Activation of CD14+ Monocytes via the IFN-γ Signaling Pathway Is Associated with Immune-Related Adverse Events in Hepatocellular Carcinoma Patients Receiving PD-1 Inhibition Combination Therapy.

(1) Background: Immune-related adverse events (irAEs) are a series of unique organ-specific inflammatory toxicities observed in patients with hepatocellular carcinoma (HCC) undergoing PD-1 inhibition combination therapy. The specific underlying mechanisms remain unclear. (2) Methods: We recruited 71 patients with HCC undergoing PD-1 inhibition combination therapy. These patients were then divided into two groups based on irAE occurrence: 34 had irAEs and 37 did not. Using Olink proteomics, we analyzed the aberrant inflammation-related proteins (IRPs) in these patient groups. For single-cell RNA sequencing (scRNA-seq) analysis, we collected peripheral blood mononuclear cells (PBMCs) from two representative patients at the pretreatment, irAE occurrence, and resolution stages. (3) Results: Our study revealed distinct plasma protein signatures in HCC patients experiencing irAEs after PD-1 inhibition combination therapy. We clarified the relationship between monocyte activation and irAEs, identified a strongly associated CD14-MC-CCL3 monocyte subset, and explored the role of the IFN-γ signaling pathway in monocyte activation during irAEs. (4) Conclusions: The activation of monocytes induced by the IFN-γ signaling pathway is an important mechanism underlying the occurrence of irAEs in HCC patients receiving PD-1 inhibition combination therapy.

Efficient adsorption of phosphorus by macroscopic MOF/chitosan composites and preliminary investigation of subsequent phosphorus recovery through electrochemically-driven struvite precipitation.

The proper management of phosphorus (P) from wastewater is crucial for sustainable development consideration. Herein, we developed a strategy which combines adsorption via tailored adsorbents and electrochemically-driven struvite precipitation (ESP) for P recovery. Novel polydopamine-modified Ce-MOF/chitosan composite beads (PDA@Ce-MOF-CS) were prepared by a facile in situ growth of Ce-MOF crystals incorporated natural polymers and PDA coating. The physicochemical properties of PDA@Ce-MOF-CS were characterized. Both batch and fixed-bed column experiments were conducted to evaluate its adsorption performances. Representatively, PDA@Ce-MOF-CS performed good selectivity for P removal and exhibited a maximum adsorption capacity of 161.13 mg P/g at pH 3 and 318 K. Meanwhile, the developed adsorbent showed great reusability after ten regeneration cycles as well as good adsorption stability. The dominant mechanism for efficient P adsorption included electrostatic attraction, surface precipitation and ligand exchange. Interestingly, PDA@Ce-MOF-CS exhibited a remarkable adsorption capacity of 92.86 mg P/g by treating real P-rich electroplating wastewater, and the desorbed P in the eluate could be effectively recovered and converted into a solid fertilizer as struvite via ESP. Overall, this work provided a new research direction for P recovery from wastewater as struvite by combined technologies with the help of macroscopic MOF architectures.

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.

Roles of Arf6 in cancer cell invasion, metastasis and proliferation.

ADP-ribosylation factor 6 (Arf6), a member of small GTPases ADP-ribosylation factor (Arf) family, expresses widely in mammalian cells and mainly regulates the functions of membrane traffic and actin remodeling. Current studies indicated that the activation and high expression of Arf6 protein may be significantly correlated with the invasion and metastasis of several tumors, such as breast cancer, pancreatic cancer, lung cancer, etc. Meanwhile, the ability of tumor invasion and metastasis can be suppressed when Arf6 activity is blocked by the inhibitors or small-interfering RNAs of Arf6. To explore the precisely potential mechanisms between Arf6 and the process of tumor invasion, metastasis and proliferation, we concludes the functions and potential signaling pathways of Arf6 in tumor cells and provides an overview about clinical prospects of Arf6 in the screening, diagnosis, treatment and evaluation of prognosis of neoplasms.