Breast cancer is one of the most common malignant tumors among women worldwide. About 70-75% of primary breast cancers belong to estrogen receptor (ER)-positive breast cancer. In the development of ER-positive breast cancer, abnormal activation of the ERα pathway plays an important role and is also a key point leading to the failure of clinical endocrine therapy. In this study, we found that the small molecule peptide chlorotoxin (CTX) can significantly inhibit the proliferation, migration and invasion of breast cancer cells. In in vitro study, CTX inhibits the expression of ERα in breast cancer cells. Further studies showed that CTX can directly bind to ERα and change the protein secondary structure of its LBD domain, thereby inhibiting the ERα signaling pathway. In addition, we also found that vasodilator stimulated phosphoprotein (VASP) is a target gene of ERα signaling pathway, and CTX can inhibit breast cancer cell proliferation, migration, and invasion through ERα/VASP signaling pathway. In in vivo study, CTX significantly inhibits growth of ER overexpressing breast tumor and, more importantly, based on the mechanism of CTX interacting with ERα, we found that CTX can target ER overexpressing breast tumors in vivo. Our study reveals a new mechanism of CTX anti-ER-positive breast cancer, which also provides an important reference for the study of CTX anti-ER-related tumors.

This study aimed to determine the prognostic value of preoperative plasma fibrinogen concentration (PFC) in patients with stage I-II gastric cancer after curative gastrectomy. The preoperative PFC and clinicopathological data of 793 patients with stage I-II gastric cancer who underwent curative gastrectomy were analyzed retrospectively. PFC of <4.0 g/L and ≥4.0 g/L were considered as PFC0 and PFC1, respectively. The association between PFC and the clinicopathological features of gastric cancer and the value of PFC in survival prediction were investigated. PFC1 indicated poorer overall survival and cancer-specific survival among patients with tumor-node-metastasis (TNM) stage I-II, and PFC was identified as an independent indicator of survival via multivariate analysis. Importantly, PFC stage was proven to be an independent prognostic factor for stage I and T1-4aN0 gastric cancer. PFC stage combined with the American Joint Committee on Cancer (AJCC)-TNM stage has better accuracy for predicting disease prognosis than AJCC-TNM stage alone. The prognosis of patients with stage I-II gastric cancer can be further stratified by PFC level. For patients with stage I gastric cancer, PFC1 can be considered a high-risk prognostic factor, and adjuvant chemotherapy should be recommended for patients with PFC1.

Nuclear receptor coactivator 1 (NCOA1) plays crucial roles in the regulation of gene expression mediated by a wide spectrum of steroid receptors such as androgen receptor (AR), estrogen receptor α (ER α), and estrogen receptor β (ER β). Therefore, dysregulations of NCOA1 have been found in a variety of cancer types. However, the clinical relevance and the functional roles of NCOA1 in human esophageal squamous cell carcinoma (ESCC) are less known. We found in this study that elevated levels of NCOA1 protein and/or mRNA as well as amplification of the NCOA1 gene occur in human ESCC. Elevated levels of NCOA1 due to these dysregulations were not only associated with more aggressive clinic-pathologic parameters but also poorer survival. Results from multiple cohorts of ESCC patients strongly suggest that the levels of NCOA1 could serve as an independent predictor of overall survival. In addition, silencing NCOA1 in ESCC cells remarkably decreased proliferation, migration, and invasion. These findings not only indicate that NCOA1 plays important roles in human ESCC but the levels of NCOA1 also could serve as a potential prognostic biomarker of ESCC and targeting NCOA1 could be an efficacious strategy in ESCC treatment.

Breast cancer was the highest incidence of tumor in women, which seriously threaten women's health. Our previous study found that the expression of IQUB (IQ motif and ubiquitin domain containing) was significantly increased in the development of breast cancer by transcriptome sequencing. However, there were no studies on the mechanism of IQUB in tumorigenesis. Further study showed that IQUB expression was significantly increased in breast cancer, which had a significantly positive correlation with pathological differentiation of breast cancer by tissue microarray analysis. Furthermore, we also discovered that IQUB overexpression could obviously promote the proliferation and migration of MCF-7 cells and increase the proportion of MCF-7 cells in S and G2/M phase in vitro study, while knockdown of IQUB caused inhibition of cell proliferation and migration in MDA-MB-231 cells and increased the proportion of MDA-MB-231 cells in G1 phase. Furthermore, IQUB overexpression or knockdown combined with treatment of Licl or MG-132 showed that IQUB activated Akt to promote GSK3β phosphorylation, which in turn activated Wnt/β-catenin signaling pathway in breast cancer cells. Taken together, these results indicated that upregulated IQUB promoted breast cancer cell proliferation and migration via activating Akt/GSK3β/β-catenin signaling pathway, which played an important part in the tumorigenesis and development of breast cancer.

The objective of the study was to identify trends in incidence of adult diffuse gliomas in the United States and evaluate the contribution of age, period, and cohort effects to the trends.

Despite the benefit with cancer immunotherapies in clinical implication, immunotherapeutic resistance occurred in many patients and the mechanism remains unknown. Increasing evidence has revealed that cell-intrinsic programmed cell death ligand 1 (PD-L1) may play a non-negotiable part in immunotherapeutic resistance. Our present study aimed to elucidate the immune-independent acquired resistance mechanism to PD-L1 antibody. We found elevated PD-L1 expression induced by PD-L1 antibodies in cancer cell and vascular endothelial cells (VECs) with substantially acquired resistance to PD-L1 antibodies. Moreover, proliferation of resistant cells was accelerated and the apoptosis was reduced in the absence of immune compared with parental cells. Subsequently, we confirmed that the activation of the PI3K/AKT pathway is involved in the upregulation of PD-L1 expression. Finally, we found that low dose of anlotinib downregulated PD-L1 expression only in VECs via inhibiting the PI3K/AKT pathway; however, the same effect was not observed in cancer cells. To sum up, our findings revealed that upregulation of PD-L1 via activation of the PI3K/AKT signal pathway may promote acquired resistance to PD-L1 antibodies in an immune-independent manner. SIGNIFICANCE: These findings provide new mechanisms of immunotherapeutic resistance and effective evidence of anlotinib combined with immunotherapy.

Liver metastasis is common in advanced small cell lung cancer (SCLC). There is no evidence-proven treatment beyond the second line in patients with SCLC and liver metastasis. This study aimed to investigate survival in patients with SCLC and liver metastasis treated with anlotinib compared with placebo. This study was a post hoc analysis of the phase II ALTER 1202 trial, including patients who had liver metastasis at baseline. The participants were randomized 2:1 to receive either 12 mg/day anlotinib (anlotinib group) or placebo (placebo group). Tumor response, progression-free survival (PFS), and overall survival (OS) were compared. In the original trial, there were 39 participants with liver metastasis at baseline, including 27 and 12 in the anlotinib and placebo groups, respectively. The objective response rate was 3.7% and 0% in the anlotinib and placebo groups, respectively (p = 0.9999). An elevated disease control rate was found in the anlotinib group (44.4%) compared with the placebo group (8.3%, p = 0.0173). The median PFS was 1.51 vs. 0.71 months in favor of anlotinib (hazard ratio [HR] = 0.365, 95% confidence interval [CI]: 0.17-0.78; p = 0.0064), with no marked difference in median OS (3.29 vs. 1.91 months; HR = 0.51, 95% CI: 0.22-1.16; p = 0.0996). The most common AEs in the anlotinib group were hypertension (40.7%), fatigue (29.6%), loss of appetite (22.2%), and weight loss (22.2%). There were no grade 5 AE. In conclusion, anlotinib increased PFS compared with placebo in patients with SCLC and liver metastasis.

Our previous studies revealed that the level of activated circulating endothelial cells (aCECs) was correlated with the progression-free survival (PFS) in antiangiogenesis therapy. Anlotinib displayed affirmatory efficacies in several clinical trials of non-small-cell lung cancer (NSCLC). To find a marker predicting the efficacy of anlotinib treatment, we investigated the correlations of aCECs with PFS and overall survival (OS) in patients with NSCLC treated with anlotinib and the impact of anlotinib on human umbilical vascular endothelial cells (HUVECs). The blood samples of 78 patients with NSCLC were collected. aCECs were identified by flow cytometry as CD45- /CD146+ /CD31+ cells and CD45- /CD146+ /CD105+ cells. The mean value of baseline aCECs counts was defined as the cutoff value, according to which patients were divided into high and low baseline groups. Statistical correlation between high baseline CD31-labeled aCECs counts and number of metastatic lesions (>3) (χ2  = 4.905, P = .027) was analyzed. The 49 patients treated with anlotinib were stratified according to the ratio of minimal aCECs counts at any time points to baseline (aCECs min/baseline) as <1 or ≥1. Interestingly, the patients with aCECs (CD31) min/baseline <1 displayed longer PFS [HR = 0.439, 95%CI (0.211-0.912), P = .023]. The biological effect of anlotinib on HUVECs was investigated using MTT assays. Western blot analysis was conducted to evaluate the expression levels of CD31 and CD105 under anlotinib treatment and the underlying mechanisms. In vitro experiment data demonstrated that CD31 exhibited more sensitive changes than CD105 under anlotinib treatment through PI3K-AKT pathway. Thus, our finding provides new insights into the mechanism by which the CD31-labeled aCECs are a more sensitive marker for predicting the efficiency of anlotinib treatment.