Background and Aims
There is growing evidence that single‐stranded, circular RNA (circRNA) plays a key role in the development of certain cancers, including hepatocellular carcinoma (HCC). It is less ...clear, however, what role circRNA plays in HCC metastasis.
Approach and Results
In this study, through circRNA sequencing, we identified a circRNA: circASAP1 (a circRNA derived from exons 2 and 3 of the ASAP1 gene, hsa_circ_0085616), which is associated with pulmonary metastasis after curative resection in patients with HCC. CircASAP1 was overexpressed in HCC cell lines with high metastatic potential and in metastatic HCCs. In vitro, circASAP1 promoted cell proliferation, colony formation, migration, and invasion, and in vivo, it enhanced tumor growth and pulmonary metastasis. Mechanism studies showed that circASAP1 acts as a competing endogenous RNA for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), both of which are tumor suppressors in HCC. We found that mitogen‐activated protein kinase (MAPK) 1 and colony stimulating factor (CSF)‐1 were direct common targets for microRNA 326 (miR‐326) and microRNA 532‐5p (miR‐532‐5p), which were regulated by circASAP1. CircASAP1 promotes HCC cell proliferation and invasion by regulating miR‐326/miR‐532‐5p‐MAPK1 signaling and, furthermore, mediates tumor‐associated macrophage infiltration by regulating the miR‐326/miR‐532‐5p‐CSF‐1 pathway. Clinical HCC samples exhibited a positive correlation between circASAP1 expression and levels of CSF‐1, MAPK1, and CD68+ tumor‐associated macrophages, all of which were predictive of patient outcomes.
Conclusion
We identified circASAP1 as a key regulator of HCC metastasis that acts on miR‐326/miR‐532‐5p‐MAPK1/CSF‐1 signaling and serves as a prognostic predictor in patients with HCC.
MicroRNAs (miRNAs) play a critical role in regulation of tumor metastasis. However, the role of these molecules in hepatocellular carcinoma (HCC) has not been fully elucidated. In this study, we ...employed miRNA‐sequencing and identified 22 miRNAs involved in HCC metastasis. One of these, miR‐28‐5p, was down‐regulated in HCCs. This down‐regulation correlated with tumor metastasis, recurrence, and poor survival. Biofunctional investigations revealed that miR‐28‐5p deficiency promoted tumor growth and metastasis in nude mice without altering the in vitro biological characteristics of HCC cells. Through gene expression profiles and bioinformatics analysis, we identified interleukin‐34 (IL‐34) as a direct target of miR‐28‐5p, and the effects of miR‐28‐5p deficiency on HCC growth and metastasis was dependent on IL‐34‐mediated tumor‐associated macrophage (TAM) infiltration. Moreover, we found that TAMs induced by miR‐28‐5p‐IL‐34 signaling inhibit miR‐28‐5p expression on HCC cells by transforming growth factor beta 1, resulting in an miR‐28‐5p‐IL‐34‐macrophage‐positive feedback loop. In clinical HCC samples, miR‐28‐5p levels were inversely correlated with IL‐34 expression and the number of TAMs. Patients with low miR‐28‐5p expression, high IL‐34 levels, and high numbers of TAMs had a poor prognosis with shorter overall survival and time to recurrence. Conclusion: A miR‐28‐5p‐IL‐34‐macrophage feedback loop modulates HCC metastasis and serves as a novel prognostic factor as well as a therapeutic target for HCC. (Hepatology 2016;63:1560‐1575)
Tumor‐associated neutrophils (TANs) play a crucial role in tumor development and progression in the cancer microenvironment. Despite increased understanding of TAN contributions to hepatocellular ...carcinoma (HCC) progression and prognosis, the direct interaction between TANs and HCC cells is not fully understood. In this study, we tested the effect of TANs on HCC cells in vitro and in vivo and investigated the mechanism of interaction between them. Our results showed that TANs secreted bone morphogenetic protein 2 and transforming growth factor beta 2 and triggered microRNA 301b‐3p (miR‐301‐3p) expression in HCC cells, subsequently suppressed gene expression of limbic system–associated membrane protein (LSAMP) and CYLD lysine 63 deubiquitinase (CYLD), and increased stem cell characteristics in HCC cells. These TAN‐induced HCC stem‐like cells were hyperactive in nuclear factor kappa B signaling, secreted higher levels of chemokine (C‐X‐C motif) ligand 5 (CXCL5), and recruited more TAN infiltration, suggesting a positive feedback loop. In clinical HCC samples, increased TANs correlated with elevated miR‐301b‐3p, decreased LSAMP and CYLD expression, and increased nuclear p65 accumulation and CXCL5 expression, all of which predicted patient outcome. Conclusion: Our work identified a positive feedback loop governing cancer stem‐like cells and TANs in HCC that controls tumor progression and patient outcome.
Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health
. Bats have been recognized as one of the most important reservoirs for emerging ...viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS)
. Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth.
Background and Purpose
Icariin, a major active ingredient in traditional Chinese medicines, is attracting increasing attention because of its unique pharmacological effects against ischaemic heart ...disease. The histone deacetylase, sirtuin‐1, plays a protective role in ischaemia/reperfusion (I/R) injury, and this study was designed to investigate the protective role of icariin in models of cardiac I/R injury and to elucidate the potential involvement of sirtuin‐1.
Experimental Approach
I/R injury was simulated in vivo (mouse hearts), ex vivo (isolated rat hearts) and in vitro (neonatal rat cardiomyocytes and H9c2 cells). Prior to I/R injury, animals or cells were exposed to icariin, with or without inhibitors of sirtuin‐1 (sirtinol and SIRT1 siRNA).
Key Results
In vivo and in vitro, icariin given before I/R significantly improved post‐I/R heart contraction and limited the infarct size and leakage of creatine kinase‐MB and LDH from the damaged myocardium. Icariin also attenuated I/R‐induced mitochondrial oxidative damage, decreasing malondialdehyde content and increasing superoxide dismutase activity and expression of Mn‐superoxide dismutase. Icariin significantly improved mitochondrial membrane homeostasis by increasing mitochondrial membrane potential and cytochrome C stabilization, which further inhibited cell apoptosis. Sirtuin‐1 was significantly up‐regulated in hearts treated with icariin, whereas Ac‐FOXO1 was simultaneously down‐regulated. Importantly, sirtinol and SIRT1 siRNA either blocked icariin‐induced cardioprotection or disrupted icariin‐mediated mitochondrial homeostasis.
Conclusions and Implications
Pretreatment with icariin protected cardiomyocytes from I/R‐induced oxidative stress through activation of sirtuin‐1 /FOXO1 signalling.
A novel Ebola virus (EBOV) first identified in March 2014 has infected more than 25,000 people in West Africa, resulting in more than 10,000 deaths. Preliminary analyses of genome sequences of 81 ...EBOV collected from March to June 2014 from Guinea and Sierra Leone suggest that the 2014 EBOV originated from an independent transmission event from its natural reservoir followed by sustained human-to-human infections. It has been reported that the EBOV genome variation might have an effect on the efficacy of sequence-based virus detection and candidate therapeutics. However, only limited viral information has been available since July 2014, when the outbreak entered a rapid growth phase. Here we describe 175 full-length EBOV genome sequences from five severely stricken districts in Sierra Leone from 28 September to 11 November 2014. We found that the 2014 EBOV has become more phylogenetically and genetically diverse from July to November 2014, characterized by the emergence of multiple novel lineages. The substitution rate for the 2014 EBOV was estimated to be 1.23 × 10(-3) substitutions per site per year (95% highest posterior density interval, 1.04 × 10(-3) to 1.41 × 10(-3) substitutions per site per year), approximating to that observed between previous EBOV outbreaks. The sharp increase in genetic diversity of the 2014 EBOV warrants extensive EBOV surveillance in Sierra Leone, Guinea and Liberia to better understand the viral evolution and transmission dynamics of the ongoing outbreak. These data will facilitate the international efforts to develop vaccines and therapeutics.
Abstract
Atomically thin two-dimensional semiconducting materials integrated into van der Waals heterostructures have enabled architectures that hold great promise for next generation ...nanoelectronics. However, challenges still remain to enable their applications as compliant materials for integration in logic devices. Here, we devise a reverted stacking technique to intercalate a wrinkle-free boron nitride tunnel layer between MoS
2
channel and source drain electrodes. Vertical tunnelling of electrons therefore makes it possible to suppress the Schottky barriers and Fermi level pinning, leading to homogeneous gate-control of the channel chemical potential across the bandgap edges. The observed features of ambipolar
pn
to
np
diode, which can be reversibly gate tuned, paves the way for future logic applications and high performance switches based on atomically thin semiconducting channel.
In this work, we employ the ∂¯-steepest descent method to investigate the Cauchy problem of the complex short pulse (CSP) equation with initial conditions in weighted Sobolev space H(R). Firstly, we ...successfully derive the Hamiltonian function of the CSP equation based on its Lax pair. Furthermore, the long time asymptotic behavior of the solution u(x,t) is derived in a fixed space-time cone S(y1,y2,v1,v2)={(y,t)∈R2:y=y0+vt,y0∈y1,y2,v∈v1,v2}. On the basis of the resulting asymptotic behavior, we prove the soliton resolution conjecture of the CSP equation which includes the soliton term confirmed by N(I)-soliton on discrete spectrum and the t−12 order term on continuous spectrum with residual error up to O(t−1).
Consider a supercritical branching Wiener process in Rd. Let Zn(A) be the number of the nth generation particles located in a given set A⊂Rd. Under the moment condition of EX(lnX)1+λ type, the ...complete asymptotic expansions of Zn(A) as n tends to infinity are obtained. This result gives an alternative version of the work by Révész, Rosen and Shi (2005), hence generalizing theirs by weakening the second moment condition therein.
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