Previous study revealed that the protective effect of TIGAR in cell survival is mediated through the increase in PPP (pentose phosphate pathway) flux. However, it remains unexplored if TIGAR plays an important role in DNA damage and repair. This study investigated the role of TIGAR in DNA damage response (DDR) induced by genotoxic drugs and hypoxia in tumor cells. Results showed that TIGAR was increased and relocated to the nucleus after epirubicin or hypoxia treatment in cancer cells. Knockdown of TIGAR exacerbated DNA damage and the effects were partly reversed by the supplementation of PPP products NADPH, ribose, or the ROS scavenger NAC. Further studies with pharmacological and genetic approaches revealed that TIGAR regulated the phosphorylation of ATM, a key protein in DDR, through Cdk5. The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR defines a new role of TIGAR in cancer cell survival and it suggests that TIGAR may be a therapeutic target for cancers.

SHP2 mediates the activities of multiple receptor tyrosine kinase signaling and its function in endothelial processes has been explored extensively. However, genetic studies on the role of SHP2 in tumor angiogenesis have not been conducted. Here, we show that SHP2 is activated in tumor endothelia. Shp2 deletion and pharmacological inhibition reduce tumor growth and microvascular density in multiple mouse tumor models. Shp2 deletion also leads to tumor vascular normalization, indicated by increased pericyte coverage and vessel perfusion. SHP2 inefficiency impairs endothelial cell proliferation, migration, and tubulogenesis through downregulating the expression of proangiogenic SRY-Box transcription factor 7 (SOX7), whose re-expression restores endothelial function in SHP2-knockdown cells and tumor growth, angiogenesis, and vascular abnormalization in Shp2-deleted mice. SHP2 stabilizes apoptosis signal-regulating kinase 1 (ASK1), which regulates SOX7 expression mediated by c-Jun. Our studies suggest SHP2 in tumor associated endothelial cells is a promising anti-angiogenic target for cancer therapy.

Development of chemoresistance remains a major hurdle for triple negative breast cancer treatment. Previous studies suggest that CD44+/CD24- cells, subpopulation of cancer stem cells with self-renewing and tumor-initiating capacities, are partly responsible for chemoresistance and therapeutic failure of triple negative breast cancer. Therefore, novel agents that target cancer stem cells (CSCs) may improve the clinical outcome. KIF11 (kinesin family member 11), overexpressed in many cancer cells, is a molecular motor protein that plays essential role in mitosis. In this study, we assess its role in docetaxel resistant triple negative breast cancer (TNBC). We found that the expression of KIF11 was significantly increased in CD44+/CD24- subpopulation of docetaxel resistant TNBC cells. Knockdown of KIF11 resulted in a significant decrease in the percentage of CSCs and mammosphere formation. KIF11 knockdown also inhibits cell growth and induces cell cycle G2/M arrest followed by cell mitosis and apoptosis. Further docetaxel resistant TNBC xenograft models demonstrated that KIF11 inhibitor exerts growth inhibitory effect in vivo . Of note, we also found that KIF11 was highly expressed in TNBC and its expression was correlated with shorter disease free survival time. All these data indicate that KIF11 is critical for proliferation and self-renewal in TNBC tumor cells in vitro and in vivo , suggesting that KIF11 may be a promising therapeutic target for treating chemoresistant TNBC.

Inflammation has been believed to contribute to coronavirus disease 2019 (COVID-19). Risk factors for death of COVID-19 pneumonia have not yet been well established. In this retrospective cohort study, we included the deceased patients in COVID-19 specialized ICU with laboratory-confirmed COVID-19 from Guanggu hospital area of Tongji Hospital from February 8th to March 30th. Demographic, clinical, laboratory, and outcome data were extracted from electronic medical records using a standard data collection form. We used Spearman rank correlation and Cox regression analysis to explore the risk factors associated with in-hospital death, especially the association between inflammatory cytokines and death. A total of 205 severe/critical COVID-19 pneumonia patients were admitted in the COVID-19 specialized ICU and 75 deceased patients were included in the final analysis. The median age of the deceasing patients was 70 years (IQR 65–79). The common symptoms were fever (78.9%), cough (70.4%), and expectoration (39.4%). The BNP and CRP levels were far beyond the normal reference range. In the Spearman rank correlation analysis, IL-8 was found to be significantly associated with the time from onset to death (rs= −0.30, P = .034) and that from admission to death (rs= −0.32, P = .019). Cox regression showed after adjusting age and sex, IL-8 levels were still significantly associated with the time from onset to death (P = .003) and that from admission to death (P  = .01). IL-8 levels were associated with in-hospital death in severe/critical COVID-19 patients, which could help clinicians to identify patients with high risk of death at an early stage.