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Aggregated mining development has direct and indirect impacts on vegetation changes. This impact shows spatial differences due to the complex influence of multiple mines, which is a common issue in resource regions. To estimate the spatial heterogeneity of vegetation response to mining activities, we coupled vegetation changes and mining development through a geographically weighted regression (GWR) model for three cumulative periods between 1999 and 2018 in integrated resource regions of northwestern China. Vegetation changes were monitored by Sen’s slope and the Mann–Kendall test according to a total of 72 Landsat images. Spatial distribution of mining development was quantified, due to four land-use maps in 2000, 2005, 2010, and 2017. The results showed that 80% of vegetation in the study area experienced different degrees of degradation, more serious in the overlapping areas of multiple mines and mining areas. The scope of influence for single mines on vegetation shrunk by about 48%, and the mean coefficients increased by 20%, closer to mining areas. The scope of influence for multiple mines on vegetation gradually expanded to 86% from the outer edge to the inner overlapping areas of mining areas, where the mean coefficients increased by 92%. The correlation between elevation and vegetation changes varied according to the average elevation of the total mining areas. Ultimately, the available ecological remediation should be systematically considered for local conditions and mining consequences.

The KRASG12C mutation is found in 11% of non-small cell lung cancers, 4% of colorectal cancers, and 2% of pancreatic cancers in the U.S., and drives these cancers by shifting the cellular equilibrium of KRAS towards the GTP-bound, active state, KRASG12C(ON). The resulting increased levels of KRASG12C(ON) in turn increase signaling output to initiate and support the oncogenic state. In recent years, a class of KRASG12C(OFF) inhibitors has transformed the treatment landscape for patients with cancers bearing KRASG12C. These inhibitors work via sequestration of the GDP-bound, inactive state, KRASG12C(OFF), starving cancer cells of their oncogenic driver, KRASG12C(ON). Recent reports on the nature of resistance to KRASG12C(OFF) inhibitors suggest this class of drugs can be overcome through reactivation of KRASG12C to the ON form. Direct inhibition of KRASG12C(ON) with a first in class, potent, orally bioavailable, selective, tri-complex inhibitor RMC-6291, represents a more robust approach and presents the possibility that RMC-6291 will be a ‘best-in-class’ inhibitor of tumors harboring KRASG12C. RMC-6291 is a potent covalent inhibitor of KRASG12C(ON) that forms a tri-complex within tumor cells between KRASG12C(ON) and cyclophilin A (CypA), a highly abundant immunophilin. The assembled tri-complex prevents KRASG12C(ON) from signaling via steric blockade of RAS effector binding. In cells, kinetic analyses demonstrate near-immediate disruption of RAS effector binding and extinction of KRASG12C(ON) signaling. Oral administration of RMC-6291 produces deep and durable suppression of RAS pathway activity in KRASG12C tumor models and drives profound tumor regressions in vivo at well-tolerated doses. In a mouse clinical trial consisting of multiple patient- and cell line-derived xenograft models of KRASG12C NSCLC, RMC-6291 outperformed adagrasib, a KRASG12C(OFF) inhibitor, by increasing the number of responses, the depth of tumor regressions, and the durability of responses. Combination treatment with RMC-6291 and SHP2 or SOS1 inhibitors was well tolerated in preclinical models and further increased anti-tumor activity, likely by preventing reactivation of wild-type RAS proteins that cooperate with KRASG12C to fuel cancer growth. RMC-6291 also combined well with immune checkpoint inhibitors, sensitizing KRASG12C-bearing cancer models to anti-tumor immunity. RMC-6291 is a next-generation, mutant-selective inhibitor of KRASG12C(ON) that overcomes limitations of first-generation KRASG12C(OFF) inhibitors in preclinical models by directly targeting the active form of this important oncogenic driver. Citation Format: Robert J. Nichols, Y.C. Yang, Jim Cregg, Chris J. Schulze, Zhican Wang, Richa Dua, Jingjing Jiang, Lindsay S. Garrenton, Nicole Nasholm, Alun Bermingham, John E. Knox, Kyle Seamon, Michael Longhi, Kang-Jye Chou, Shaoling Li, David P. Wildes, Mallika Singh, Elena S. Koltun, Adrian L. Gill, Jacqueline A.M. Smith. RMC-6291, a next-generation tri-complex KRASG12C(ON) inhibitor, outperforms KRASG12C(OFF) inhibitors in preclinical models of KRASG12C cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3595.

Aims: Isoliquiritigenin (ISL), a flavonoid from Glycyrrhiza glabra, has previously been reported to have anti-tumor effects in vivo and in vitro. However, the mechanisms whereby ISL exerts its anticancer effects remain poorly understood in hepatocellular carcinoma (HCC). Purpose: In the present study, we investigated the anticancer efficacy and associated mechanisms of ISL in HCC MHCC97-H and SMMC7721 cells. Results: We found that ISL inhibited cell viability and proliferation and induced apoptosis in a dose-and time-dependent manner in liver cancer lines. Furthermore, ISL could activate autophagy in HCC cells, and the autophagy inhibitor HCQ enhances ISL-induced apoptosis in HCC cells. Additionally, ISL induced apoptosis and autophagy through inhibition of the PI3K/Akt/mTOR pathway. Most importantly, in a xenograft tumor model in nude mice, data showed that the administration of ISL decreased tumor growth and concurrently promoted the expression of LC3-II and cleaved-caspase-3. Interestingly, we found that ISL inhibits mTOR by docking onto the ATP-binding pocket of mTOR (ie, it competes with ATP). We thus suggest that mTOR is a potential target for ISL inhibition of hepatocellular carcinoma development, which could be of interest for future investigations. Conclusion: Taken together, the results reveal that ISL effectively inhibited proliferation and induced apoptosis in HCC through autophagy induction in vivo and in vitro, probably via the PI3K/Akt/mTOR pathway. ISL may be a potential therapeutic agent for hepatocellular carcinoma.