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Hepatectomy for hepatocellular carcinoma (HCC) beyond the Milan criteria is shown to be beneficial. However, a high rate of post-operative HCC recurrence hinders the long-term survival of the patients. This study aimed to investigate and compare the impacts of tenofovir (TDF) and entecavir (ETV) on the recurrence of hepatitis B viral (HBV)-related HCC beyond the Milan criteria. Data pertaining to 1532 patients who underwent hepatectomy and received antiviral therapy between January 2014 and January 2019 were collected from five centers. Recurrence-free survival (RFS) analysis was performed using the Kaplan-Meier method. Cox proportional hazards regression analysis was performed to determine prognostic factors for HCC recurrence. The analysis incorporates 595 HBV-related HCC patients. The overall 5-year RFS was 21.3%. Among them, 533 and 62 patients received ETV and TDF treatment, respectively. The 1-, 3-, and 5-year RFS rates were 46.3%, 27.4%, and 19.6%, respectively, in the ETV group compared with 65.1%, 41.8%, and 37.2%, respectively, in the TDF group (P < 0.001). Multivariate analysis showed that TDF treatment (hazard ratio [HR]: 0.604, P = 0.005), cirrhosis (HR: 1.557, P = 0.004), tumor size (HR: 1.037, P = 0.008), microvascular invasion (MVI) (HR: 1.403, P = 0.002), portal vein tumor thrombus (PVTT) (HR: 1.358, P = 0.012), capsular invasion (HR: 1.228, P = 0.040), and creatinine levels (CREA) (HR: 0.993, P = 0.031) were statistically significant prognostic factors associated with RFS. Patients with HCC beyond the Milan criteria exhibited a high rate of HCC recurrence after hepatectomy. Compared to the ETV therapy, TDF administration significantly lowered the risk of HCC recurrence.

Geriatric nutritional risk index (GNRI) is a novel and useful screening tool for evaluating nutritional status in elderly in-patients. We aimed to investigate whether the preoperative GNRI could be a predictive factor for outcomes in patients over 65 years of age with a diagnosis of hepatocellular carcinoma (HCC). We retrospectively enrolled 261 consecutive HCC patients after hepatectomy and classified them into four risk groups based on the GNRI values: high risk (GNRI, <82), moderate risk (GNRI, 82–92), low risk (GNRI, 92–98), and normal (GNRI, >98). We found that the lower GNRI value was significantly associated with severe postoperative complications ( P  < 0.001) and liver failure ( P  < 0.001). By multivariate logistic regression analysis, high risk- and moderate risk GNRI groups were identified as independent risk factors for postoperative serve complications and liver failure. Multivariate Cox regression analysis revealed preoperative GNRI ( P  < 0.001) adversely affected overall survival. In conclusion, preoperative GNRI could predict severe postoperative complications included liver failure, and the lower GNRI value was associated with worse overall survival after hepatectomy in elderly HCC patients.

Glutamine synthetase (GS) and arginase 1 (Arg1) are widely used pathological markers that discriminate hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma; however, their clinical significance in HCC remains unclear. We retrospectively analyzed 431 HCC patients: 251 received hepatectomy alone, and the other 180 received sorafenib as adjuvant treatment after hepatectomy. Expression of GS and Arg1 in tumor specimens was evaluated using immunostaining. mRNA sequencing and immunostaining to detect progenitor markers (cytokeratin 19 [CK19] and epithelial cell adhesion molecule [EpCAM]) and mutant TP53 were also conducted. Up to 72.4% (312/431) of HCC tumors were GS positive (GS+). Of the patients receiving hepatectomy alone, GS negative (GS-) patients had significantly better overall survival (OS) and recurrence-free survival (RFS) than GS+ patients; negative expression of Arg1, which is exclusively expressed in GS- hepatocytes in the healthy liver, had a negative effect on prognosis. Of the patients with a high risk of recurrence who received additional sorafenib treatment, GS- patients tended to have better RFS than GS+ patients, regardless of the expression status of Arg1. GS+ HCC tumors exhibit many features of the established proliferation molecular stratification subtype, including poor differentiation, high alpha-fetoprotein levels, increased progenitor tumor cells, TP53 mutation, and upregulation of multiple tumor-related signaling pathways. GS- HCC patients have a better prognosis and are more likely to benefit from sorafenib treatment after hepatectomy. Immunostaining of GS may provide a simple and applicable approach for HCC molecular stratification to predict prognosis and guide targeted therapy.

This study reports on the impact of rainfall patterns and land surface changes on flood dynamics in the Meijiang River Basin, located in the upper reaches of the Ganjiang River. We formulated a range of rainfall patterns and spatial distribution scenarios and employed the MIKE SHE model to evaluate variations in flood volume, flood peak, and the timing of flood peaks. We found that under comparable areal rainfall conditions, flood volumes fluctuated by up to 6.22% among the different rainfall patterns, whereas flood peaks exhibited differences of up to 36.23%. When the rainfall center moved from upstream to downstream, both flood volume and flood peak initially increased before decreasing, with maximum values of 4.2 billion m3 and 4900 m3/s, respectively. We selected three basin scales (i.e., 10,000, 1000, and 100 km2) for comparative analysis. In the period between 1985 and 2020, the changes in land surface conditions resulted in decreases in the flood peaks of the three basins by 7.61, 11.53, and 15.79%, respectively; a reduction in the flood volumes of the three basins by 6.58, 9.60, and 10.48%, respectively; and delayed peak times by 3, 2, and 2 h, respectively. The results of this study show the significant influence exerted by rainfall patterns, the location of the rainfall centers, and the impact of changes in land surface conditions on flood processes. In particular, when the area of the basin was reduced, the influence of the underlying surface was more obvious. These results also show that flood prediction needs to consider the complex interaction of multiple factors.

With the rapid process of urbanization, water conflicts between different water use industries and areas are increasing. Therefore, China has implemented the three-cordons system of water resources management since 2012, when how to make more reasonable regulation of water resources became an urgent problem in most areas of China. In this study, taking the Yuanhe River Basin as an example, an integrated model for the simulation and regulation of water resources considering water quantity and quality from a river basin perspective was proposed, where the water supply was constrained by requirements of water resources management. First, the water resources system was conceptualized into a topologically hydraulic network in the form of point, line, and area elements, including 80 water use units and 79 water supply units. Then, taking the water quantity and quality as constraint conditions in the water supply for corresponding water use sectors, a management-oriented integrated model was established, which highlights the cordon control of the total water use and the pollution load limits of a basin. Finally, through a model simulation, the total water supply was controlled by regulating the water resources, while the pollutant loads into rivers depended on the discharge of water users. Based on the model, strategies for the utilization of water resources and achieving emission reductions of pollution loads were provided. The results of the proposed model in the Yuanhe River Basin showed that benchmarked against the total water demand of 1.705 billion m3, the water shortage was 212 million m3 with a rate of 13.5%, and the loads of COD (Chemical Oxygen Demand) and NH3-N (Ammonia Nitrogen) were 29,096.7 and 2587.3 tons, respectively. The model can provide support for integrated water resources regulation in other basins or regions through a simulation of the natural–social water resources systems, and help stakeholders and decision-makers establish and implement advantageous strategies for regional efficient utilization of water resources.

Chemokine (C-X3-C motif) Receptor 1 (CX3CR1) primarily mediates the chemotaxis and adhesion of immune cells. However, its role in hepatitis C virus (HCV)-induced early-stage liver cirrhosis remains unexplored. GSE15654 was downloaded from the GEO database. The Cox regression model, CIBERSORT, and LASSO technique were utilized to identify CX3CR1-associated immune infiltration genes (IIGs). Surgical resection samples were collected for verification, including 3 healthy controls (HC), 4 individuals with HCV-induced hepatic cirrhosis, and 3 with HCV-induced liver failure. High CX3CR1 expression correlated with worse prognosis in early-stage cirrhosis. CX3CR1-associated IIGs, namely ACTIN4, CD1E, TMCO1, and WSF1, were identified, showing specific expression in the livers of individuals with post-hepatic cirrhosis and liver failure compared to HC. LOC400499 and MTHFD2 were elevated in individuals with liver failure in comparison to those with hepatocirrhosis. Notably, high infiltration of plasma cells and low infiltration of monocytes were predictive of poor prognosis in early-stage cirrhosis. The combined risk model predicted that high expression of CX3CR1-associated IIGs and increased infiltration of plasma cells were associated with unfavorable prognosis in individuals with HCV-induced early-stage liver cirrhosis. The developed combined risk model effectively predicted the prognosis of these individuals.

Background Postoperative oral antiviral treatment with nucleoside or nucleotide analogues can suppress viral replication and reduce tumour recurrence for patients with hepatitis b virus–related hepatocellular carcinoma (HBV-related HCC) after curative resection. However, the superior antiviral treatment is still unclear. We conducted this study to investigate the different effects of nucleotide and nucleoside analogues on the prognosis of HBV-related HCC after curative resection. Methods From February 2007 to February 2016, 487 consecutive patients with newly diagnosed HCC according to the Milan criteria who underwent R0 resection were enrolled according to the inclusion and exclusion criteria. According to their postoperative antiviral treatment, they were divided into the nucleotide group (NtA, n  = 111) and the nucleoside group (NsA, n  = 376). Results The baseline characteristics, serologic parameters, tumour characteristics, and operative data of the 2 groups were comparable. Nucleotide analogue use significantly decreased HCC recurrence ( P  = 0.028) and HCC-related death ( P  = 0.004), with hazard ratios (HRs) of 0.685 (95% CI, 0.484 to 0.971, P  = 0.033) and 0.507 (95% CI, 0.310 to 0.830, P  = 0.004), respectively, in multivariate Cox analyses. After the study patients were stratified according to three variables, we found that nucleotide analogue use was significantly associated with increased disease-free and overall survival among patients with cirrhosis, HBeAg-negative patients, and patients with positive HBV-DNA. Conclusions In patients with HBV-related HCC, nucleotide analogues but not nucleoside analogues significantly reduced HCC recurrence and improved overall survival after R0 hepatic resection.

Cancer associated fibroblasts (CAFs) support tumors via multiple mechanisms, including maintaining the immunosuppressive tumor microenvironment and limiting infiltration of immune cells. The prolyl isomerase Pin1, whose overexpression in CAFs has not been fully profiled yet, plays critical roles in tumor initiation and progression. To decipher effects of selective Pin1 inhibition in CAFs on pancreatic cancer, here we formulate a DNA-barcoded micellular system (DMS) encapsulating the Pin1 inhibitor AG17724. DMS functionalized with CAF-targeting anti-FAP-α antibodies (antiCAFs-DMS) can selectively inhibit Pin1 in CAFs, leading to efficacious but transient tumor growth inhibition. We further integrate DNA aptamers (AptT), which can engage CD8+ T lymphocytes, to obtain a bispecific antiCAFs-DMS-AptT system. AntiCAFs-DMS-AptT inhibits tumor growth in subcutaneous and orthotopic pancreatic cancer models. Pharmacological inhibition of the prolyl isomerase PIN1, highly expressed in cancer cells and cancer associated fibroblasts (CAF), has been proposed for cancer therapy. Here the authors report the design of a DNA-barcoded micellular system functionalized with antibodies targeting CAFs and a T cell recruiting aptamer to deliver the PIN1 inhibitor AG17724, showing antitumor response in preclinical models of pancreatic cancer.

AimThe role of tumor differentiation in the prognosis of hepatocellular carcinoma (HCC) after hepatectomy remains controversial. The present study aimed to classify the impact of tumor differentiation on solitary hepatitis B viral (HBV)-associated HCC using propensity score matching analysis.MethodsBetween January 2009 and March 2015, the data of 721 HCC patients in West China Hospital were prospectively collected and analyzed. Propensity matching analysis was applied to overcome the imbalance in baseline characteristics. Survival analysis was performed using the Kaplan–Meier method. Risk factors were identified by the Cox proportional hazards model.ResultsAll HCC patients were classified into the moderately well-differentiated HCCs group (group A, n = 442, 61.3%) or poorly differentiated HCCs group (group B, n = 279, 38.7%). Patients with poorly differentiated HCCs commonly had a larger tumor size, more advanced tumors, and a higher alpha-fetoprotein (AFP) level. Patients with poorly differentiated HCCs had a poorer recurrence-free survival and overall survival before and after propensity score matching analysis. Poorly differentiated tumors, positive serum hepatitis B viral e antigen, positive hepatitis B virus deoxyribonucleic acid load, tumor size, microvascular invasion, and AFP > 400 ng/ml were risk factors of a poor outcome.ConclusionsOur propensity model provided strong evidence that a poorly differentiated tumor had a negative impact on the recurrence and long-term survival of solitary HBV-associated HCCs after curative hepatectomy. Antiviral therapy might improve their prognosis.