Arsenic trioxide augments immunogenic cell death and induces cGAS-STING-IFN pathway activation in hepatocellular carcinoma.

The treatment of hepatocellular carcinoma (HCC) is particularly challenging due to the inherent tumoral heterogeneity and easy resistance towards chemotherapy and immunotherapy. Arsenic trioxide (ATO) has emerged as a cytotoxic agent effective for treating solid tumors, including advanced HCC. However, its effectiveness in HCC treatment remains limited, and the underlying mechanisms are still uncertain. Therefore, this study aimed to characterize the effects and mechanisms of ATO in HCC. By evaluating the susceptibilities of human and murine HCC cell lines to ATO treatment, we discovered that HCC cells exhibited a range of sensitivity to ATO treatment, highlighting their inherent heterogeneity. A gene signature comprising 265 genes was identified to distinguish ATO-sensitive from ATO-insensitive cells. According to this signature, HCC patients have also been classified and exhibited differential features of ATO response. Our results showed that ATO treatment induced reactive oxygen species (ROS) accumulation and the activation of multiple cell death modalities, including necroptosis and ferroptosis, in ATO-sensitive HCC cells. Meanwhile, elevated tumoral immunogenicity was also observed in ATO-sensitive HCC cells. Similar effects were not observed in ATO-insensitive cells. We reported that ATO treatment induced mitochondrial injury and mtDNA release into the cytoplasm in ATO-sensitive HCC tumors. This subsequently activated the cGAS-STING-IFN axis, facilitating CD8+ T cell infiltration and activation. However, we found that the IFN pathway also induced tumoral PD-L1 expression, potentially antagonizing ATO-mediated immune attack. Additional anti-PD1 therapy promoted the anti-tumor response of ATO in ATO-sensitive HCC tumors. In summary, our data indicate that heterogeneous ATO responses exist in HCC tumors, and ATO treatment significantly induces immunogenic cell death (ICD) and activates the tumor-derived mtDNA-STING-IFN axis. These findings may offer a new perspective on the clinical treatment of HCC and warrant further study.

The expressions and significance of B7-H3 and CTLA-4 in the clinical stages of non-small-cell lung cancer.

The aim of this study was to analyze the expressions and significance of B7-H3 and CTLA-4 in the clinical stages of non-small-cell lung cancer (NSCLC). Seventy patients with NSCLC who underwent surgical resection or biopsy between January 2016 and February 2018 were enrolled. Among them, 30 were cases of paracancerous tissues and were assigned to the control group (CON). These cases were analyzed using immunochemical methods. Of the 70 cases, 48 were of adenocarcinoma, 19 were of squamous cell carcinoma, and 3 were of adenosquamous carcinoma. The expression rates of B7-H3 and CTLA-4 in the observation group (OBS) were 64.2% and 57.1% respectively, and those in the CON group were 6.7% and 0%, respectively (χ2=27.988, 28.571, P<0.001). The expression levels of B7-H3 and CTLA-4 in patients with poor differentiation, in stages III-IV, or with lymph node metastasis were significantly higher than those in patients with good-to-moderate differentiation, in stages I-II, and without lymph node metastasis (P<0.05). There was a positive correlation between the expressions of B7-H3 and CTLA-4 in the OBS group (r=0.74, P<0.05). B7-H3 and CTLA-4 are highly expressed and positively correlated with each other in NSCLC patients and are also closely related to clinical stages.

Effect of the emphysema subtypes of patients with chronic obstructive pulmonary disease on airway inflammation and COTE index.

The aim of the present study was investigate the association of the severity of emphysema of patients with chronic obstructive pulmonary disease (COPD) with airway inflammation and the COPD-specific comorbidity test (COTE) index. A total of 94 patients with COPD were divided into four groups according to the severity of their emphysema; in each patient, comorbidities were recorded and inflammatory biomarkers, including MMP-9 and TIMP-1 were determined in circulating blood. The unbalanced proportion of MMP-9 and its inhibitor, TIMP-1, led to the airway inflammation and lung remodeling in the patients with COPD. A total of 80.85% of the patients had emphysema of different degrees. The quantity of male patients and the smoking index in the three emphysema groups were significantly higher than those in the non-emphysema group (F=7.67 and 5.42, P<0.05). The level of the predicted percent offorced expiratory volume in 1 sec in the non-emphysema group were significantly higher than those in the emphysema group (4.33; P<0.05), and the level of D-dimer in the non-emphysema group was significantly lower than that in the mild and moderate emphysema groups (F=9.38, P<0.05). The low-attenuation area score was negatively correlated with inhaled bronchodilators (r=-0.240, P=0.007) but positively correlated with the frequency of acute exacerbations in the previous year (r=0.211, P=0.001). In terms of treatment, the use of systemic hormone therapy in the emphysema group was more frequent than that in the non-emphysema group (F=6.21, 12.92 and 4.08, P<0.05). The level of MMP-9 was significantly higher in COPD patients with >3 comorbidities, a COTE index of ≥4 and cardiovascular disease as well as coronary heart disease (t=6.40, 2.53, 3.65 and 2.90, P<0.05). The level of MMP-9 was positively correlated with the neutrophilic granulocyte percentage, the number of comorbidities and the COTE index (r=0.193, 0.402 and 0.311, P<0.01). The severity of emphysema in patients with COPD was correlated with the persistence of inflammatory factors in the circulating blood and the frequency of acute exacerbations. It was indicated that MMP-9 has a critical role in numerous comorbidities of COPD.

Typing of chronic obstructive pulmonary disease using high-resolution computed tomography and the association with smoking, airway inflammation, and common comorbidities

Background/aim: This study performed typing of chronic obstructive pulmonary disease (COPD) using high-resolution computed tomography (HRCT) to determine the association with smoking, matrix metalloproteinases, and common comorbidities. Materials and methods: The study enrolled 94 hospitalized patients. Participants were divided into a group of 69 current and former smokers (group A) and a group of 25 that had never smoked (group B). Patients were also divided into 3 categories according to the degree of emphysema and bronchial wall thickness using HRCT to determine the association with levels of matrix metalloproteinase 9 (MMP-9) and TIMP-1, as well as associated comorbidities. These three categories were: type A - no or mild emphysema, with or without bronchial wall thickening; type E - emphysema without bronchial wall thickening; and type M - both emphysema and bronchial wall thickening. Results: The low attenuation area (LAA) scores in group A patients were higher than those in group B (t = 2.86, P < 0.01); correlation analysis showed that smoking was associated with a decline of the forced expiratory volume in 1 s and forced vital capacity ratio (FEV1/ FVC%) and higher LAA scores in patients with COPD (F = 4.46, F = 8.20, P < 0.05). The levels of MMP-9 in group A were higher than those in group B (t = 3.65, P < 0.01). Among COPD patients with more than 3 comorbidities, there were statistically significant differences in both the smoking group and the nonsmoking group (chi-square = 12.08, P < 0.01). When compared to type A patients, who had coincident cardiovascular diseases in the smoking group, patients of type M and E showed statistically significant differences (F = 2.42 and 2.12, P < 0.05). Conclusion: Emphysema was more severe in smokers. Metalloproteinase levels in smokers were higher than those in nonsmokers. Moreover, comorbidities were more severe in smokers.