Preclinical and phase I studies of an antisense oligonucleotide drug targeting IGF-1R in liver cancer.

Aim: To evaluate a novel antisense oligonucleotide drug targeting human IGF-1R in preclinical and phase I studies of liver cancer. Materials & methods: The tolerability and safety of an investigational new drug were evaluated in a dose-escalation trial involving 17 patients with advanced liver cancer after preclinical assessment of pharmacokinetics and pharmacodynamics. Results: The drug exposure levels in the phase I trial were determined by the in vivo efficacy with pharmacokinetics evaluation in rats and rhesus monkeys. This clinical study showed that the maximum tolerated dose was 3.96 mg/kg, and the dose-limiting toxicity dose was 4.4 mg/kg. Conclusion: The drug was safe and tolerable in patients with advanced liver cancer. Clinical Trial Registration: ChiCTR2100044235 (www.chictr.org.cn).

CT102 is a potential new drug for liver cancer treatment. It belongs to a new form of medicine using gene therapy technology called antisense oligonucleotides. There are some antisense oligonucleotides approved for treating rare diseases. This study evaluated the antitumor effect, metabolism and safety of CT102 in preclinical and clinical trials. The results showed that CT102 could inhibit tumor growth in mice with liver cancer and maintain high levels in the liver. It was found that CT102 was safe and tolerable in patients with advanced liver cancer. This suggests that CT102 has therapeutic potential for liver cancer treatment. The good tolerability and safety of CT102 in patients supports further studies on liver cancer treatment.

Predicting haemorrhagic transformation through serum biochemical indices for patients after endovascular treatment: a retrospective study.

INTRODUCTION: The aim of this study was to determine the serum biochemical markers that can predict the risk of haemorrhagic transformation (HT) before and after endovascular treatment (EVT). MATERIAL AND METHODS: This study included patients with anterior circulation large vessel occlusion (ACLVO) who underwent EVT within six hours of symptom onset between September 2017 and September 2022. These patients were retrospectively categorised into two groups: an HT group and a No-HT group. RESULTS: A total of 180 patients were included in the study, of whom 55 (30.6%) had HT. The monocyte count before EVT (p = = 0.005, OR = 0.694, 95% CI 0.536-0.898), the activated partial thromboplastin time before EVT (p = 0.009, OR = 0.186, 95% CI 0.699-0.952), and the eosinophil count after EVT (p = 0.038, OR = 0.001, 95% CI 0.000-0.018) were all found to be independent predictors of HT, with warning values of 6.65%, 22.95 seconds, and 0.035*10^9/L, respectively. When compared to prediction using only demographic data [AUC = 0.662,95% CI (0.545, 0.780)], adding biochemical indices before EVT [AUC = 0.719,95% CI (0.617, 0.821)], adding biochemical indices after EVT [AUC = 0.670,95% CI (0.566, 0.773)], and adding both [AUC = 0.778,95% CI (0.686, 0.870)], the prediction efficiency of HT was improved among all three combinations, with no statistical significance. CONCLUSIONS: The levels of serum biochemical markers were found to show significant changes before and after EVT in ACLVO patients. A combination of demographic data and serum biochemical markers proved to be effective in predicting the occurrence of HT in patients with ACLVO who underwent EVT.

Multi-Time-Scale Optimal Scheduling Strategy for Marine Renewable Energy Based on Deep Reinforcement Learning Algorithm.

Surrounded by the Shandong Peninsula, the Bohai Sea and Yellow Sea possess vast marine energy resources. An analysis of actual meteorological data from these regions indicates significant seasonality and intra-day uncertainty in wind and photovoltaic power generation. The challenge of scheduling to leverage the complementary characteristics of various renewable energy sources for maintaining grid stability is substantial. In response, we have integrated wave energy with offshore photovoltaic and wind power generation and propose a day-ahead and intra-day multi-time-scale rolling optimization scheduling strategy for the complementary dispatch of these three energy sources. Using real meteorological data from this maritime area, we employed a CNN-LSTM neural network to predict the power generation and load demand of the area on both day-ahead 24 h and intra-day 1 h time scales, with the DDPG algorithm applied for refined electricity management through rolling optimization scheduling of the forecast data. Simulation results demonstrate that the proposed strategy effectively meets load demands through complementary scheduling of wave power, wind power, and photovoltaic power generation based on the climatic characteristics of the Bohai and Yellow Sea regions, reducing the negative impacts of the seasonality and intra-day uncertainty of these three energy sources on the grid. Additionally, compared to the day-ahead scheduling strategy alone, the day-ahead and intra-day rolling optimization scheduling strategy achieved a reduction in system costs by 16.1% and 22% for a typical winter day and a typical summer day, respectively.

Adsorption, natural attenuation, and microbial community response of ofloxacin and oxolinic acid in marine sediments.

The pollution of quinolone antibiotics in the marine environment has attracted widespread attention, especially for ofloxacin (OFL) and oxolinic acid (OXO) due to their frequent detection. However, few studies have been conducted to assess the behaviors and microbial community response to these antibiotics in marine sediments, particularly for potential antibiotic-resistant bacteria. In this work, the adsorption characteristics, natural attenuation characteristics, and variation of microbial communities of OFL and OXO in marine sediments were investigated. The adsorption process of antibiotics in sediments occurred on the surface and internal pores of organic matter, where OFL was more likely to be transferred from seawater to sediment compared with OXO. Besides, the adsorption of two antibiotics on sediment surfaces was attributed to physisorption (pore filling, electrostatic interaction) and chemisorption (hydrogen bonding). The natural attenuation of OFL and OXO in marine sediment followed second-order reaction kinetics with half-lives of 6.02 and 26.71 days, respectively, wherein biodegradation contributed the most to attenuation, followed by photolysis. Microbial community structure in marine sediments exposure to antibiotics varied by reducing abundance and diversity of microbial communities, as a whole displaying as an increase in the relative abundance of Firmicutes whereas a decrease of Proteobacteria. In detail, Escherichia-Shigella sp., Blautia sp., Bifidobacterium sp., and Bacillus sp. were those antibiotic-resistant bacteria with potential ability to degrade OFL, while Bacillus sp. may be resistant to OXO. Furthermore, functional predictions indicated that the microbial communities in sediment may resist the stress caused by OFL and OXO through cyano-amino acid metabolism, and ascorbate and aldarate metabolism, respectively. The research is key to understanding fate and bacterial resistance of antibiotics in marine sediments.

Emergency response to ecological protection in maritime phenol spills: Emergency monitor, ecological risk assessment, and reduction.

Recently, hundreds of maritime accidental spills of hazardous chemicals have raised public concerns, especially for phenol due to its potential of spills and highly toxicity. Therefore, for marine ecological protection, this article prepared specific strategies of emergency response to phenol spills. Through the identification for phenol behavior at sea, migration prediction, emergency monitor, as well as their new methods were reviewed. Further, ecological risk assessment and seawater quality criteria were conducted by using a species sensitivity distribution (SSD) approach, wherein, risk quotient (RQ) indicated phenol of simulated marine spills posed a high risk (RQ > 1) in 30 days. The method with eco-friendliness and high-efficiency for phenol reduction was constructed by combination of dredging equipment such as pneumatic dredgers (Airlift) and bioremediation, where marine microorganisms that degraded phenol were summarized, as well as future research needs. This study provided a guidance for emergency response and policy development of phenol spills.

Detection and dietary risk of per- and polyfluoroalkyl substances in shellfish products from the coasts of Bohai Sea and South China Sea.

Artificial per- and polyfluoroalkyl substances (PFASs) are widely distributed in the environment and are potentially harmful to human health. This study assessed the matrix effect of different shellfish on LC-MS analysis and the recoveries of PFASs in purified extracts purified by adding ENVI-Carb graphitized carbon black. Total 76 samples were collected from coastal cities of the Bohai Sea and South China Sea in China. Results showed that the signal response of perfluorocarboxylic acid increased with the length of fluorocarbon chains. ENVI-Carb can mitigate the shellfish matrix effects for analysis of PFASs. Ten PFASs components were detected in shellfish samples at concentrations ranging from 1.3 to 8.5 ng/g wet weight. The PFOA and PFHxS were the dominant components, and PFOA, PFTrDA and PFNA were detected at high rates of 58-93%. The highest levels of ∑PFASs were accumulated in clams, while the lowest levels were found in mussels. The dietary risk assessment indicated that PFASs potentially threaten human health via consumption of clam products in the Bohai Sea region. This study will improve the understanding of the contamination status and the dietary risk of PFASs in shellfish products along the coasts of Bohai Sea and South China Sea in China.

Efficiency, mechanism, influencing factors, and integrated technology of biodegradation for aromatic compounds by microalgae: A review.

Aromatic compounds have received widespread attention because of their threat to ecosystem and human health. However, traditional physical and chemical methods are criticized due to secondary pollution and high cost. As a result of ecological security and the ability of carbon sequestration, biodegradation approach based on microalgae has emerged as a promising alternative treatment for aromatic pollutants. In light of the current researches, the degradation efficiency of BTEX (benzene, toluene, ethylbenzene, and xylene), polycyclic aromatic hydrocarbons (PAHs), and phenolic compounds by microalgae was reviewed in this study. We summarized the degradation pathways and metabolites of p-xylene, benzo [a]pyrene, fluorene, phenol, bisphenol A, and nonylphenol by microalgae. The influence factors on the degradation of aromatic compounds by microalgae were also discussed. The integrated technologies based on microalgae for degradation of aromatic compounds were reviewed. Finally, this study discussed the limitations and future research needs of the degradation of these compounds by microalgae.

Ecological risk assessment for xylenes and propylbenzenes in aquatic environment using a species sensitivity distribution approach.

Xylenes and propylbenzenes (PBZs) are volatile aromatic hydrocarbons with high aquatic toxicity. Xylenes can be present in three isomers: o-xylene (OX), m-xylene (MX), and p-xylene (PX), while PBZs include two isomers: n-propylbenzene (n-PBZ) and isopropylbenzene (i-PBZ). Their accidental spills and improper discharges from petrochemical industries can cause severe contamination in water bodies posing potential ecological risks. In this study, the published acute toxicity data of these chemicals for aquatic species were collected to calculate hazardous concentrations protecting 95% species (HC5) using a species sensitivity distribution (SSD) approach. The acute HC5 values for OX, MX, PX, n-PBZ, and i-PBZ were estimated to be 1.73, 3.05, 1.23, 1.22, and 1.46 mg/L, respectively. The risk quotient (RQ) values calculated based on HC5 indicated their high risk (RQ: 1.23 ∼ 21.89) in groundwater, but low risk (RQ < 0.1) in natural seawater, river water, and lake water. When xylenes or PBZs leaked into the sea, they were expected to pose a high risk (RQ > 1) at the start and then a low risk (RQ < 0.1) after 10 days due to natural attenuation. These results may help to derive more reliable protection thresholds for xylenes and PBZs in aquatic environment and provide a basis for evaluating their ecological risks.

Rational design of a self-assembly promoting fusion domain enhances high molecular weight levan synthesis by levansucrase SacB.

The catalytic product of levansucrase from Bacillus subtilis (SacB) is mainly composed of 10 % high molecular weight levan (HMW, ~2000 kDa) and 90 % low molecular weight levan (LMW, ~7000 Da). In order to achieve efficient production of food hydrocolloid, high molecular weight levan (HMW), with the help of molecular dynamics simulation software, a protein self-assembly element, Dex-GBD, was found and fused with the C-terminus of SacB to construct a novel fusion enzyme, SacB-GBD. The product distribution of SacB-GBD was reversed compared with SacB, and the proportion of HMW in the total polysaccharide was significantly increased to >95 %. We then confirmed that the self-assembly was responsible for the reversal of the SacB-GBD product distribution by the simultaneous modulation of SacB-GBD particle size and product distribution by SDS. The hydrophobic effect may be the main driver of self-assembly as analyzed by molecular simulations and hydrophobicity determination. Our study provides an enzyme source for the industrial production of HMW and provides a new theoretical basis for guiding the molecular modification of levansucrase towards the size of the catalytic product.

Elimination of tetracyclines in seawater by laccase-mediator system.

Long-term exposure of antibiotics at low level leads to the accumulation of antibiotics in environmental media and organisms, inducing the formation of antibiotic resistance genes. Seawater is an important sink for many contaminants. Here, laccase from Aspergillus sp. and mediators that follow different oxidation mechanisms were combined to degrade tetracyclines (TCs) at environmentally relevant levels (ng·L-1-µg·L-1) in coastal seawater. The high salinity and alkaline of seawater changed the enzymatic structure of laccase, resulting in a reduced affinity of laccase to the substrate in seawater (Km of 0.0556 mmol·L-1) than that in buffer (Km of 0.0181 mmol·L-1). Although the stability and activity of the laccase decreased in seawater, laccase at a concentration of 200 U·L-1 with a laccase/syringaldehyde (SA) ratio of 1 U: 1 µmol could completely degrade TCs in seawater at initial concentrations of less than 2 µg·L-1 in 2 h. Molecular docking simulation showed that the interaction between TCs and laccase mainly includes hydrogen bond interaction and hydrophobic interaction. TCs were degraded into small molecular products through a series of reactions: demethylation, deamination, deamidation, dehydration, hydroxylation, oxidation, and ring-opening. Prediction of the toxicity of intermediates showed that the majority of TCs can be degraded into low-toxic or non-toxic, small-molecule products within 1 h, indicating that the degradation process of TCs by a laccase-SA system has good ecological safety. The successful removal of TCs by the laccase-SA system demonstrates its potential for the elimination of pollutants in marine environment.

Clinical relevance of plasma EBV DNA as a biomarker for nasopharyngeal carcinoma in non-endemic areas: A multicenter study in southwestern China.

BACKGROUND: Numerous clinical studies have validated plasma EBV DNA as a reliable biomarker for nasopharyngeal carcinoma (NPC) screening, tumor load monitoring, and prognosis prediction in endemic regions. However, the clinical relevance of plasma EBV DNA as a biomarker for NPC in non-endemic areas is still unclear. METHOD: The pretreatment plasma EBV DNA of 1405 newly diagnosed NPC patients from three major regional hospitals in non-endemic areas were analyzed retrospectively. The medical records of 244 age- and gender-matched healthy individuals were reviewed. EBV DNA was detected using Polymerase Chain Reaction (PCR). Based on the baseline of 400 and 0 copies/mL, the distribution characteristics of the pretreatment EBV DNA load in different clinical stages and geographic regions were analyzed. The diagnostic value of pretreatment plasma EBV DNA for NPC with two baselines was evaluated using the ROC curve. RESULTS: NPC patients had a significantly higher pretreatment EBV DNA level than healthy controls (P＜0.001). Pretreatment EBV DNA was closely associated with clinical and TNM stages in non-endemic areas, as it was in endemic areas. However, when 400 copies/mL set as the detection baseline, the sensitivity and specificity for NPC diagnosis were 40.8 % and 100 %, respectively (AUC = 0.704, cut off = 200.5 copies/mL). This sensitivity was lower than that reported in endemic regions (41.5 % - 97.1 %). Lower sensitivity may result in false negatives, missing diagnoses during NPC screening. Further investigation revealed that 39.7 % (558/1405) of NPC patients had detectable EBV DNA and S amplification curves. Optimizing the detection limit to 0 copies/mL, the sensitivity could be improved to 80.5 % (AUC = 0.901). CONCLUSIONS: In non-endemic areas, the clinical significance of plasma EBV DNA as a biomarker for NPC was restricted due to the low detection limit of 400 copies/mL. More efficient nucleic acid extraction and detection methods are needed to optimize the detection limit and increase the clinical application of plasma EBV DNA for NPC.

Regulatory T cells differentiation in visceral adipose tissues contributes to insulin resistance by regulating JAZF-1/PPAR-γ pathway.

Regulatory T cell (Treg) activity and differentiation in visceral adipose tissue (VAT) play an important role in inhibiting chronic inflammation and insulin resistance. Whether JAZF-1 and PPAR-γ mediate VAT Treg differentiation to promote the inhibition of chronic inflammation and insulin resistance remains unclear. Here, we investigated the roles of JAZF-1 and PPAR-γ in VAT Treg differentiation, inflammation and insulin resistance using a transgenic mouse model. First, we determined that the levels of glucose and insulin biochemical markers in the JAZF-1 transgenic general feeding or high-fat groups were lower than those in the wild-type general feeding or high-fat groups. Second, the levels of CD4+ , CD25+ , and FOXP3+ differentiation markers in the JAZF-1 transgenic general feeding or high-fat groups were significantly higher than those in the wild-type groups. PPAR-γ inhibition was associated with low levels of CD4+ , CD25+ and FOXP3+ differentiation markers. Third, the levels of TNF-α, IL-1ß and IL-6 in the JAZF-1 transgenic groups were lower than those in the wild-type groups, whereas IL-10 and TGF-ß levels were higher in the JAZF-1 transgenic groups than in the wild-type groups. After using the PPAR-γ inhibitor, we observed that TNF-α, IL-1ß and IL-6 increased, while IL-10 and TGF-ß decreased. We found that JAZF-1 and PPAR-γ could promote Tregs differentiation and regulate insulin resistance by synergistically decreasing the expression levels of TNF-α, IL-1ß and IL-6 and increasing those of IL-10 and TGF-ß.

An-Luo-Hua-Xian Pill Improves the Regression of Liver Fibrosis in Chronic Hepatitis B Patients Treated with Entecavir.

Background and Aims: Chronic hepatitis B (CHB) can cause liver fibrosis and lead to cirrhosis and cancer. As the effectiveness of antiviral therapy to reverse liver fibrosis is limited, We aimed to evaluate the effect of An-Luo-Hua-Xian pill (ALHX) on fibrosis regression in CHB patients treated with entecavir (ETV). Methods: Treatment-naïve patients with CHB were randomly treated with ETV alone or combined with ALHX (ETV+ALHX) between October 1, 2013 and December 31, 2020. Demographic, laboratory, and liver histology data before and after 78 weeks of treatment were collected. The Ishak fibrosis score (F) was used and fibrosis regression required a decrease in F of ≥1 after treatment. Results: A total of 780 patients were enrolled, and 394 with a second liver biopsy after treatment were included in the per-protocol population, 132 in ETV group and 262 in ETV+ALHX group. After 78 weeks of treatment, the fibrosis regression rate in the ETV+ALHX group was significantly higher than that of the ETV group at baseline F≥3 patients: 124/211 (58.8%) vs. 45/98 (45.9%), p=0.035. The percentage of patients with a decreased liver stiffness measurement (LSM) was higher in the ETV+ALHX group: 156/211 (73.9%) vs. 62/98 (63.%), p=0.056. Logistic regression analysis showed that ETV combined with ALHX was associated with fibrosis regression [odds ratio (OR)=1.94, p=0.018], and a family history of hepatocellular carcinoma was on the contrary. (OR=0.41, p=0.031). Conclusions: ETV combined with ALHX increased liver fibrosis regression in CHB patients.

Single-cell RNA sequencing reveals intrahepatic and peripheral immune characteristics related to disease phases in HBV-infected patients.

OBJECTIVE: A comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure. DESIGN: We performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation. RESULTS: Both IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell-cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores. CONCLUSION: Our study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.

Putative biosynthesis mechanism of the neurotoxin ß-N-methylamino-L-alanine in marine diatoms based on a transcriptomics approach.

The neurotoxin ß-N-methylamino-L-alanine (BMAA) has been presumed as an environmental cause of human neurodegenerative disorders, such as Alzheimer's disease. Marine diatoms Thalassiosira minima are demonstrated here to produce BMAA-containing proteins in axenic culture while the isomer diaminobutyric acid was bacterially produced. In the co-culture with Cyanobacterium aponinum, diatom growth was inhibited but the biosynthesis of BMAA-containing proteins was stimulated up to seven times higher than that of the control group by cell-cell interactions. The stimulation effect was not caused by the cyanobacterial filtrate. Nitrogen deprivation also doubled the BMAA content of T. minima cells. Transcriptome analysis of the diatom in mixed culture revealed that pathways involved in T. minima metabolism and cellular functions were mainly influenced, including KEGG pathways valine and leucine/isoleucine degradation, endocytosis, pantothenate and CoA biosynthesis, and SNARE interactions in vesicular transport. Based on the expression changes of genes related to protein biosynthesis, it was hypothesized that ubiquitination and autophagy suppression, and limited COPII vesicles transport accuracy and efficiency were responsible for biosynthesis of BMAA-containing proteins in T. minima. This study represents a first application of transcriptomics to investigate the biological processes associated with BMAA biosynthesis in diatoms.

Increased Circulating Levels of CRP and IL-6 and Decreased Frequencies of T and B Lymphocyte Subsets Are Associated With Immune-Related Adverse Events During Combination Therapy With PD-1 Inhibitors for Liver Cancer.

Background: Programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) immune-related adverse events (irAEs) are inevitable in patients with liver cancer. Although the incidence of severe irAEs is low, but can result in fatal consequences. To date, only a few commonly used clinical biomarkers have been reported. Aim: To assess commonly used clinical biomarkers associated with the occurrence of irAEs to enable better management of irAEs by clinicians. Methods: We retrospectively reviewed patients with liver cancer treated with at least one cycle of PD-1 immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs). IrAEs were documented according to the common terminology criteria for adverse events version 5. Clinical and laboratory parameters were also evaluated. Results: A total of 67 patients were included, 36 with irAEs and 31 without irAEs. A total of 104 adverse events occurred; 83 of these events were grade 1/2 (G1/G2), 21 were grade 3/4 (G3/G4), and one died of G4 hepatitis. Patients with irAEs had higher levels of C-reactive protein (CRP) and interleukin-6 (IL-6) and lower levels of lymphocyte subsets, except natural killer (NK) cell counts, than those without irAEs (P <0.05). Patients who experienced G3/G4 irAEs had higher levels of CRP and IL-6 and lower levels of CD4+ T lymphocytes and B lymphocytes than those who experienced G1/G2 irAEs (P <0.05). Of note, impairments in liver function and routine blood tests were also observed (P <0.05). The results of univariate and multivariate analyses for any grade of irAEs revealed that the combination of sintilimab and lenvatinib (P= 0.004, odds ratio [OR]: 7.414, 95% confidence interval [95% CI]: 1.925-28.560) and CRP ≥8.2 mg/L (P= 0.024, OR: 3.727, CI: 1.185-11.726) were independent risk factors. Univariate and multivariate analyses of the risk factors of G3/G4 irAEs suggested that the combination of sintilimab and lenvatinib was a potential risk factor (P = 0.049, OR: 8.242, CI: 1.006-67.532). Conclusion: Changes in patient CRP, IL-6, and lymphocyte subsets were associated with irAE onset and may act as potential biomarkers of irAEs. Impairments in liver function and routine blood tests owing to the occurrence of irAEs may become new concerns for clinicians.

Correlation of HBV DNA and Hepatitis B Surface Antigen Levels With Tumor Response, Liver Function and Immunological Indicators in Liver Cancer Patients With HBV Infection Undergoing PD-1 Inhibition Combinational Therapy.

Background: Thus far, few studies have investigated the safety and efficacy of programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) antibodies in patients with hepatitis B virus (HBV)-related liver cancer. Objective: To investigate the effect of combination therapy with programmed death-1 (PD-1) immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) on HBV-related liver cancer. Methods: Until January 31, 2022, liver cancer patients with hepatitis B surface antigen (HBsAg) or HBV DNA positivity, treated with PD-1 ICIs and TKIs combined with nucleoside analogs (NAs), were retrospectively reviewed. The correlation between the change in HBV DNA and HBsAg levels and tumor response was analyzed using the χ2 test. Cox univariate and multivariate survival analyses and Kaplan-Meier curves were used to identify and compare risk factors and overall survival (OS). Results: A total of 48 patients were enrolled in the study, with an objective response rate (ORR) of 31.3%, a disease control rate (DCR) of 66.7%; the incidence of adverse events was mostly mild. A significant decrease in HBV DNA and HBsAg levels was observed at 12 and 24 weeks compared with the baseline (p < 0.05). Compared to patients with progressive disease (PD), patients with disease control showed a more significant decrease in HBV DNA and HBsAg levels at 12 and 24 weeks (p < 0.001). Eleven patients showed elevations in HBV DNA level and one of them showed HBV reactivation; however, the reactivation was not associated hepatitis. Moreover, eight patients showed elevation in HBsAg. Elevation in HBV DNA level was associated with poor tumor response (P=0.001, OR=18.643 [95% CI: 3.271-106.253]). Cox survival analysis suggested that HBV DNA increase (P=0.011, HR=4.816, 95% CI: 1.439-16.117) and HBsAg increase (P=0.022, HR=4.161, 95% CI: 1.224-16.144) were independent risk factors associated with survival time. Kaplan-Meier curves suggested that patients who exhibited an increase in HBV DNA (6.87 months vs undefined, log-rank test: p= 0.004) and HBsAg (8.07 months vs undefined, log-rank test: p= 0.004) levels had a shorter median survival time (MST). Patients without increased HBsAg showed better baseline liver function and routine blood tests (p<0.05) than patients with increased HBsAg. An increase in C-reactive protein (CRP) and interleukin-6 (IL-6), and a decrease in T lymphocytes, CD4+ T lymphocytes, and B lymphocytes at 1-week post-treatment associated with HBsAg well-controlled. Conclusion: HBV-related liver cancer patients treated with combination therapy showed improved efficacy and safety profiles. Combination therapy has some effect on HBV infection, and a correlation between tumor response and antiviral efficacy was found. Elevation of HBV DNA and HBsAg levels may indicate poorer tumor response and survival time. Better baseline liver function and early immune activation may be associated with decline in HBsAg levels.

Practice guidance for the use of terlipressin for liver cirrhosis-related complications.

Background: Liver cirrhosis is a major global health burden worldwide due to its high risk of morbidity and mortality. Role of terlipressin for the management of liver cirrhosis-related complications has been recognized during recent years. This article aims to develop evidence-based clinical practice guidance on the use of terlipressin for liver cirrhosis-related complications. Methods: Hepatobiliary Study Group of the Chinese Society of Gastroenterology of the Chinese Medical Association and Hepatology Committee of the Chinese Research Hospital Association have invited gastroenterologists, hepatologists, infectious disease specialists, surgeons, and clinical pharmacists to formulate the clinical practice guidance based on comprehensive literature review and experts' clinical experiences. Results: Overall, 10 major guidance statements regarding efficacy and safety of terlipressin in liver cirrhosis were proposed. Terlipressin can be beneficial for the management of cirrhotic patients with acute variceal bleeding and hepatorenal syndrome (HRS). However, the evidence regarding the use of terlipressin in cirrhotic patients with ascites, post-paracentesis circulatory dysfunction, and bacterial infections and in those undergoing hepatic resection and liver transplantation remains insufficient. Terlipressin-related adverse events, mainly including gastrointestinal symptoms, electrolyte disturbance, and cardiovascular and respiratory adverse events, should be closely monitored. Conclusion: The current clinical practice guidance supports the use of terlipressin for gastroesophageal variceal bleeding and HRS in liver cirrhosis. High-quality studies are needed to further clarify its potential effects in other liver cirrhosis-related complications.

Oxidative stress responses in two marine diatoms during acute n-butyl acrylate exposure and the toxicological evaluation with the IBRv2 index.

n-Butyl acrylate (nBA), a typical hazardous and noxious substance (HNS), is the largest-volume acrylate ester used to produce various types of polymers. With the increasing volume of nBA subject to maritime transportation, its accidental leakage poses a great risk to the marine organisms. Therefore, it is necessary to evaluate the ecological risk of nBA in marine environments. In this study, two species of marine microalgae, Skeletonema costatum and Phaeodactylum tricornutum, were used to explore the toxic effects of nBA based on their growth, pigment content, and oxidative stress. The growth of each species was significantly inhibited by nBA, showing a 96 h-EC50 value of 2.23 mg/L for P. tricornutum and 8.19 mg/L for S. costatum, respectively. Although chlorophylls a and c exerted a hormesis effect in P. tricornutum, contents of pigments generally decreased at high concentrations. In P. tricornutum, all detected antioxidants (reduced glutathione, GSH; superoxide dismutase, SOD; catalase, CAT; and glutathione peroxidase, GPx) were stimulated at concentrations ranging from 1.50 to 3.82 mg/L. However, these elevations were not enough to reduce the oxidative damage caused by nBA, because the content of malondialdehyde (MDA) increased continuously during 96-h exposure. For S. costatum, the activities of only two antioxidants (GSH and CAT) were enhanced, which is enough to prevent the MDA content from rising, even at higher concentrations of nBA (5-10 mg/L). The Integrated Biomarker Response Version 2 (IBRv2) index that combines responses of the above five oxidative stress biomarkers, was not only correlated positively with nBA concentration but could also indicate the occurrence of oxidative stress caused by acute concentration of nBA. These findings showed that P. tricornutum was sensitive to nBA compared to S. costatum, and the IBRv2 index was an effective tool for evaluating ecotoxicological effects on marine microalgae due to nBA spills.

Natural attenuation of sulfometuron-methyl in seawater: Kinetics, intermediates, toxicity change and ecological risk assessment.

This research aims to evaluate the environmental feasibility of sulfometuron-methyl (SM) as a growth inhibitor for restricting the growth of Spartina alterniflora. To achieve this purpose, the natural attenuation characteristics, ecological risk, degradation pathway, and comprehensive toxicity changes of SM in seawater were investigated under the simulated marine environmental conditions of Jiaozhou Bay, China. The natural attenuation of SM in seawater followed first-order reaction kinetics with a rate constant (K) of 0.0694 d-1 and a half-life of 9.99 days. When photolysis, hydrolysis, and biodegradation pathways act alone, the rate constants K of SM were 0.0167, 0.0143, and 0.0099 d-1 respectively, indicating that their contributions to the total removal of SM decreased in turn. The calculation results of risk quotient (RQ) showed that the seawater containing 10 mg/L of SM demonstrated a very high risk to marine diatom Skeletonema costatum before and after 21 days of attenuation with RQ values of 24.46 and 6.32, respectively, however, the risk to other marine organisms (fish, crustaceans, and bivalves) decreased from moderate (RQ < 1) to low (RQ < 0.01). Four attenuation products of SM were identified and two degradation pathways of SM in seawater were proposed. Based on the rate of inhibition of bioluminescence, SM in seawater was not harmful to Photobacterium phosphoreum T3, whereas the toxicity of seawater containing SM increased with the extension of attenuation time, suggesting the formation of intermediate products with high aquatic toxicity. According to the toxicity values predicted by ECOSAR, the toxicity of one identified attenuation product was higher than that of SM. To the best of our knowledge, this is the first report on the attenuation characteristics and toxicity changes of SM in seawater. The results indicated that the toxicity of both SM and its degradation products to non-target marine organisms should be considered in evaluating the feasibility of SM in controlling coastal Spartina alterniflora.