRNA.33186 in vivo markedly alleviated DMM-induced OA. Mechanistic study showed that circRNA.33186 directly binds to and inhibits miR-127-5p, thereby increasing MMP-13 expression, and contributes to OA pathogenesis. Taken together, our findings demonstrated a fundamental role of circRNA.33186 in OA progression and provide a potential drug target in OA therapy.
Zhu and colleagues demonstrate that circRNA.33186 regulates chondrocyte functions, including ECM catabolism, proliferation, and apoptosis. Silencing of circRNA.33186 alleviated OA by acting as a sponge of miR-127-5p. These findings reveal a fundamental role of circRNA.33186 in OA progression and provide a potential drug target in OA therapy.
Copper‐catalyzed silylarylation of N‐(arylsulfonyl)acrylamides via a tandem silyl radical addition/1,4‐aryl migration/desulfonylation sequence has been developed. This method employs silanes as the ...precursor of silyl radical and di‐tert‐butyl peroxide (DTBP) as the initiator. By using this cascade procedure, a series of β‐silyl amide‐pharmaceutical hybrids which contain an α‐all‐carbon quaternary stereocenter were facilely synthesized.
This paper introduces an isogeometric framework for the numerical analysis of contact problems. In this approach, NURBS is utilized as basis for geometric representation and analysis. The contact ...surfaces and the underlying solids are parameterized in an identical paradigm. The use of NURBS geometry eliminates at the onset the geometric discontinuities induced by the traditional faceted approximation. Contact detection is carried out patch-wise, instead of element-wise, leading to an efficient and robust numerical algorithm. A strategy for smoothing sharp corners is also described. The algorithm does not rely on fillets but entails only a minor perturbation to the NURBS parameters. A variationally consistent surface-to-surface formulation is developed in the context of frictionless contact. Numerical examples are presented to demonstrate the performance and utility of the method.
Natural killer (NK) cells play a critical role in the innate antitumor immune response. Recently, NK cell dysfunction has been verified in various malignant tumors, including hepatocellular carcinoma ...(HCC). However, the molecular biological mechanisms of NK cell dysfunction in human HCC are still obscure.
The expression of circular ubiquitin-like with PHD and ring finger domain 1 RNA (circUHRF1) in HCC tissues, exosomes, and cell lines was detected by qRT-PCR. Exosomes were isolated from the culture medium of HCC cells and plasma of HCC patients using an ultracentrifugation method and the ExoQuick Exosome Precipitation Solution kit and then characterized by transmission electronic microscopy, NanoSight and western blotting. The role of circUHRF1 in NK cell dysfunction was assessed by ELISA. In vivo circRNA precipitation, RNA immunoprecipitation, and luciferase reporter assays were performed to explore the molecular mechanisms of circUHRF1 in NK cells. In a retrospective study, the clinical characteristics and prognostic significance of circUHRF1 were determined in HCC tissues.
Here, we report that the expression of circUHRF1 is higher in human HCC tissues than in matched adjacent nontumor tissues. Increased levels of circUHRF1 indicate poor clinical prognosis and NK cell dysfunction in patients with HCC. In HCC patient plasma, circUHRF1 is predominantly secreted by HCC cells in an exosomal manner, and circUHRF1 inhibits NK cell-derived IFN-γ and TNF-α secretion. A high level of plasma exosomal circUHRF1 is associated with a decreased NK cell proportion and decreased NK cell tumor infiltration. Moreover, circUHRF1 inhibits NK cell function by upregulating the expression of TIM-3 via degradation of miR-449c-5p. Finally, we show that circUHRF1 may drive resistance to anti-PD1 immunotherapy in HCC patients.
Exosomal circUHRF1 is predominantly secreted by HCC cells and contributes to immunosuppression by inducing NK cell dysfunction in HCC. CircUHRF1 may drive resistance to anti-PD1 immunotherapy, providing a potential therapeutic strategy for patients with HCC.
Amplification of chromosome 7q21-7q31 is associated with tumor recurrence and multidrug resistance, and several genes in this region are powerful drivers of hepatocellular carcinoma (HCC). We aimed ...to investigate the key circular RNAs (circRNAs) in this region that regulate the initiation and development of HCC.
We used qRT-PCR to assess the expression of 43 putative circRNAs in this chromosomal region in human HCC and matched nontumor tissues. In addition, we used cultured HCC cells to modify circRNA expression and assessed the effects in several cell-based assays as well as gene expression analyses via RNA-seq. Modified cells were implanted into immunocompetent mice to assess the effects on tumor development. We performed additional experiments to determine the mechanism of action of these effects.
circMET (hsa_circ_0082002) was overexpressed in HCC tumors, and circMET expression was associated with survival and recurrence in HCC patients. By modifying the expression of circMET in HCC cells in vitro, we found that circMET overexpression promoted HCC development by inducing an epithelial to mesenchymal transition and enhancing the immunosuppressive tumor microenvironment. Mechanistically, circMET induced this microenvironment through the miR-30-5p/Snail/ dipeptidyl peptidase 4(DPP4)/CXCL10 axis. In addition, the combination of the DPP4 inhibitor sitagliptin and anti-PD1 antibody improved antitumor immunity in immunocompetent mice. Clinically, HCC tissues from diabetic patients receiving sitagliptin showed higher CD8
T cell infiltration than those from HCC patients with diabetes without sitagliptin treatment.
circMET is an onco-circRNA that induces HCC development and immune tolerance via the Snail/DPP4/CXCL10 axis. Furthermore, sitagliptin may enhance the efficacy of anti-PD1 therapy in a subgroup of patients with HCC.
AbstractObjectiveTo investigate whether vitamin D supplementation is associated with lower mortality in adults.DesignSystematic review and meta-analysis of randomised controlled trials.Data ...sourcesMedline, Embase, and the Cochrane Central Register from their inception to 26 December 2018.Eligibility criteria for selecting studiesRandomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group.Main outcome measuresAll cause mortality.Results50 trials with a total of 74 655 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I2=0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.85, 0.74 to 0.97, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D3 supplementation than in trials with vitamin D2 supplementation (P for interaction=0.04); neither vitamin D3 nor vitamin D2 was associated with a statistically significant reduction in all cause mortality.ConclusionsVitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 15%. Additional large clinical studies are needed to determine whether vitamin D3 supplementation is associated with lower all cause mortality.Study registrationPROSPERO registration number CRD42018117823.
The in‐depth study on reduction–specified coupling reactions of the nitroarenes by heterogeneous cobalt catalysis opens a door for diversified syntheses of functional N‐containing molecules. Guided ...by the structure–function relationship of heterogeneous materials, rational design of nano–catalysts can effectively regulate the routes of organic reactions. Precise transformation of the intermediates generated during the nitroarene reduction with a suitable nano–catalyst is a promising way to develop new tandem reactions, and to synthesize structurally novel compounds that are of difficult access with the conventional approaches.
Being different from conventional reductive coupling reactions of nitroarenes, structurally modifiable heterogeneous cobalt catalysts reveal excellent performance in precise use of a single intermediate during the catalytic transfer hydrogenation of the nitroarenes. This concept would provide a novel direction for the efficient utilization of nitroaromatics in the manufacture of high‐value products.
Due to the generation of multiple intermediates during the nitroarene reduction, precise interception of single one to develop tandem reactions involving both C−C and C−N bond formations still ...remains a significant challenge. Herein, the relay catalysis of a supported bifunctional cobalt catalyst with l‐proline has been successfully applied to establish a bran‐new reductive annulation reaction of nitroarenes and formaldehyde, which enables direct and diverse construction of both symmetrical and unsymmetrical 1,3‐diaryl imidazolines. It proceeds with operational simplicity, good substrate and functionality compatibility, and excellent step and atom‐efficiency. Mechanistic studies reveal that the Co‐catalyst exhibits a synergistic effect on the formation of key N‐hydroxy imine, and the l‐proline subsequently facilitates the key C−C bond formation. The current work opens a door to develop useful transformations with nitroarenes by reduction‐interrupted strategy.
By relay catalysis of a supported bifunctional cobalt catalyst and L‐proline, a reductive annulation reaction of nitroarenes and formaldehyde involving both C−C and C−N bond formations is presented, which enables direct and diverse access to 1,3‐diaryl imidazolines.
Recently, the dysregulation of circular RNA (circRNA) have been shown to have important regulatory roles in cancer development and progression, including hepatocellular carcinoma (HCC). However, the ...roles of most circRNAs in HCC are still unknown.
The expression of circular tripartite motif containing 33-12 (circTRIM33-12) in HCC tissues and cell lines was detected by qRT-PCR. The role of circTRIM33-12 in HCC progression was assessed by western blotting, CCK-8, flow cytometry, transwell and a subcutaneous tumor mouse assays both in vitro and in vivo. In vivo circRNA precipitation, RNA immunoprecipitation, luciferase reporter assays were performed to evaluate the interaction between circTRIM33-12 and miR-191.
Here, we found that circTRIM33-12, is downregulated in HCC tissues and cell lines. The downregulation of circTRIM33-12 in HCC was significantly correlated with malignant characteristics and served as an independent risk factor for the overall survival (OS) and recurrence-free survival (RFS) of patients with HCC after surgery. The reduced expression of circTRIM33-12 in HCC cells increases tumor proliferation, migration, invasion and immune evasion. Mechanistically, we demonstrated that circTRIM33-12 upregulated TET1 expression by sponging miR-191, resulting in significantly reduced 5-hydroxymethylcytosine (5hmC) levels in HCC cells.
These results reveal the important role of circTRIM33-12 in the proliferation, migration, invasion and immune evasion abilities of HCC cells and provide a new perspective on circRNAs in HCC progression.
ObjectiveTo monitor trastuzumab resistance and determine the underlying mechanisms for the limited response rate and rapid emergence of resistance of HER2+ metastatic gastric cancer ...(mGC).DesignTargeted sequencing of 416 clinically relevant genes was performed in 78 paired plasma and tissue biopsy samples to determine plasma-tissue concordance. Then, we performed longitudinal analyses of 97 serial plasma samples collected from 24 patients who were HER2+ to track the resistance during trastuzumab treatment and validated the identified candidate resistance genes.ResultsThe results from targeted sequencing-based detection of somatic copy number alterations (SCNA) of HER2 gene were highly consistent with fluorescence in situ hybridisation data, and the detected HER2 SCNA was better than plasma carcinoembryonic antigen levels at predicting tumour shrinkage and progression. Furthermore, most patients with innate trastuzumab resistance presented high HER2 SCNA during progression compared with baseline, while HER2 SCNA decreased in patients with acquired resistance. PIK3CA mutations were significantly enriched in patients with innate resistance, and ERBB2/4 genes were the most mutated genes, accounting for trastuzumab resistance in six (35.3%) and five (29.4%) patients in baseline and progression plasma, respectively. Patients with PIK3CA/R1/C3 or ERBB2/4 mutations in the baseline plasma had significantly worse progression-free survival. Additionally, mutations in NF1 contributed to trastuzumab resistance, which was further confirmed through in vitro and in vivo studies, while combined HER2 and MEK/ERK blockade overcame trastuzumab resistance.ConclusionLongitudinal circulating tumour DNA sequencing provides novel insights into gene alterations underlying trastuzumab resistance in HER2+mGC.
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