Background and Aims
Cancer‐associated fibroblasts (CAFs) are key players in multicellular, stromal‐dependent alterations leading to HCC pathogenesis. However, the intricate crosstalk between CAFs and ...other components in the tumor microenvironment (TME) remains unclear. This study aimed to investigate the cellular crosstalk among CAFs, tumor cells, and tumor‐associated neutrophils (TANs) during different stages of HCC pathogenesis.
Approach and Results
In the HCC‐TME, CAF‐derived cardiotrophin‐like cytokine factor 1 (CLCF1) increased chemokine (C‐X‐C motif) ligand 6 (CXCL6) and TGF‐β secretion in tumor cells, which subsequently promoted tumor cell stemness in an autocrine manner and TAN infiltration and polarization in a paracrine manner. Moreover, CXCL6 and TGF‐β secreted by HCC cells activated extracellular signal‐regulated kinase (ERK) 1/2 signaling of CAFs to produce more CLCF1, thus forming a positive feedback loop to accelerate HCC progression. Inhibition of ERK1/2 or CLCF1/ciliary neurotrophic factor receptor signaling efficiently impaired CLCF1‐mediated crosstalk among CAFs, tumor cells, and TANs both in vitro and in vivo. In clinical samples, up‐regulation of the CLCF1−CXCL6/TGF‐β axis exhibited a marked correlation with increased cancer stem cells, “N2”‐polarized TANs, tumor stage, and poor prognosis.
Conclusions
This study reveals a cytokine‐mediated cellular crosstalk and clinical network involving the CLCF1−CXCL6/TGF‐β axis, which regulates the positive feedback loop among CAFs, tumor stemness, and TANs, HCC progression, and patient prognosis. These results may support the CLCF1 cascade as a potential prognostic biomarker and suggest that selective blockade of CLCF1/ciliary neurotrophic factor receptor or ERK1/2 signaling could provide an effective therapeutic target for patients with HCC.
The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, we ...reported the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination. A novel chiral spiro phosphoric acid, STRIP, was identified as a superior ligand for this transformation. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee). Density functional theory was used to gain a theoretical understanding of the enantioselectivities in this reaction.
The discovery of proper ligands to simultaneously modulate the reactivity and effectively control the stereoselectivity is a central topic in the field of enantioselective C−H activation. Herein, the synthesis of axially chiral biaryls by Pd‐catalyzed atroposelective C−H olefination is reported. A broad range of axially chiral quinoline derivatives were synthesized in good yields with excellent enantioselectivities (up to 98 % ee).
The atroposelective synthesis of atropisomers with vicinal diaxes remains rare and challenging, due to the steric influence between the two axes and their unique topology. Herein, we disclose a ...single‐step construction of atropisomers with vicinal C−C and C−N chiral diaxes by cyclopentadiene (Cp)‐free cobalt‐catalyzed intramolecular atroposelective C−H annulation, providing the desired diaxial atropisomers of unique structures with decent stereocontrols of both axes (up to >99 % ee and 70 : 1 dr). The optically pure products bearing fluorophores show circular polarized luminescence (CPL) properties, being candidate materials for potential CPL applications. Atropisomerization experiments and density function theory (DFT) calculations are conducted to study the rotational barriers and rotation pathways of the diaxes.
A single‐step construction of atropisomers with vicinal C−C and C−N chiral diaxes by cyclopentadiene (Cp)‐free cobalt‐catalyzed intramolecular atroposelective C−H annulation with decent stereocontrols (up to >99 % ee and 70/1 dr) was reported. Atropisomerization experiments and DFT calculations are done to study the rotational barriers and pathways of the diaxes.
With the development of economy and technology, the Internet is becoming more and more popular. Internet addiction has gradually become a serious issue in public health worldwide. The number of ...Internet users in China has reached 731 million, with an estimated 24 million adolescents determined as having Internet addiction. In this meta-analysis, we attempted to estimate the prevalence of Internet addiction among College Students in the People's Republic of China in order to improve the mental health level of college students and provide evidence for the prevention of Internet addiction.
Eligible articles about the prevalence of Internet addiction among college students in China published between 2006 and 2017 were retrieved from online Chinese periodicals, the full-text databases of Wan Fang, VIP, and the Chinese National Knowledge Infrastructure, as well as PubMed. Stata 11.0 was used to perform the analyses.
A total of 26 papers were included in the analyses. The overall sample size was 38,245, with 4573 diagnosed with Internet addiction. The pooled detection rate of Internet addiction was 11% (95% confidence interval CI 9-13%) among college students in China. The detection rate was higher in male students (16%) than female students (8%). The Internet addiction detection rate was 11% (95% CI 8-14%) in southern areas, 11% (95% CI 7-14%) in northern areas, 13% (95% CI 8-18%) in eastern areas and 9% (95% CI 8-11%) in the mid-western areas. According to different scales, the Internet addiction detection rate was 11% (95% CI 8-15%) using the Young scale and 9% (95% CI 6-11%) using the Chen scale respectively. Cumulative meta analysis showed that the detection rate had a slight upward trend and gradually stabilized in the last 3 years.
The pooled Internet addiction detection rate of Chinese college students in out study was 11%, which is higher than in some other countries and strongly demonstrates a worrisome situation. Effective measures should be taken to prevent further Internet addiction and improve the current situation.
Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of ...hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer‐specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR = 1.87, 95% CI: 1.22–2.86; p < 0.01 for trend) and OS (Q4 vs. Q1: HR = 2.06, 95% CI: 1.36–3.11; p < 0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR = 1.31, 95% CI: 0.89–1.92; P = 0.04 for trend) and OS (Q4 vs. Q1: HR = 1.43, 95% CI: 0.99–2.08; P = 0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival.
What's new?
Copper and zinc are essential micronutrients whose imbalance may be involved in development and progression of cancer. Currently, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) however remains unclear. The authors examine for the first time whether serum levels of copper, zinc, and their ratios are associated with survival in a large prospective cohort of newly diagnosed patients. The findings suggest that higher copper levels and copper/zinc ratios are associated with worse survival, but serum zinc levels are not associated with HCC survival. The results may have important implications for the prognosis of HCC.
Atherosclerosis is the primary underlying cause of myocardial infarction, ischemic stroke, and peripheral artery disease. The disease preferentially occurs in arterial regions exposed to disturbed ...blood flow, in part, by altering expression of flow-sensitive coding- and non-coding genes. In this review, we summarize the role of noncoding RNAs, microRNAs (miRNAs) and long noncoding RNAs(lncRNAs), as regulators of gene expression and outline their relationship to the pathogenesis of atherosclerosis. While miRNAs are small noncoding genes that post-transcriptionally regulate gene expression by targeting mRNA transcripts, the lncRNAs regulate gene expression by diverse mechanisms, which are still emerging and incompletely understood. We focused on multiple flow-sensitive miRNAs such as, miR-10a, -19a, -23b, -17~92, -21, -663, -92a, -143/145, -101, -126, -712, -205, and -155 that play a critical role in endothelial function and atherosclerosis by targeting inflammation, cell cycle, proliferation, migration, apoptosis, and nitric oxide signaling. Flow-dependent regulation of lncRNAs is just emerging, and their role in vascular dysfunction and atherosclerosis is unknown. Here, we discuss the flow-sensitive lncRNA STEEL along with other lncRNAs studied in the context of vascular pathophysiology and atherosclerosis such as MALAT1, MIAT1, ANRIL, MYOSLID, MEG3, SENCR, SMILR, LISPR1, and H19. Also discussed is the use of these noncoding RNAs as potential biomarkers and therapeutics to reduce and regress atherosclerosis.
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The mammalian intestinal epithelium self-renews rapidly and homeostasis is preserved via tightly controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control ...different cell functions, but little is known about their role in maintaining the integrity of the intestinal epithelium. We searched for T-UCRs that regulate growth of the intestinal mucosa and investigated the mechanism by which T-UCR uc.173 regulates epithelial renewal.
C57BL/6J mice were deprived of food for 48 hours in fasting experiments. Some mice were given intraperitoneal injections of a plasmid encoding LNA-anti-uc.173, to knock down endogenous uc.173. For studies using organoids, primary enterocytes were isolated from the intestine and transfected with the uc.173 transgene to increase uc.173 levels. Intestinal epithelial cells (Caco-2 and IEC-6 lines) were transfected with LNA-anti-uc.173 or uc.173 transgene. We quantified intestinal epithelial renewal based on BrdU incorporation, villus height and crypt depth, and cell number. The association of uc.173 with microRNA 195 (miRNA195) was determined by RNA pull-down assays.
Genome-wide profile analyses identified 21 T-UCRs, including uc.173, that were differentially expressed between intestinal mucosa of fasted vs non-fasted mice. Increasing levels of uc.173 by expression of a transgene increased growth of intestinal epithelial cells and organoids. Decreasing uc.173 levels by LNA-anti-uc.173 in mice reduced renewal of the intestinal epithelium. We found that uc.173 interacted directly with the primary transcript of miRNA195, leading to miRNA195 degradation.
In analyses of intestinal epithelial cells and mice, we identified uc.173 noncoding RNA that regulates growth of the intestinal mucosa and stimulates intestinal epithelial renewal by reducing levels of miRNA195.
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Abstract
Aims
Facial features were associated with increased risk of coronary artery disease (CAD). We developed and validated a deep learning algorithm for detecting CAD based on facial photos.
...Methods and results
We conducted a multicentre cross-sectional study of patients undergoing coronary angiography or computed tomography angiography at nine Chinese sites to train and validate a deep convolutional neural network for the detection of CAD (at least one ≥50% stenosis) from patient facial photos. Between July 2017 and March 2019, 5796 patients from eight sites were consecutively enrolled and randomly divided into training (90%, n = 5216) and validation (10%, n = 580) groups for algorithm development. Between April 2019 and July 2019, 1013 patients from nine sites were enrolled in test group for algorithm test. Sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were calculated using radiologist diagnosis as the reference standard. Using an operating cut point with high sensitivity, the CAD detection algorithm had sensitivity of 0.80 and specificity of 0.54 in the test group; the AUC was 0.730 (95% confidence interval, 0.699–0.761). The AUC for the algorithm was higher than that for the Diamond–Forrester model (0.730 vs. 0.623, P < 0.001) and the CAD consortium clinical score (0.730 vs. 0.652, P < 0.001).
Conclusion
Our results suggested that a deep learning algorithm based on facial photos can assist in CAD detection in this Chinese cohort. This technique may hold promise for pre-test CAD probability assessment in outpatient clinics or CAD screening in community. Further studies to develop a clinical available tool are warranted.
Graphical Abstract
Upregulated expression of immune checkpoint molecules correlates with exhausted phenotype and impaired function of cytotoxic T cells to evade host immunity. By disrupting the interaction of PD-L1 and ...PD1, immune checkpoint inhibitors can restore immune system function against cancer cells. Growing evidence have demonstrated apigenin and luteolin, which are flavonoids abundant in common fruits and vegetables, can suppress growth and induce apoptosis of multiple types of cancer cells with their potent anti-inflammatory, antioxidant and anticancer properties. In this study, the effects and underlying mechanisms of luteolin, apigenin, and anti-PD-1 antibody combined with luteolin or apigenin on the PD-L1 expression and anti-tumorigenesis in KRAS-mutant lung cancer were investigated. Luteolin and apigenin significantly inhibited lung cancer cell growth, induced cell apoptosis, and down-regulated the IFN-γ-induced PD-L1 expression by suppressing the phosphorylation of STAT3. Both luteolin and apigenin showed potent anti-cancer activities in the H358 xenograft and Lewis lung carcinoma model in vivo, and the treatment with monoclonal PD1 antibody enhanced the infiltration of T cells into tumor tissues. Apigenin exhibited anti-tumor activity in Genetically engineered KRASLA2 mice. In conclusion, both apigenin and luteolin significantly suppressed lung cancer with KRAS mutant proliferation, and down-regulated the IFN-γ induced PD-L1 expression. Treatment with the combination of PD-1 blockade and apigenin/luteolin has a synergistic effect and might be a prospective therapeutic strategy for NSCLC with KRAS-mutant.
•Luteolin and apigenin can downregulate the PD-L1 expression in NSCLC with KRAS mutation.•The combination of apigenin or luteolin with PD-1 mAb enhanced tumor growth control and improved survival.•Apigenin but not luteolin exhibited anti-tumor activity in KRASLA2 mice.
Residue‐selective bioconjugation methods for biomolecules are highly sought to expand the scope of their biological and medical applications. Inspired by the mechanism of the generation of natural ...vinylogous γ‐pyridones (vPDNs), we have developed a novel unique azaphilone‐based, activation‐free primary‐amine‐selective bioconjugation method for biomolecules. Our strategy allows facile functionalization of primary amine groups in peptides and proteins, including the clinically used therapeutic antibody trastuzumab, by generating a highly stable vPDN linkage. Excellent chemoselectivity toward primary amines also enables the azaphilone derivatives to specifically modify the lipid components of Gram‐positive bacteria while bypassing Gram‐negative bacteria and mammalian cells. The new method shows significant advantages including chemoselectivity, efficiency, flexibility and biocompatibility, and therefore provides a valuable addition to the current toolbox for biomolecule conjugation.
Inspired by the unique natural reaction of azaphilones with amines, an efficient, highly chemoselective and activation‐free primary amine bioconjugation protocol has been developed and demonstrated in a variety of applications.
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