Background: Chronic liver injury induces pathological repair, resulting in fibrosis, during which hepatic stellate cells (HSCs) are activated and transform into myofibroblasts. CD248 is mainly expressed on myofibroblasts and was considered as a promising target to treat fibrosis. The primary aim of this study was to generate a CD248 specific antibody-drug conjugate (ADC) and evaluate its therapeutic efficacy for liver fibrosis and its safety in vivo. Methods: CD248 expression was examined in patients with liver cirrhosis and in mice with CCl₄-induced liver fibrosis. The ADC IgG78-DM1, which targets CD248, was prepared and its bioactivity on activated primary HSCs was studied. The anti-fibrotic effects of IgG78-DM1 on liver fibrosis were evaluated in CCl₄-induced mice. The reproductive safety and biosafety of IgG78-DM1 were also evaluated in vivo. Results: CD248 expression was upregulated in patients with liver cirrhosis and in CCl₄-induced mice, and was mainly expressed on alpha smooth muscle actin (α-SMA)⁺ myofibroblasts. IgG78-DM1 was successfully generated, which could effectively bind with and kill CD248⁺ activated HSCs in vitro and inhibit liver fibrosis in vivo. In addition, IgG78-DM1 was demonstrated to have qualified biosafety and reproductive safety in vivo. Conclusions: Our study demonstrated that CD248 could be an ideal target for myofibroblasts in liver fibrosis, and CD248-targeting IgG78-DM1 had excellent anti-fibrotic effects in mice with liver fibrosis. Our study provided a novel strategy to treat liver fibrosis and expanded the application of ADCs beyond tumors. Graphic

Background: The coronavirus disease 2019 (COVID-19) pandemic has spread worldwide. However, the impact of baseline lipid profile on clinical endpoints in COVID-19 and the potential effect of COVID-19 on lipid profile remain unclear.Methods: In this retrospective cohort study, we consecutively enrolled 430 adult COVID-19 patients from two Chinese hospitals (one each in Chengdu and Wuhan). The lipid profile before admission and during the disease course and the clinical endpoint including in-hospital death or oropharyngeal swab test positive again (OSTPA) after discharge were collected. We used Kaplan–Meier and Cox regression to explore the lipid risk factors before admission associated with endpoints. Then, we assessed the lipid level change along with the disease course to determine the relationship between pathology alteration and the lipid change.Results: In the Chengdu cohort, multivariable Cox regression showed that low-density lipoprotein cholesterol (LDL-C) dyslipidemia before admission was associated with OSTPA after discharge for COVID-19 patients (RR: 2.51, 95% CI: 1.19, 5.29, p = 0.006). In the Wuhan cohort, the patients with triglyceride (TG) dyslipidemia had an increased risk of in-hospital death (RR: 1.92, 95% CI: 1.08, 3.60, p = 0.016). In addition, in both cohorts, the lipid levels gradually decreased in the in-hospital death or OSTPA subgroups since admission. On admission, we also noticed the relationship between the biomarkers of inflammation and the organ function measures and this lipid level in both cohorts. For example, after adjusting for age, sex, comorbidities, smoking, and drinking status, the C-reactive protein level was negatively associated with the TC lipid level [β (SE) = -0.646 (0.219), p = 0.005]. However, an increased level of alanine aminotransferase, which indicates impaired hepatic function, was positively associated with total cholesterol (TC) lipid levels in the Chengdu cohort [β (SE) = 0.633 (0.229), p = 0.007].Conclusions: The baseline dyslipidemia should be considered as a risk factor for poor prognosis of COVID-19. However, lipid levels may be altered during the COVID-19 course, since lipidology may be distinctly affected by both inflammation and organic damage for SARS-CoV-2.

Background: Cardiac autonomic dysfunction (CAD) is a common pathology in cardiovascular diseases; however, the role of glycolipid metabolic disorders in CAD development in obstructive sleep apnea (OSA) remains poorly understood. Methods: In total, 4152 patients with suspected OSA were recruited in our sleep center. Metabolic characteristics including anthropometric and glycolipid data were collected. Heart rate variability (HRV) was measured to assess the risk of CAD; its dose–response relationship with OSA severity was evaluated via restricted cubic spline (RCS) analysis. A segmented multivariate linear regression (SMLR) model was used to evaluate the roles of metabolic variables in different stages of OSA. Results: The RCS showed that CAD risk increased in a nonlinear relationship pattern with OSA severity, from slow fluctuation at earlier stages to rapid change in later stages. After integrating the clinical definition and RCS selected knots, we obtained the new four OSA severity stages. SMLR model showed that the overall value of glycolipid variables for prediction of HRV abnormalities was greater than the value of OSA variables at earlier stages, while OSA variables were more effective predictors in more severe stages. The discordance in respective relationship of HRV with metabolic and OSA variables sheds the light how metabolic disorders promoted the development of CAD in OSA, the later further in turn deteriorates cardiac function. Conclusion: These results are indicative of stage-specific involvement of glycolipid metabolic factors underlying CAD nonlinear changes in patients with OSA. Early control glycolipid disorders may help the control of CAD development in patients with OSA.

Smoke inhalation injury is the main cause of fatalities for fire victims. Understanding in the pathophysiology of the injury has not been fully explored in recent years. To further explore the pathophysiological mechanism, a dynamic and controllable animal model is necessary. To develop a rat model of smoke inhalation injury to simulate human victims in air-restricted vehicle cabin fires. Smoke concentration, including CO, O2, VOCs and smoke temperature under different combustion conditions, were detected. Levels of COHb, respiratory function, lung wet-to-dry weight ratio and protein concentration in BALF and blood were measured. Pathological evaluations of lung in tissues were conducted at 1, 6, 24 and 48 h post-exposure. Smoke concentration rose with the increase of combustion temperature and decrease of oxygen flow. Further, 215 kinds of VOCs in the smoke were detected, and the concentrations of benzene, methylbenzene, ethylbenzene, dimethylbenzene, phenylethylene and trimethylbenzene was 32.93, 402.06, 764.03, 113.73, 1006.61 and 89.28 mg/m(3), respectively. Significant hypoxemia and CO poisoning occurred in rats. The FCOHb after exposure for 14 min immediately rose to (44.2 ± 12.3) % and then gradually decrease to a normal level at 300 min post-exposure. At 24 h post-exposure, Penh increased significantly (p < 0.05), and high pulmonary vascular permeability and significant lung edema (p < 0.05) were observed in the smoke inhalation group. In summary, the novel rat model of smoke inhalation injury system used in the study is dynamic and controllable, and appropriate for use in smoke inhalation injury studies of air-restricted cabins in vehicles.