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Total column ozone (TCO) over the Tibetan Plateau (TP) is lower than that over other regions at the same latitude, particularly in summer. This feature is known as the “TP ozone valley”. This study evaluates long-term changes in TCO and the ozone valley over the TP from 1984 to 2100 using Coupled Model Intercomparison Project Phase 6 (CMIP6). The TP ozone valley consists of two low centers, one is located in the upper troposphere and lower stratosphere (UTLS), and the other is in the middle and upper stratosphere. Overall, the CMIP6 models simulate the low ozone center in the UTLS well and capture the spatial characteristics and seasonal cycle of the TP ozone valley, with spatial correlation coefficients between the modeled TCO and the Multi Sensor Reanalysis version 2 (MSR2) TCO observations greater than 0.8 for all CMIP6 models. Further analysis reveals that models which use fully coupled and online stratospheric chemistry schemes simulate the anticorrelation between the 150 hPa geopotential height and zonal anomaly of TCO over the TP better than models without interactive chemistry schemes. This suggests that coupled chemical-radiative-dynamical processes play a key role in the simulation of the TP ozone valley. Most CMIP6 models underestimate the low center in the middle and upper stratosphere when compared with the Microwave Limb Sounder (MLS) observations. However, the bias in the middle and upper stratospheric ozone simulations has a marginal effect on the simulation of the TP ozone valley. Most CMIP6 models predict the TP ozone valley in summer will deepen in the future.

Hepatocellular carcinoma (HCC) constitutes a major global health threat due to the high incidence and mortality. Sorafenib is known as the first-line medication for advanced HCC; however, it only extends the limited benefit for HCC patients as the development of acquired resistance. Withaferin A exerts broad pharmaceutical applications in several cancers. However, its effects on HCC cell metastatic potential and sorafenib resistance remain elusive. Here, we corroborated that Withaferin A greatly restrained cell viability, invasion, vasculogenic mimicry (VM) formation, and VE-cadherin levels in HepG2 and SNU449 cells. Moreover, Withaferin A sensitized sorafenib (SR)-resistant HCC cells to sorafenib. In striking contrast to the parental cells, lower ferroptosis was observed in SR-resistant cells as the lower ROS, MDA, and higher intracellular GSH levels in SR-resistant cells. Of interest, Withaferin A enhanced ferroptosis in SR-resistant cells, which was reversed by ferroptosis antagonist liproxstation-1. Notably, Withaferin A elevated Keap1 expression to mitigate Nrf2 signaling activation-mediated epithelial to mesenchymal transition (EMT) and ferroptosis-related protein xCT expression. Importantly, blockage of the Keap1/Nrf2 signaling overturned Withaferin A-evoked ferroptosis and facilitated sorafenib resistance. In addition, knockdown of Keap1 antagonized the inhibitory efficacy of Withaferin A on HCC cell viability, invasion, and VM formation. Consequently, Withaferin A may attenuate the metastatic potential and sorafenib resistance by regulating Keap1/Nrf2-associated EMT and ferroptosis. Thus, Withaferin A may serve as a promising agent for HCC therapy, especially for advanced HCC.

Shuangchi Liu,1 Zhiduan Xu,1 Zhuling Fang,2 Dengyong Zhang,1 Zhongqiang Qin,1 Longfei Fan,1 Jiakang Duan,1 Hongxiang Yin,1 Yigang Zhang,1 Qing Pang,1,3 Yi Tan1 1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, 233000, Anhui, People’s Republic of China; 2Department of Medical Laboratory, Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of China; 3Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, Shaanxi, People’s Republic of ChinaCorrespondence: Yi Tan; Qing PangDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, 233000, People’s Republic of ChinaEmail doctortanyi2007@126.com; portxiu2@126.comBackground: Advanced liver fibrosis can lead to cirrhosis, portal hypertension and liver failure. Besides, advanced liver fibrosis and cirrhosis are the major risk factors for hepatocellular carcinoma (HCC). Almost all patients with HCC also have liver cirrhosis. This study aims to predict the survival rate of hepatitis B-related hepatocellular carcinoma (HCC) by age, international standardized ratio, albumin and γ-glutamyl transpeptidase (AIAG), an indicator measuring the degree of cirrhosis.Methods: A total of 501 hepatitis B-related HCC patients experiencing radical surgery were analyzed, retrospectively. General data about demographics and labs were collected at the date of diagnosis to calculate AIAG [age, international standardized ratio (INR), albumin and gamma-glutamyl transferase (GGT)]. The Kaplan–Meier curves and Cox analysis were used to evaluate overall survival (OS) and recurrence-free survival (RFS). The C-index was calculated in R software (version 4.0.3) to evaluate the accuracy of the prognostic model.Results: During a median follow-up period of 30 months, 31.1% (156/501) of the patients died, and 34.3% (172/501) experienced the recurrence of HCC. Compared with patients with lower AIAG score, patients with higher AIAG score had higher Child-Pugh grade and were at higher Barcelona Clinic Liver Cancer (BCLC) stage (both P< 0.05). Multivariate analysis suggested that GGT, alpha fetoprotein (AFP), tumor size, BCLC stage and AIAG grade were independent predictors of OS and RFS. Furthermore, the combined use of tumor size, AFP and AIAG stage could predict survival significantly better (C-index=0.710, 95% CI: 0.669– 0.751) than BCLC stage.Conclusion: AIAG is significantly associated with survival of HCC patients, and provides additional prognostic information for patients with HCC. Our findings suggest that the combination of AIAG, tumor size and AFP stage has a better predictive value for the prognosis of patients with hepatitis B-related hepatocellular carcinoma. However, it is necessary for more external evidences to determine clinical utility.Keywords: AIAG, hepatocellular carcinoma, survival, prognosis

The stratospheric quasi-biennial oscillation (QBO) is known to cause variations in the transport of chemical tracers but the role of chemical processes in modulating their QBO signals remains unclear. Using ozone observations (Stratospheric Water and OzOne Satellite Homogenized, SWOOSH) and a chemical transport model (SLIMCAT), we analyze the role of chemical processes in the QBO impact on stratospheric ozone in the tropics and Northern Hemisphere during winter and early spring over the period 1979–2015. During easterly QBO (EQBO) phases tropical ozone concentrations decrease in the lower stratosphere (40–100 hPa, ~16–23 km) and middle stratosphere (above 15 hPa, ~30 km) but increase in the transition region between 15 and 40 hPa (~23–30 km) compared to westerly (WQBO) phases. Although the contributions of chemical processes to the ozone QBO signal are less than those of dynamical processes, this study highlights their non-negligible role. The negative chemical ozone tendencies in the tropical lower stratosphere, that are attributed to less downward ultraviolet radiation and weaker oxygen photolysis, partially contribute to the negative ozone anomalies at this altitude during EQBO phases, particularly in February and March. In contrast, the negative chemical ozone tendencies related to increased NO2 and stronger NO2-catalyzed ozone loss, which are important in the middle stratosphere, cannot explain the ozone increases in the transition region during EQBO phases, which is mainly caused by the QBO-induced transport of ozone-rich air from above. The positive chemical ozone tendencies in the extratropics during EQBO phases are mainly related to lower temperatures and less active catalytic ozone loss cycles. In addition, reduction in polar stratospheric cloud occurrence associated with the warmer Arctic stratosphere during EQBO phases weakens the heterogeneous chemical processes in the lower stratosphere and decreases chlorine activation, partially contributing to the positive chemical ozone tendency and ozone increases in this region.