Na Liu’s research while affiliated with Xi'an Jiaotong University and other places

The amplification of MET is a major cause of acquired resistance to targeted therapy in EGFR‐mutant non‐small‐cell lung cancer (NSCLC), only to be temporarily restrained by the partial efficacy of MET inhibitors. This study reveals that the MET inhibitor has unexpectedly limited efficacy due to amplified MET triggering a strong positive feedback loop in the Wnt/β‐catenin signaling pathway, allowing optimal functionality even when the MET pathway is suppressed again. To test this conjecture and specifically target the Wnt/β‐catenin pathway, a cleverly designed Wnt condensative pro drug called WntSI is developed using reversible supramolecular self‐assembly driven by liquidliquid phase separation (LLPS). This process involves a MET/pH‐responsive peptide (Tyr‐Pep) and a potent Wnt inhibitor known as CA. Upon recognition and phosphorylation of Tyr‐Pep by over expressed MET in cells, it disrupts LLPS propensity and facilitates the disintegration of WntSI. Consequently,this enables it to suppress the carcinogenic effect mediated by β‐catenin,effectively overcoming acquired resistance to EGFR‐TKIs caused by MET amplification in both cell line‐derived and patient‐derived tumor xenograft (PDX) mouse models while maintaining exceptional biosecurity. This effective strategy not only suppresses the Wnt/β‐catenin signaling pathway selectively, but also serves as an innovative example for pro‐drug development through biologically responsive LLPS.

Objectives To evaluate the effects of platinum-based neoadjuvant chemotherapy (NACT) on the STING/IFN pathway and tumor-infiltrating lymphocytes (TILs) in non-small cell lung cancer (NSCLC), as well as clinicopathological factors affecting patient survival. Materials and methods A total of 68 patients aged 34-77 years with NSCLC who received neoadjuvant chemotherapy and surgical treatment from March 2012 to February 2019 were reviewed, and the clinical pathological data and paired tissue specimens before and after NACT were collected. Immunohistochemistry and immunofluorescence were used to detect the protein levels of STING, PD-L1 and IFN-β, and the infiltration density of CD3⁺ TILs and CD8⁺TILs. The correlation between the expression of STING, PD-L1, IFN-β and the infiltration density of CD3⁺ TILs and CD8⁺ TILs as well as the clinicopathological characteristics before and after NACT was analyzed. The relationship between the related indexes, clinicopathological features and prognosis was also discussed. Results NACT increased the expression of STING, IFN-β and PD-L1 in tumor cells, and the infiltration of CD3⁺ and CD8⁺ TILs. In addition, ypTNM stage, ypN stage, changes in CD3⁺ TILs and in PD-L1 were associated with DFS (disease-free survival). CD3⁺ TILs changes and ypN stage were associated with OS (overall survival). Notably, ypN stage and CD3⁺ TILs changes were independent prognostic factors for DFS and OS. Conclusion NACT stimulates STING/IFN-β pathway, promotes infiltration of CD3⁺ and CD8⁺ TILs, triggers innate and adaptive immunity, and also upregulates PD-L1, which complemented the rationale for neoadjuvant chemotherapy in combination with immunotherapy. In addition, DFS was longer in patients with ypTNM I, ypN0-1, and elevated CD3⁺TILs after NACT. Patients with ypN0 and elevated CD3⁺ TILs after NACT had better OS benefits.

Background Elderly cancer patients are more predisposed to developing nosocomial infections during anti-neoplastic treatment, and are associated with a bleaker prognosis. This study aimed to develop a novel risk classifier to predict the in-hospital death risk of nosocomial infections in this population. Methods Retrospective clinical data were collected from a National Cancer Regional Center in Northwest China. The Least Absolute Shrinkage and Selection Operator (LASSO) algorithm was utilized to filter the optimal variables for model development and avoid model overfitting. Logistic regression analysis was performed to identify the independent predictors of the in-hospital death risk. A nomogram was then developed to predict the in-hospital death risk of each participant. The performance of the nomogram was evaluated using receiver operating characteristics (ROC) curve, calibration curve, and decision curve analysis (DCA). Results A total of 569 elderly cancer patients were included in this study, and the estimated in-hospital mortality rate was 13.9%. The results of multivariate logistic regression analysis showed that ECOG-PS (odds ratio [OR]: 4.41, 95% confidence interval [CI]: 1.95-9.99), surgery type (OR: 0.18, 95%CI: 0.04-0.85), septic shock (OR: 5.92, 95%CI: 2.43-14.44), length of antibiotics treatment (OR: 0.21, 95%CI: 0.09-0.50), and prognostic nutritional index (PNI) (OR: 0.14, 95%CI: 0.06-0.33) were independent predictors of the in-hospital death risk of nosocomial infections in elderly cancer patients. A nomogram was then constructed to achieve personalized in-hospital death risk prediction. ROC curves yield excellent discrimination ability in the training (area under the curve [AUC]=0.882) and validation (AUC=0.825) cohorts. Additionally, the nomogram showed good calibration ability and net clinical benefit in both cohorts. Conclusion Nosocomial infections are a common and potentially fatal complication in elderly cancer patients. Clinical characteristics and infection types can vary among different age groups. The risk classifier developed in this study could accurately predict the in-hospital death risk for these patients, providing an important tool for personalized risk assessment and clinical decision-making.

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

Acetyl-CoA synthetase 2 (ACSS2), an important member of the acetyl-CoA synthetase (ACSS) family, can catalyze the conversion of acetate to acetyl coenzyme A (acetyl-CoA). Currently, acetyl-CoA is considered an important intermediate metabolite in the metabolism of energy substrates. In addition, nutrients converge through acetyl-CoA into a common metabolic pathway, the tricarboxylic acid cycle and oxidative phosphorylation. Not only does ACSS2 play a crucial role in material energy metabolism, it is also involved in the regulation of various acetylation processes, such as regulation of histone and transcription factor acetylation. ACSS2-mediated regulation of acetylation is related to substance metabolism and tumorigenesis. In mammalian cells, ACSS2 utilizes intracellular acetate to synthesize acetyl-CoA, a step in the process of DNA and histone acetylation. In addition, studies in tumors have shown that cancer cells adapt to the growth conditions in the tumor microenvironment (TME) by activating or increasing the expression level of ACSS2 under metabolic stress. Therefore, this review mainly outlines the role of ACSS2 in substance metabolism and tumors and provides insights useful for investigating ACSS2 as a therapeutic target.

Background Patients with extensive-stage small-cell lung cancer (ES-SCLC) have high recurrence rates and bleak prognosis. This multicenter real-world study aimed to explore the efficacy and safety of anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment of ES-SCLC. Methods Pathologically confirmed ES-SCLC patients receiving anlotinib plus platinum-etoposide chemotherapy as the first-line treatment were enrolled in this retrospective study. The primary endpoint of this study was progression-free survival (PFS), and secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and adverse reactions. The Cox regression analyses were employed to investigate the independent prognostic factors for OS and PFS of these individuals. Results In total, 58 patients were included in this study. The median PFS was 6.0 months [95% confidence interval (CI): 3.5-8.5], and the median OS was 10.5 months (95%CI 8.7-12.3). Thirty-four patients achieved partial response (PR), 18 patients achieved stable disease (SD), and 6 patients achieved progressive disease (PD). The ORR and DCR were 58.6% and 89.6%. The main treatment-related adverse reactions were generally tolerated. Myelosuppression (44.8%) was the most common adverse reaction, followed by hypertension (41.4%), fatigue (34.5%), gastrointestinal reaction (32.7%), and hand-foot syndrome (24.1%). Multivariate analysis showed that post-medication hand-foot syndrome [PFS 8.5 vs. 5.5 months, Hazards Ratio (HR)=0.23, 95%CI 0.07-0.72, P =0.012] was the independent predictor of PFS, and hypertension (OS 15.9 vs. 8.3 months, HR=0.18, 95%CI 0.05-0.58, P =0.005) was the independent predictor of OS. Conclusion Anlotinib combined with platinum-etoposide chemotherapy as the first-line treatment for ES-SCLC appears to be effective and well-tolerated in the real-world. Well-designed large-scale prospective studies are urgently needed in the future to verify our findings.

Background V-domain Ig-containing suppressor of T cell activation (VISTA), a critical immune checkpoint protein, can regulate the immune system. Nevertheless, little information is available on the expression level of VISTA and its clinical significance as well. The immunological and prognostic role of VISTA in triple-negative breast cancer (TNBC) still remains unclear. Methods The clinical significance and expression of VISTA in TNBC were examined using RNA sequencing and clinical data. Cancer single-cell state atlas (CancerSEA), gene set enrichment analyses (GSEA), single sample GSEA, ESTIMATE algorithm, immunohistochemistry (IHC) were utilized to assess the functions of VISTA. Results VISTA was down-regulated and closely associated with good prognosis in TNBC. The expression of VISTA was higher in Immunity-H group and immunomodulatory (IM) subtype. The level of VISTA expression in TNBC gradually increased with the degree of stromal tumor infiltrating lymphocytes (sTILs) infiltration. In addition, the high expression of VISTA was strongly linked to higher proportion of CD8 (+) T cell and M1 macrophages. Conclusion VISTA was remarkably correlated with a favorable prognosis and high immune infiltration in patients with TNBC.