Previous clinical studies have found that the levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in hepatocellular carcinoma (HCC). However, these conclusions and data remain controversial. We performed a systematic review and meta-analysis to assess the prognostic value and clinical utilization of TILs in patients with HCC. A total of 23 relevant studies of 3173 patients were included into our meta-analysis. The results demonstrated that high levels of CD8+ and CD3+ TILs had a better prognostic value on overall survival (OS), with HRs of 0.71 (P = 0.04) and 0.63 (P = 0.03), respectively, compared to low levels, as did high levels of CD8+, CD3+ and CD4+ TILs on disease/recurrence-free survival (DFS/RFS), with HRs of 0.66 (P = 0.01), 0.60 (P = 0.01) and 0.79 (P = 0.04), respectively. In contrast, high levels of FoxP3+ TILs had a worse prognostic value on OS and DFS/RFS, with HRs of 2.06 (P < 0.00001) and 1.77 (P < 0.00001), respectively. The FoxP3+/CD4+ and FoxP3+/CD8+ ratios negatively correlated with OS and DFS/RFS. These findings suggest that TILs may serve as a prognostic biomarker in HCC. However, further research should be performed to clarify the clinical value of TILs in HCC.

Axin is a key scaffolding protein responsible for the formation of the β-catenin destruction complex. Stability of Axin protein is regulated by the ubiquitin-proteasome system, and modulation of cellular concentration of Axin protein has a profound effect on Wnt/β-catenin signaling. Although E3s promoting Axin ubiquitination have been identified, the deubiquitinase responsible for Axin deubiquitination and stabilization remains unknown. Here, we identify USP7 as a potent negative regulator of Wnt/β-catenin signaling through CRISPR screens. Genetic ablation or pharmacological inhibition of USP7 robustly increases Wnt/β-catenin signaling in multiple cellular systems. USP7 directly interacts with Axin through its TRAF domain, and promotes deubiquitination and stabilization of Axin. Inhibition of USP7 regulates osteoblast differentiation and adipocyte differentiation through increasing Wnt/β-catenin signaling. Our study reveals a critical mechanism that prevents excessive degradation of Axin and identifies USP7 as a target for sensitizing cells to Wnt/β-catenin signaling.

The Wnt/β-catenin signaling pathway plays essential roles in embryonic development and adult tissue homeostasis. Axin is a concentration-limiting factor responsible for the formation of the β-catenin destruction complex. Wnt signaling itself promotes the degradation of Axin. However, the underlying molecular mechanism and biological relevance of this targeting of Axin have not been elucidated. Here, we identify SIAH1/2 (SIAH) as the E3 ligase mediating Wnt-induced Axin degradation. SIAH proteins promote the ubiquitination and proteasomal degradation of Axin through interacting with a VxP motif in the GSK3-binding domain of Axin, and this function of SIAH is counteracted by GSK3 binding to Axin. Structural analysis reveals that the Axin segment responsible for SIAH binding is also involved in GSK3 binding but adopts distinct conformations in Axin/SIAH and Axin/GSK3 complexes. Knockout of SIAH1 blocks Wnt-induced Axin ubiquitination and attenuates Wnt-induced β-catenin stabilization. Our data suggest that Wnt-induced dissociation of the Axin/GSK3 complex allows SIAH to interact with Axin not associated with GSK3 and promote its degradation and that SIAH-mediated Axin degradation represents an important feed-forward mechanism to achieve sustained Wnt/β-catenin signaling.

BackgroundNorovirus (NoV) has been recognized as the leading cause of both outbreaks and sporadic cases of acute gastroenteritis in children and adults worldwide. Stool samples collected from outpatients with clinical symptoms of acute gastroenteritis in all age groups at the First People’s Hospital in Huzhou, Huzhou, China between March 2014 and February 2015 were analyzed to gain insight into the epidemiology and genetic variation in NoV strains circulating in China.MethodReal-time RT-PCR (qPCR) was performed for Norovirus detection. RT-PCR were used for genomic amplification and sequencing. Genogroup and genotype were assigned using the NoV Noronet typing tool and the strains were named according to the time of isolation. The phylogenetic analysis was conducted using MEGA 5.ResultsOf the 809 specimens, 193 (23.9 %) were positive for NoV, with GII.4 and GII.17 the most commonly identified strains. Phylogenetic analysis confirmed the presence of five recombinant strains in Huzhou. Recombinants GII.P13/GII.17 and GII.P12/GII.4 were newly detected in China. The GII.P13/GII.17 recombinant was first identified in October 2014 and steadily replaced GII.Pe/GII.4 (GII.4 Sydney 2012) as the predominant circulating NoV genotype.ConclusionThis is the first report of the detection of GII.17 in the Huzhou area and of a NoV genotype being detected in greater numbers than GII.4. Furthermore, our results indicated that following the emergence of GII.17 in October 2014, it steadily replaced the previous circulating GII.4 Sydney2012 strain, which was the dominant circulating genotype for the past 2 years. As norovirus are the important cause of nonbacterial gastroenteritis, continuous and comprehensive study of the norovirus strains involved in large and cost-effective acute gastroenteritis would help understanding the molecular epidemiology of norovirus infections and development of improved prevention and control measures.

Infection caused by noroviruses (NoVs) is one of the most important causes of acute gastroenteritis in humans worldwide. To gain insight into the epidemiology of and genetic variation in NoV strains, stool samples collected from 18 outbreaks of acute gastroenteritis in Huzhou, China, between January 2008 and December 2012 were analyzed. Samples were tested for NoVs by real-time RT-PCR. Partial sequences of the RNA- dependent RNA polymerase (RdRp) and capsid gene of the positive samples were amplified by RT-PCR, and the PCR products were sequenced and used for phylogenetic analysis. NoVs were found to be responsible of 88.8% of all nonbacterial acute gastroenteritis outbreaks in Huzhou over the last 5 years. Genogroup II outbreaks largely predominated and represented 93% of all outbreaks. A variety of genotypes were found among genogroups I and II, including GI.4, GI.8, GII.4, and GII.b. Moreover, phylogenetic analyses identified two recombinant genotypes (polymerase/capsid): GI.2/GI.6 and GII.e/GII.4 2012 Sydney. GII.4 was predominant and involved in 8/10 typed outbreaks. During the study period, GII.4 NoV variants 2006b, New Orleans 2009, and Sydney 2012 were identified. This is the first report of the detection of GII.4 New Orleans 2009 variant, GII.e/GII.4 Sydney 2012 recombinant in outbreaks of acute gastroenteritis in China.

No abstract

Adenomatous polyposis coli (APC) and Axin are core components of the β-catenin destruction complex. How APC's function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the β-catenin destruction complex is not clear. Through a CRISPR screen of β-catenin stability, we have identified ICAT, a polypeptide previously known to block β-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks β-catenin-APC interaction and prevents β-catenin-mediated APC-Axin interaction, enhancing stabilization of β-catenin in cells harboring truncated APC or stimulated with Wnt, but not in cells deprived of a Wnt signal. Using ICAT as a tool to disengage β-catenin-mediated APC-Axin interaction, we demonstrate that Wnt quickly inhibits the direct interaction between APC and Axin. Our study highlights an important scaffolding function of β-catenin in the assembly of the destruction complex and suggests Wnt-inhibited APC-Axin interaction as a mechanism of Wnt-dependent inhibition of the destruction complex.

BackgroundIn late 2016, an uncommon recombinant NoV genotype called GII.P16-GII.2 caused a sharp increase in outbreaks of acute gastroenteritis in different countries of Asia and Europe, including China. However, we did not observe a drastic increase in sporadic norovirus cases in the winter of 2016 in Huzhou. Therefore, we investigate the prevalence and genetic diversity of NoVs in the sporadic acute gastroenteritis (AGE) cases from January 2016 to December 2017 in Huzhou City, Zhejiang, China.MethodsFrom January 2016 to December 2017, a total of 1001 specimens collected from patients with AGE were screened for NoV by real-time RT-PCR. Partial sequences of the RNA-dependent RNA polymerase (RdRp) and capsid gene of the positive samples were amplified by RT-PCR and sequenced. Genotypes of NoV were confirmed by online NoV typing tool and phylogenetic analysis. Complete VP1 sequences of GII.P16-GII.2 strains detected in this study were further obtained and subjected into sequence analysis.ResultsIn total, 204 (20.4%) specimens were identified as NoV-positive. GII genogroup accounted for most of the NoV-infected cases (98.0%, 200/204). NoV infection was found in all age groups tested (< 5, 5–15, 16–20, 21–30, 31–40, 41–50, 51–60, and >60 years), with the 5–15 year age group having the highest detection rate (17/49, 34.7%). Higher activity of NoV infection could be seen in winter-spring season. The predominant NoV genotypes have changed from GII.Pe-GII.4 Sydney2012 and GII.P17-GII.17 in 2016 to GII.P16-GII.2, GII.Pe-GII.4 Sydney2012 and GII.P17-GII.17 in 2017. Phylogenetic analyses revealed that 2016–2017 GII.P16-GII.2 strains were most closely related to Japan 2010–2012 cluster in VP1 region and no common mutations were found in the amino acids of the HBGA-binding sites and the predicted epitopes.ConclusionsWe report the emergence of GII.P16-GII.2 strains and characterize the molecular epidemiological patterns NoV infection between January 2016 and December 2017 in Huzhou. The predominant genotypes of NoV during our study period are diverse. VP1 amino acid sequences of 2016–2017 GII.P16-GII.2 strains remain static after one year of circulation.Electronic supplementary materialThe online version of this article (10.1186/s12879-018-3259-6) contains supplementary material, which is available to authorized users.