Unresolved inflammation can lead to tissue fibrosis and impaired organ function. Macrophage–myofibroblast transition (MMT) is one newly identified mechanism by which ongoing chronic inflammation ...causes progressive fibrosis in different forms of kidney disease. However, the mechanisms underlying MMT are still largely unknown. Here, we discovered a brain-specific homeobox/POU domain protein Pou4f1 (Brn3a) as a specific regulator of MMT. Interestingly, we found that Pou4f1 is highly expressed by macrophages undergoing MMT in sites of fibrosis in human and experimental kidney disease, identified by coexpression of the myofibroblast marker, α-SMA. Unexpectedly, Pou4f1 expression peaked in the early stage in renal fibrogenesis in vivo and during MMT of bone marrow-derived macrophages (BMDMs) in vitro. Mechanistically, chromatin immunoprecipitation (ChIP) assay identified that Pou4f1 is a Smad3 target and the key downstream regulator of MMT, while microarray analysis defined a Pou4f1-dependent fibrogenic gene network for promoting TGF-β1/Smad3-driven MMT in BMDMs at the transcriptional level. More importantly, using two mouse models of progressive renal interstitial fibrosis featuring the MMT process, we demonstrated that adoptive transfer of TGF-β1-stimulated BMDMs restored both MMT and renal fibrosis in macrophage-depleted mice, which was prevented by silencing Pou4f1 in transferred BMDMs. These findings establish a role for Pou4f1 in MMT and renal fibrosis and suggest that Pou4f1 may be a therapeutic target for chronic kidney disease with progressive renal fibrosis.
Src activation has been associated with fibrogenesis after kidney injury. Macrophage-myofibroblast transition is a newly identified process to generate collagen-producing myofibroblasts locally in ...the kidney undergoing fibrosis in a TGF-β/Smad3-dependent manner. The potential role of the macrophage-myofibroblast transition in Src-mediated renal fibrosis is unknown. In studying this by RNA sequencing at single-cell resolution, we uncovered a unique Src-centric regulatory gene network as a key underlying mechanism of macrophage-myofibroblast transition. A total of 501 differentially expressed genes associated with macrophage-myofibroblast transition were identified. However, Smad3-knockout largely reduced the transcriptome diversity. More importantly, inhibition of Src largely suppresses ureteral obstruction-induced macrophage-myofibroblast transition in the injured kidney in vivo along with transforming growth factor-β1-induced elongated fibroblast-like morphology, α-smooth muscle actin expression and collagen production in bone marrow derived macrophages in vitro. Unexpectedly, we further uncovered that Src serves as a direct Smad3 target gene and also specifically up-regulated in macrophages during macrophage-myofibroblast transition. Thus, macrophage-myofibroblast transition contributes to Src-mediated tissue fibrosis. Hence, targeting Src may represent as a precision therapeutic strategy for macrophage-myofibroblast transition-driven fibrotic diseases.
Previous exposure to hepatitis B virus (HBV) may increase the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C. We aim to study the impact of previous HBV infection on the ...severity and outcomes of patients with nonalcoholic fatty liver disease (NAFLD).
This was a multicenter study of 489 patients with biopsy-proven NAFLD and 69 patients with NAFLD-related or cryptogenic HCC. Antihepatitis B core antibody (anti-HBc) was used to detect the previous HBV infection.
In the biopsy cohort, positive anti-HBc was associated with lower steatosis grade but higher fibrosis stage. 18.8% and 7.5% of patients with positive and negative anti-HBc had cirrhosis, respectively (P < 0.001). The association between anti-HBc and cirrhosis remained significant after adjusting for age and metabolic factors (adjusted odds ratio 2.232; 95% confidence interval, 1.202-4.147). At a mean follow-up of 6.2 years, patients with positive anti-HBc had a higher incidence of HCC or cirrhotic complications (6.5% vs 2.2%; P = 0.039). Among patients with NAFLD-related or cryptogenic HCC, 73.9% had positive anti-HBc. None of the patients had positive serum HBV DNA. By contrast, antihepatitis B surface antibody did not correlate with histological severity.
Positive anti-HBc is associated with cirrhosis and possibly HCC and cirrhotic complications in patients with NAFLD. Because a significant proportion of NAFLD-related HCC may develop in noncirrhotic patients, future studies should define the role of anti-HBc in selecting noncirrhotic patients with NAFLD for HCC surveillance.
Liver stiffness measurement using transient elastography appears to be an excellent tool for detection of liver fibrosis and cirrhosis with high accuracy. The aim of this study is to evaluate the ...efficacy of preoperative liver stiffness measurement in predicting post-hepatectomy liver failure.
A prospective cohort study of all consecutive patients undergoing hepatectomy for hepatocellular carcinoma from February 2010 to August 2014 was studied. All patients received detailed preoperative assessments including liver stiffness measurement. The primary outcome was post-hepatectomy liver failure according to the International Study Group of Liver Surgery definition.
A total of 255 patients were included. Liver stiffness measurement showed significant correlation with grade B or C post-hepatectomy liver failure. (P = 0.003) Using the cutoff at 12 kPa, liver stiffness measurement had a sensitivity of 52.4% and specificity of 73.3% in predication of high-grade (grade B or C) post-hepatectomy liver failure. Liver stiffness measurement > 12 kPa was also an independent prognostic factor for both high-grade post-hepatectomy liver failure and major postoperative complications by multivariate analysis. The diagnostic accuracy was better in patients without right lobe tumor with an area under the receiver operating characteristic of 0.83 compared with an area under the receiver operating characteristic of only 0.62 in patients with right lobe tumor.
Liver stiffness measurement using Fibroscan is good to predict high-grade post-hepatectomy liver failure especially in patients without right lobe tumor.
Myeloid-derived suppressor cells (MDSCs) contribute to tumour immunosuppressive microenvironment and immune-checkpoint blockade resistance. Emerging evidence highlights the pivotal functions of ...cyclin-dependent kinases (CDKs) in tumour immunity. Here we elucidated the role of tumour-intrinsic CDK20, or cell cycle-related kinase (CCRK) on immunosuppression in hepatocellular carcinoma (HCC).
Immunosuppression of MDSCs derived from patients with HCC and relationship with CCRK were determined by flow cytometry, expression analyses and co-culture systems. Mechanistic studies were also conducted in liver-specific
-inducible transgenic (TG) mice and Hepa1-6 orthotopic HCC models using CRISPR/Cas9-mediated
depletion and liver-targeted nanoparticles for interleukin (IL) 6 trapping. Tumorigenicity and immunophenotype were assessed on single or combined antiprogrammed death-1-ligand 1 (PD-L1) therapy.
Tumour-infiltrating CD11b
CD33
HLA-DR
MDSCs from patients with HCC potently inhibited autologous CD8
T cell proliferation. Concordant overexpression of CCRK and MDSC markers (CD11b/CD33) positively correlated with poorer survival rates. Hepatocellular CCRK stimulated immunosuppressive CD11b
CD33
HLA-DR
MDSC expansion from human peripheral blood mononuclear cells through upregulating IL-6. Mechanistically, CCRK activated nuclear factor-κB (NF-κB) via enhancer of zeste homolog 2 (EZH2) and facilitated NF-κB-EZH2 co-binding to
promoter. Hepatic
induction in TG mice activated the EZH2/NF-κB/IL-6 cascade, leading to accumulation of polymorphonuclear (PMN) MDSCs with potent T cell suppressive activity. In contrast, inhibiting tumorous
or hepatic IL-6 increased interferon γ
tumour necrosis factor-α
CD8
T cell infiltration and impaired tumorigenicity, which was rescued by restoring PMN-MDSCs. Notably, tumorous
depletion upregulated PD-L1 expression and increased intratumorous CD8
T cells, thus enhancing PD-L1 blockade efficacy to eradicate HCC.
Our results delineate an immunosuppressive mechanism of the hepatoma-intrinsic CCRK signalling and highlight an overexpressed kinase target whose inhibition might empower HCC immunotherapy.
Background
Endoscope is the eye of surgeon in minimally invasive surgery (MIS). Prevailing handheld endoscopes are manually steered, which can cause endoscope-instrument fencing. Robotic endoscopes ...can reduce the fatigue but could not reduce collisions. Handheld endoscopes with a flexible bending tip can reduce the shaft pivoting and collisions. However, its steering is challenging. In this paper, we present a robotic flexible endoscope with auto-tracking function and compare it with the conventional rigid endoscopes.
Methods
A robotic flexible endoscope (RFE) with shared autonomy is developed. The RFE could either track the instruments automatically or be controlled by a foot pedal. A mockup cholecystectomy was designed to evaluate the performance. Five surgeons were invited to perform the mockup cholecystectomy in an abdominal cavity phantom with a manual rigid endoscope (MRE), a robotic rigid endoscope (RRE), and the RFE. Space occupation, time consumption, and questionnaires based on the NASA task load index were adopted to evaluate the performances and compare the three endoscope systems. An ex vivo experiment was conducted to demonstrate the feasibility of using the RFE in a biological tissue environment.
Results
All surgeons completed the mockup cholecystectomy with the RFE independently. Failure occurred in the cases involving the RRE and the MRE. Inside the body cavity, the space occupied when using the RFE is 17.28% and 23.95% (
p
< 0.05) of that when using the MRE and the RRE, respectively. Outside the body cavity, the space occupied when using the RFE is 14.60% and 15.53% (
p
< 0.05) of that by using MRE and RRE. Time consumed in the operations with MRE, RRE, and RFE are 28.3 s, 93.2 s and 34.8 s, respectively. Questionnaires reveal that the performance of the RFE is the best among the three endoscope systems.
Conclusions
The RFE provides a wider field of view (FOV) and occupies less space than rigid endoscopes.
Prognosis of patients that have undergone liver resection can be predicted preoperatively. Albumin-Bilirubin (ALBI) is a useful score to evaluate liver function objectively. This score is simple to ...use, uses objective parameters, and can stratify patients into grades. In combination with other liver cancer scores, the prognosis and survival of patients can be evaluated with more accuracy. Current literatures supporting the use of the ALBI score relating to prognosis of post hepatectomy, radiofrequency ablation (RFA), transarterial chemoembolization (TACE), radiotherapy and systemic therapy are available. Therefore, ALBI score is worthy of clinical application. The following is a review of the current literatures on the ALBI score.
•Albumin-Bilirubin (ALBI) is a useful score to evaluate liver function objectively.•ALBI score is simple to use, uses objective parameters, and can stratify patients into grades.•In combination with other liver cancer scores, the prognosis and survival of patients can be evaluated with more accuracy.•ALBI score is worthy of clinical application.
Programmed death ligand 1 (PD-L1) protein expression by immunohistochemistry is a promising biomarker for PD-1/PD-L1 blockade in hepatocellular carcinoma. There are a number of commercially available ...PD-L1 assays. Our study aimed to compare the analytical performance of different PD-L1 assays and evaluate the reliability of pathologists in PD-L1 scoring. Consecutive sections from tumor samples from 55 patients with surgically resected primary hepatocellular carcinoma were stained with four standardized PD-L1 assays (22C3, 28-8, SP142, and SP263). We also correlated the PD-L1 protein level by immunohistochemistry with the mRNA level of those genes associated with tumor immune microenvironment by the NanoString platform. Five pathologists independently assessed PD-L1 expression on tumor cells tumor proportion score together with tumor-infiltrating immune cells (combined positive score). The 22C3, 28-8, and SP263 assays had comparable sensitivity in detecting PD-L1 expression, whereas the SP142 assay was the least sensitive assay. The inter-assay agreement measured by intraclass correlation coefficients for the tumor proportion score and combined positive score were 0.646 and 0.780, respectively. The inter-rater agreement was good to excellent (the overall intraclass correlation coefficient for the tumor proportion score and combined positive score was 0.946 and 0.809, respectively). Pathologists were less reliable in scoring combined positive score than tumor proportion score, particularly when using the SP142 assay. Up to 18% of samples were misclassified by individual pathologists in comparison to the consensus score at the cutoff of combined positive score ≥ 1. The combined positive score by the 22C3 assay demonstrated the strongest correlation with immune-related gene mRNA signatures, closely followed by combined positive scores by the 28-8 and SP263 assays. In conclusion, the 22C3, 28-8, and SP263 assays are highly concordant in PD-L1 scoring and suggest the interchangeability of these three assays. Further improvement of the accuracy in assessing PD-L1 expression at a low cutoff is still necessary.
ATP-binding cassette (ABC) transporters mediate multidrug resistance and cancer stem cell properties in various model systems. Yet, their biological significance in cancers, especially in ...hepatocellular carcinoma (HCC), remains unclear. In this study, we investigated the function of ABCF1 in HCC and explored its potential as a therapeutic target. ABCF1 was highly expressed in fetal mouse livers but not in normal adult livers. ABCF1 expression was upregulated in HCCs. These results demonstrate that ABCF1 functions as a hepatic oncofetal protein. We further demonstrated elevated ABCF1 expression in HCC cells upon acquiring chemoresistance. Suppression of ABCF1 by siRNA sensitized both parental cells and chemoresistant cells to chemotherapeutic agents. Reversely, ABCF1 overexpression promoted chemoresistance and drug efflux. In addition, overexpression of ABCF1 enhanced migration, spheroid and colony formation and epithelial-mesenchymal transition (EMT) induction. RNA sequencing analysis revealed EMT inducers HIF1α/IL8 and Sox4 as potential mediators for the oncogenic effect of ABCF1 in HCC progression. Together, this study illustrates that ABCF1 is a novel potential therapeutic target for HCC treatment.
•ABC proteins mediate multidrug resistance and stem cell properties but their clinical importance in HCCs remained unclear.•ABCF1 is a hepatic oncofetal protein. Its expression is further elevated in HCC cells upon acquiring chemoresistance.•ABCF1 expression modulateschemoresponse, migration, epithelial-mesenchymal transition (EMT), and cancer stemness properties.•ABCF1 regulates EMT inducers HIF1α/IL8 and Sox4 as potential mediators for the oncogenic effect in HCC progression.•ABCF1 serves as a novel potential therapeutic target for HCC treatment.
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