Pretransplant use of immune checkpoint inhibitors for hepatocellular carcinoma: A multicenter, retrospective cohort study.

Immune checkpoint inhibitors (ICIs) as a downstaging or bridging therapy for liver transplantation (LT) in hepatocellular carcinoma patients are rapidly increasing. However, the evidence about the feasibility and safety of pre-LT ICI therapy is limited and controversial. To this end, a multicenter, retrospective cohort study was conducted in 11 Chinese centers. The results showed that 83 recipients received pre-LT ICI therapy during the study period. The median post-LT follow-up was 8.1 (interquartile range 3.3-14.6) months. During the short follow-up, 23 (27.7%) recipients developed allograft rejection, and 7 of them (30.4%) were diagnosed by liver biopsy. Multivariate logistics regression analysis showed that the time interval between the last administration of ICI therapy and LT (TLAT) ≥ 30 days was an independent protective factor for allograft rejection (odds ratio = 0.096, 95% confidence interval 0.026-0.357; P < .001). Multivariate Cox analysis showed that allograft rejection was an independent risk factor for overall survival (hazard ratio = 9.960, 95% confidence interval 1.006-98.610; P = .043). We conclude that patients who receive a pre-LT ICI therapy with a TLAT shorter than 30 days have a much higher risk of allograft rejection than those with a TLAT longer than 30 days. The presence of rejection episodes might be associated with higher post-LT mortality.

Higher serum lipocalin 2 is associated with post-stroke depression at discharge.

BACKGROUND AND AIMS: Post-stroke depression (PSD), as one of the common complications after stroke, seriously affects the physical and mental health and functional prognosis of patients. Previous studies have shown that the increase of inflammatory mediators is associated with the occurrence of PSD. Lipocalin 2 (LCN2), as an acute phase protein, is involved in the development of acute ischemic stroke (AIS), and its expression is up-regulated in patients with depression, suggesting that there is a potential correlation between serum LCN2 and depression. The aim of this study was to explore the relationship between serum LCN2 at admission and PSD at discharge. METHODS: A total of 358 AIS patients were retrospectively included. All patients had fasting venous blood taken within 24 h of admission to detect serum LCN2. The patients were evaluated by 17-item Hamilton Depression Scale (HAMD) before discharge. Patients with HAMD score > 7 were diagnosed with PSD. The correlation between serum LCN2 and PSD was tested using binary logistic regression analysis. RESULTS: In our study, 92 (25.7%) patients were diagnosed with PSD at discharge. According to the serum LCN2 value, the patients were divided into three layers (Tertile1 ≤ 105.24ng/ml; Tertile2: 105.24-140.12ng/ml; Tertile3 ≥ 140.12ng/ml), with T1 layer (the lowest levels) as a reference, after adjusting for multiple potential confounding factors, T3 layer (the highest levels) was independently associated with the occurrence of PSD (odds ratio [OR] = 2.639, 95% confidence interval [CI]: 1.317-5.287, P = 0.006). Similar results were found when the serum LCN2 was analyzed as a continuous variable. The optimal cut-off value of serum LCN2 at admission to predict PSD at discharge was 117.60ng/ml, at this threshold, the sensitivity was 77.2%, and the specificity was 53.4%. CONCLUSIONS: High serum LCN2 levels at admission are an independent risk factor for PSD in patients with AIS at discharge.

HBV/Pregenomic RNA Increases the Stemness and Promotes the Development of HBV-Related HCC Through Reciprocal Regulation With Insulin-Like Growth Factor 2 mRNA-Binding Protein 3.

BACKGROUND AND AIMS: HBV-pgRNA (pregenomic RNA) has been proposed for predicting the response of nucleos(t)ide analogue (NA) treatment, guiding discontinuation of NA therapy and monitoring the emergence of viral mutations. However, the contributions of HBV-pgRNA to HCC remain open for study. APPROACH AND RESULTS: Double-center cohorts of serum samples with undetectable serum HBV-DNA (below the lower limit of detection) were obtained from long-term NA-treated (≥48 weeks) HBV-related HCC patients. The correlation between serum pgRNA concentration and the prognosis of HCC were analyzed. The role pgRNA played in HCC development was assessed both in vitro and in vivo. Our findings revealed that for patients who underwent long-term NA therapy with undetectable serum HBV-DNA, patients with high serum pgRNA expression had a poorer overall survival rate and higher cumulative recurrence rate after hepatectomy. Experiments demonstrated that pgRNA promotes proliferation, stemness, and tumorigenicity of HCC cells. Mechanistically, we found that pgRNA could up-regulate the expression of insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3), a well-proven oncoprotein, at the posttranscriptional level. Furthermore, interferon (IFN)-α-2a could degrade the stability of pgRNA through increasing its N6-methyladenosine (m6A) RNA modification. Collectively, our findings uncover that serum pgRNA could serve as a potential biomarker for predicting the prognosis and recurrence of HCC in patients who received long-term NA therapy with undetectable serum HBV-DNA; and the pgRNA-IGF2BP3 axis plays an important role in the development of HBV-related HCC. Moreover, IFN-α-2a could reduce the stability of pgRNA by increasing its m6A RNA modification level, thereby suppressing the development of HBV-related HCC. CONCLUSIONS: In conclusion, our studies reveal a significance and mechanism of HBV-pgRNA in increasing stemness features and offer a potential prognostic marker and a therapeutic target for HBV-related HCC.

NQO1 promotes an aggressive phenotype in hepatocellular carcinoma via amplifying ERK-NRF2 signaling.

Patients with hepatocellular carcinoma (HCC) are usually diagnosed at the later stages and have poor survival outcomes. New molecules are urgently needed for the prognostic predication and individual treatment. Our study showed that high levels of NQO1 expression frequently exist in HCC with an obvious cancer-specific pattern. Patients with NQO1-high tumors are significantly associated with poor survival outcomes and serve as independent predictors. Functional experiments showed that NQO1 promotes the growth and aggressiveness of HCC in both in vitro and in vivo models, and the underlying mechanism involved NQO1-derived amplification of ERK/p38-NRF2 signaling. Combined block of ERK and NRF2 signaling generated stronger growth inhibition compared with any single block, especially for HCC with high-NQO1. Therefore, NQO1 is a potential biomarker for HCC early diagnosis and prognosis prediction, and also attractive for cancer-specific targets for HCC treatment.

Plasma circular RNA panel to diagnose hepatitis B virus-related hepatocellular carcinoma: A large-scale, multicenter study.

To explore whether plasma circular RNAs (circRNAs) can diagnose hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), microarray and qPCR were used to identify plasma circRNAs that were increased in HBV-related HCC patients compared to controls (including healthy controls, chronic hepatitis B and HBV-related liver cirrhosis). A logistic regression model was constructed using a training set (n = 313) and then validated using another two independent sets (n = 306 and 526, respectively). Area under the receiver operating characteristic curve (AUC) was used to evaluate diagnostic accuracy. We identified a plasma circRNA panel (CircPanel) containing three circRNAs (hsa_circ_0000976, hsa_circ_0007750 and hsa_circ_0139897) that could detect HCC. CircPanel showed a higher accuracy than AFP (alpha-fetoprotein) to distinguish individuals with HCC from controls in all three sets (AUC, 0.863 [95% confidence interval, CI: 0.819-0.907] vs. 0.790 [0.738-0.842], p = 0.036 in training set; 0.843 [0.796-0.890] vs. 0.747 [0.691-0.804], p = 0.011 in validation set 1 and 0.864 [0.830-0.898] vs. 0.769 [0.728-0.810], p < 0.001 in validation set 2). CircPanel also performed well in detecting Small-HCC (solitary, ≤3 cm), AFP-negative HCC and AFP-negative Small-HCC.

Tropomodulin 3 modulates EGFR-PI3K-AKT signaling to drive hepatocellular carcinoma metastasis.

The mechanism of hepatocellular carcinoma (HCC) metastasis remains poorly understood. Tropomodulin 3 (TMOD3) is a member of the pointed end capping protein family that contributes to invasion and metastasis in several types of malignancies. It has been found to be crucial for the membranous skeleton and embryonic development, although, its role in HCC progression remains largely unclear. We observed increased levels of Tmod3 in HCCs, especially in extrahepatic metastasis. High Tmod3 expression correlated with aggressive carcinoma and poor patient with HCC survival. Loss-of-function studies conducted by us determined Tmod3 as an oncogene that promoted HCC growth and metastasis. Mechanistically, Tmod3 increases transcription of matrix metalloproteinase-2, -7, and -9 which required PI3K-AKT. Interaction between Tmod3 and epidermal growth factor receptor (EGFR) that supports the activation of EGFR phosphorylation, is essential for signaling activation of PI3K-AKT viral oncogene homolog. These findings reveal that Tmod3 enhances aggressive behavior of HCC both in vitro and in vivo by interacting with EFGR and by activating the PI3K-AKT signaling pathway.

Antiviral Therapy Reduces Hepatocellular Carcinoma Recurrence in Patients With Low HBV-DNA Levels: A Randomized Controlled Trial.

BACKGROUND: Despite antiviral treatment has been shown to reduce hepatocellular carcinoma (HCC) recurrence after curative treatment for hepatitis B virus (HBV)-related HCC in patients with high preoperative HBV-DNA levels, it is still unclear whether antiviral therapy is useful in reducing recurrence in patients with low preoperative HBV-DNA levels. METHODS: In this randomized controlled trial, 200 patients who underwent curative resection for HCC with low baseline HBV-DNA levels were randomly assigned to receive preemptive antiviral therapy or not. The primary endpoints were recurrence-free survival. This study was censored on March 31, 2015 when all surviving patients had a minimum follow-up of 60 months. The analysis was done on an intention-to-treat basis. RESULTS: The baseline clinical, laboratory, and tumor characteristics of the 2 groups were comparable. The 1-, 3-, and 5-year recurrence-free survival rates for the antiviral group and the control group were 85.9%, 55.2%, and 52.0% and 80.6%, 40.9%, and 32.3%, respectively. The corresponding overall survival rates for the 2 groups were 94.0%, 75.7%, and 64.1% and 90.0%, 62.4%, and 43.7%, respectively. The recurrence-free survival and overall survival for the antiviral group were significantly better than the control group (P = 0.016, P = 0.004, respectively). After adjusting for confounding prognostic factors in a Cox model, the relative risks of recurrence and death for antiviral treatment were 0.601 [95% confidence interval (CI), 0.409-0.884; P = 0.010] and 0.509 (95% CI, 0.333-0.778; P = 0.002), respectively. Antiviral therapy was an independent protective factor of late tumor recurrence (hazard ratio [HR] = 0.316, 95% CI 0.157-0.637; P = 0.001) but not of early tumor recurrence (HR = 0.782, 95% CI, 0.493-1.240; P = 0.296). CONCLUSIONS: In patients with low preoperative HBV-DNA levels, antiviral therapy significantly reduced HCC recurrence after R0 hepatic resection.

Small molecule agents for triple negative breast cancer: Current status and future prospects.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor prognosis. The number of cases increased by 2.26 million in 2020, making it the most commonly diagnosed cancer type in the world. TNBCs lack hormone receptor (HR) and human epidermal growth factor 2 (HER2), which limits treatment options. Currently, paclitaxel-based drugs combined with other chemotherapeutics remain the main treatment for TNBC. There is currently no consensus on the best therapeutic regimen for TNBC. However, there have been successful clinical trials exploring large-molecule monoclonal antibodies, small-molecule targeted drugs, and novel antibody-drug conjugate (ADC). Although monoclonal antibodies have produced clinical success, their large molecular weight can limit therapeutic benefits. It is worth noting that in the past 30 years, the FDA has approved small molecule drugs for HER2-positive breast cancers. The lack of effective targets and the occurrence of drug resistance pose significant challenges in the treatment of TNBC. To improve the prognosis of TNBC, it is crucial to search for effective targets and to overcome drug resistance. This review examines the clinical efficacy, adverse effects, resistance mechanisms, and potential solutions of targeted small molecule drugs in both monotherapies and combination therapies. New therapeutic targets, including nuclear export protein 1 (XPO1) and hedgehog (Hh), are emerging as potential options for researchers and become integrated into clinical trials for TNBC. Additionally, there is growing interest in the potential of targeted protein degradation chimeras (PROTACs), degraders of rogue proteins, as a future therapy direction. This review provides potentially valuable insights with clinical implications.

Association Between TCBI (Triglycerides, Total Cholesterol, and Body Weight Index) and Stroke-Associated Pneumonia in Acute Ischemic Stroke Patients.

Purpose: Stroke-associated pneumonia (SAP) usually complicates stroke and is linked to adverse prognoses. Triglycerides, total cholesterol, and body weight index (TCBI) is a new and simple calculated nutrition index. This study seeks to investigate the association between TCBI and SAP incidence, along with its predictive value. Patients and Methods: Nine hundred and sixty-two patients with acute ischemic stroke were divided into SAP group and Non-SAP group. The TCBI was divided into three layers: T1, TCBI < 948.33; T2, TCBI 948.33-1647.15; T3, TCBI > 1647.15. Binary Logistic regression analysis was used to determine the relationship between TCBI levels and the incidence of SAP. Furthermore, restricted cubic splines (RCS) analysis was utilized to evaluate the influence of TCBI on the risk of SAP. Results: TCBI in the SAP group was markedly lower compared to that in the Non-SAP group (P < 0.001). The Logistic regression model revealed that, using T3 layer as the reference, T1 layer had the highest risk for SAP prevalence (OR = 2.962, 95% CI: 1.600-5.485, P = 0.001), with confounding factors being controlled. The RCS model found that TCBI had a linear relationship with SAP (P for nonlinear = 0.490, P for overall = 0.004). Moreover, incorporating TCBI into the A2DS2 (Age, atrial fibrillation, dysphagia, sex, and severity) model substantially enhanced the initial model's predictive accuracy. Conclusion: Low TCBI was associated with a higher risk of SAP. In clinical practice, TCBI has shown predictive value for SAP, contributing to early intervention and treatment of SAP.

Preservation of Porcine Donation after Circulatory Death (DCD) Liver by Perfusion and Orthotopic Liver Transplantation.

Conventional static cold storage (SCS) exacerbates ischemic injury in the DCD liver, leading to severe complications for transplant recipients. To address this issue, clinical application of MP technology for donor liver preservation is underway. Simultaneously, efforts are focused on the development of various MP instruments, validated through relevant animal model experiments. Effective large animal trials play a pivotal role in clinical applications. However, challenges persist in the ex vivo preservation of DCD livers and the transplantation procedure in pigs. These hurdles encompass addressing the prolonged preservation of donor livers, conducting viability tests, alleviating ischemic injuries, and shortening the anhepatic phase. The use of a variable temperature-controlled MP device facilitates the prolonged preservation of DCD livers through sequential Dual Hypothermic Oxygenated Machine Perfusion (DHOPE) and Normothermic Machine Perfusion (NMP) modes. This protocol enhances the porcine OLTx model by improving the quality of DCD livers, optimizing the anastomosis technique, and reducing the duration of the anhepatic phase.

Genome-Wide Association Study of Growth and Sex Traits Provides Insight into Heritable Mechanisms Underlying Growth Development of Macrobrachium nipponense (Oriental River Prawn).

Male hybrid oriental river prawns grow significantly faster than hybrid females. In this study, the growth and sex traits of 181 individuals of Macrobrachium nipponense were recorded, and each individual genotype was evaluated using the 2b-RAD sequencing method. The genetic parameters for growth and sex traits were estimated. A genome-wide association analysis (GWAS) of these traits was performed. In total, 18 growth-related SNPs were detected from 12 chromosomes using a mixed linear model. The most significant loci of weight are located on the position of the SNP (102638935, chromosome 13), which can explain 11.87% of the phenotypic variation. A total of 11 significant SNPs were detected on four chromosomes associated with sex trait (three on chromosome 4, one on chromosome 7 and seven on chromosome 17). The heritability of this trait is 0.8998 and belongs to the range of ultra-high heritability. Genetic correlations were prevalent among the 11 traits examined, the genetic coefficient between sex and body weight reached a significant level of -0.23. This study is the first GWAS for sex of binary and growth traits in oriental river prawn. Our results provide a set of markers for the genetic selection of growth traits and help us to further understand the genetic mechanisms of growth in Macrobrachium nipponense.

Acrylate-functionalized porphyrin-covalent organic framework for bacterial-targeted and reaction-enhanced synergistic phototherapy/chemotherapy toward sterilization and wound healing.

Porphyrinic covalent organic frameworks (COFs) have emerged as prospective materials in photodynamic and photothermal sterilization. However, it is still a great challenge to construct an efficient COF-based sterilizing agent with good photothermal and photodynamic properties and bacterial targeting ability. Herein, we report a multifunctional porphyrin-COF for bacterial-targeted and reaction-enhanced synergistic phototherapy/chemotherapy for sterilization and wound healing. The ordered crystal structure of the porphyrin-COF not only effectively avoids the self-aggregation-induced quenching of the porphyrin monomer, but also facilitates the storage and transport of singlet oxygen. The acrylate substituent in the other monomer serves as a bacterial targeting moiety and the in situ reaction site with the sulfhydryl group of the bacterial surface protein via a Michael addition reaction, thus fixing the bacteria on the surface of COF and making them lose the colonization ability. Furthermore, the bonding of COF and bacteria further amplifies the therapeutic efficiency of phototherapy. Therefore, the developed multifunctional sterilization platform not only provides a new strategy for the design of novel bactericidal materials but also broadens the biological applications of COF-based materials.

Pollution characteristics and health risk assessment of phthalate esters in agricultural soil of the Yellow River Delta, China.

A total of 100 agricultural soil samples, collected in the Yellow River Delta, China, were analyzed for six U.S. Environmental Protection Agency priority phthalate esters (PAEs), focusing on the characteristics of PAEs contamination and potential health risks. The detection frequencies of ∑6PAEs were 100%, where the concentration ranged from 1.087 to 14.391 mg·kg-1, with a mean value of 4.149 mg·kg-1. The most abundant PAEs were di(2-ethylhexyl) phthalate (DEHP) and di-n-butyl phthalate (DnBP). The areas with higher contents of ∑6PAEs are distributed in the western and central parts of the Yellow River Delta region and around Laizhou Bay. PAEs in the Yellow River Delta agricultural soil were attributed to pollutant emissions from petrochemical industries, plasticizers or additives, fertilizers, and pesticides. The non-carcinogenic risk of human exposure to PAEs in agricultural soils is relatively low, but the non-carcinogenic risk is higher in children than in adults, and children are a sensitive group. Under the dietary route, both DEHP and ∑2PAEs (BBP, and DEHP) pose some degree of carcinogenic risk to both local adults and children. Efforts must be made to enhance the prevention and control of PAEs contamination of agricultural soils in the Yellow River Delta region to reduce the potential risk to humans.

Exogenous interference and autofluorescence-free ratiometric aptasensor for detection of OTA based on dual-colored persistent luminescence nanoparticles.

Accurate and sensitive detection of ochratoxin A (OTA) is highly necessary due to its high carcinogenicity, teratogenicity and mutagenicity. Herein, we reported an exogenous interference and autofluorescence-free ratiometric aptasensor based on dual-colored persistent luminescent nanoparticles for precise detection of OTA. Green-emitting ZnGeO:Mn bonded with OTA aptamer and BHQ1-modified complementary base was acted as detection and specific recognition probe (ZGM@BHQ1). Quaternary ammonium modified ZnGaGeO:Cr with red emission was employed as reference probe and further bonded to ZGM@BHQ1 through electrostatic interaction to construct the ratiometric aptasensor. The developed ratiometric aptasensor was free from real-time excitation, external interference and autofluorescence and gave low detection limit of 3.4 pg mL-1, wide linearity in the range of 0.01-50 ng mL-1 and high precision of 3.1 % (11 replicate determinations, at 1 ng mL-1 level). The applicability of the aptasensor was successfully demonstrated by analyzing OTA in in grain samples with recoveries of 97.6 %-105.2 %.

Clinical research progress on BRAF V600E-mutant advanced colorectal cancer.

Colorectal cancer is one of the malignant tumors that pose a serious threat to human health. A particularly bad prognosis might be expected for colorectal tumors with the unique molecular subtype BRAF V600E mutation. With the development of precision therapy, the advent of molecularly targeted therapies and immune checkpoint inhibitors has improved the outcome of intermediate to advanced colorectal cancer. However, the duration of drug benefit is usually short, and overall survival and progression-free survival remain suboptimal. Therefore, investigators are exploring more rational, safe, and effective drug combination regimens through clinical trials to provide longer survival for patients with such genetic mutations with metastatic colorectal cancer (mCRC). This article reviews the progress of clinical research on molecularly targeted drugs, immune checkpoint inhibitors, first-line chemotherapeutic agents, and different combination therapy regimens (including different targeted drug combinations, immune combination targeting, and chemotherapy combination targeting) for colorectal cancer patients with BRAF V600E mutation, which provides a reference for further in-depth clinical exploration of the treatment of colorectal cancer patients with BRAF V600E mutation.

Research progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma.

Hepatocellular carcinoma is a common gastrointestinal malignancy with a high mortality rate and limited treatment options. Molecularly targeted drugs combined with immune checkpoint inhibitors have shown unique advantages over single-agent applications, significantly prolonging patient survival. This paper reviews the research progress of molecular-targeted drugs combined with immune checkpoint inhibitors in the treatment of hepatocellular carcinoma and discusses the effectiveness and safety of the combination of the two drugs to provide a reference for the further application of molecular-targeted drugs combined with immune checkpoint inhibitors in clinical practice.

Association of atherogenic index of plasma with early neurological deterioration in patients with acute ischemic stroke.

PURPOSE: To explore the correlation between Atherogenic Index of Plasma (AIP) and early neurological deterioration (END) in patients with acute ischemic stroke (AIS). METHODS: A retrospective analysis of 334 patients diagnosed with AIS between January 2021 and May 2023 at the Affiliated Huai'an Hospital of Xuzhou Medical University. Patients were divided into END and non-END groups based on changes in National Institutes of Health Stroke Scale scores (NIHSS) within 7 days of admission, and the differences in the indicators between the two groups were examined using univariate analysis. The patients were then divided into three groups based on the tertile of the AIP (T1: AIP≤ -0.01; T2: 0 ≤AIP≤0.16; AIP≥0.17), and logistic regression analysis was used to examine the association between the AIP and END. Finally, the predictive ability of the AIP was evaluated using the receiver operating characteristic (ROC) curve. RESULTS: A total of 334 patients were included, of which 64 (19.20%) had END. The results of the analysis showed that the AIP was significantly higher in the END group compared to the non-END group. Multivariable logistic regression analysis showed that higher AIP was associated with END in AIS patients (OR=3.259, 95%CI, 1.490-7.125, P = 0.003), especially in large-artery atherosclerosis (LAA) subtype (OR=4.240, 95%CI,1.30-13.87, P = 0.017). ROC analysis revealed that the best predictive cutoff value of AIP was 0.115, and the area under the ROC curves for AIP was 0.681(0.604-0.758). CONCLUSION: Our study uncovered that higher AIP levels were associated with END development in AIS patients.

Corrigendum: Research progress of targeted therapy combined with immunotherapy for hepatocellular carcinoma.

[This corrects the article DOI: 10.3389/fonc.2023.1197698.].

Acute exposure to paraquat affects the phenotypic differentiation of substantia nigra microglia in rats.

The toxicity of the bipyridine cationic herbicide paraquat (PQ) to the lung and kidneys has been widely documented, but the acute toxic effects of PQ on the nervous system have received little attention. This study aimed to explore the changes in the phenotypic differentiation of microglia in rats caused by acute PQ exposure. As results, acute PQ exposure induced pyknosis, edema, and apoptosis in substantia nigra neurons. Immunohistochemistry and western blotting showed that, on day 18, with the increase of exposure dose, the number of Iba-1-positive cells presented an increasing trend with no statistically significant difference among the groups (P > 0.05). Compared with the control group, the process length of Iba-1-positive cells decreased of acute 25 mg/kg PQ exposure on day 18 (P < 0.05). Compared with the control group, on day 39, the number of Iba-1-positive cells in the SN decreased of acute 25 mg/kg PQ exposure, while that increased of acute 45 mg/kg PQ exposure (P < 0.05). The number of endpoints decreased of acute 25 mg/kg PQ exposure (P < 0.05). The process length became shorter both of acute 25 mg/kg and 45 mg/kg PQ exposure (P < 0.05). On day 69, compared with the control group, the number of Iba-1-positive cells in the SN significantly increased of acute 45 mg/kg PQ exposure (P < 0.05). The number of endpoints increased and the process length became longer of acute 25 mg/kg PQ exposure (P < 0.05). Then, the mean fluorescence intensity of inducible nitric oxide synthase (iNOS) and arginine 1 (ARG1) was compared. The number of the M1 phenotype of microglia increased during the early stage of acute 25 mg/kg PQ exposure, whereas the number of the M2 phenotype of microglia increased during the early stage of acute 45 mg/kg PQ exposure (P < 0.05). On day 39, compared with the control group, the expression of iNOS in the SN of acute 45 mg/kg PQ exposure increased than of acute 25 mg/kg exposure. The expression of Arg-1 of 25 mg/kg PQ exposure was significantly increased (P < 0.05). On day 69, the expression of iNOS and ARG1 increased in the 25 and 45 mg/kg PQ exposure groups. In summary, changes in microglia phenotypic differentiation were related to exposure dose and exposure time (P < 0.05).

DANCR deletion retards the initiation and progression of hepatocellular carcinoma based on gene knockout and patient-derived xenograft in situ hepatoma mice model.

Our previous study has demonstrated that the expression level of long noncoding RNA (lncRNA)-differentiation antagonizing non-protein coding RNA (DANCR) increases in hepatocellular carcinoma (HCC), contributing to the initiation and aggravation of such kind of malignant tumor, which is recognized as a promising therapeutic target for patients with HCC. To further investigate the effect of DANCR on HCC in preclinical models, we generated a Dancr knockout (KO) mice model by Cas9/gRNA technology and a patient-derived xenograft (PDX) in situ hepatoma mice model using immunodeficient mice and utilized adeno-associated virus 8 (AAV8) delivery DANCR-shRNA system to silence the expression of DANCR in xenograft tumor. Here, we reported that Dancr expression mainly occurred in hepatocytes and its depletion significantly alleviated hepatic fibrosis in mice and showed a prospective result with smaller tumor size and fewer number of tumors in HCC preclinical mice model. Additionally, we found that the expression of Dancr in mice cirrhotic liver was positively correlated with the content of Dancr in serum. Overall, DANCR KO can inhibit the occurrence and development of HCC and is a target worthy of further study in patients with HCC.