Efficacy and safety of anlotinib plus XELOX regimen as first-line therapy for mCRC: a single-arm, multicenter, phase II study (ALTER-C-001).

Background: Anlotinib showed encouraging anti-tumor activity in metastatic colorectal cancer (mCRC). This study was designed to assess the efficacy and safety of anlotinib plus XELOX as first-line therapy in mCRC patients. Materials and Methods: Eligible patients aged ≥18 with mCRC were enrolled in this multicenter, single-arm, phase II, exploratory study. Patients received at least 6 cycles of anlotinib, oxaliplatin, and capecitabine as initial therapy. Subsequently, patients received anlotinib monotherapy as maintenance therapy until tumor progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Results: Thirty-one patients were included between December 2019 and March 2022. The median follow-up was 17.5 (95% CI, 3.0-17.5) months. The median PFS was 8.3 (95% CI, 6.3-10.0) months, with 6- and 12-month PFS rates of 82.3% (95% CI, 59.2%-93.0%) and 18.9% (95% CI, 4.8%-40.1%), respectively. Fifteen (48.4%) achieved partial response for an ORR of 48.4% (95% CI, 30.2%-66.9%). The disease control rate was 71.0% (95% CI, 52.0%-85.8%) due to 7 (22.6%) stable diseases. The median duration of response was 6.0 (95% CI, 3.6-8.0) months and 1 patient had the longest ongoing response of 17.3 months. Of 24 patients with evaluable imaging, 23 (74.2%) obtained tumor shrinkage. The median PFS (11.0 vs. 6.9 months) and ORR (66.7% vs. 60.0%) for patients with RAS/BRAF wild-type were numerically better than those with mutation. Three patients are still ongoing treatment. The grade 3 or more treatment-emergent adverse events (TEAEs) were mainly hypertension (12.9%) and decreased neutrophil count (12.9%). Four (12.9%) had serious TEAEs, primarily including abdominal pain and incomplete intestinal obstruction. Conclusion: Anlotinib plus XELOX as first-line therapy in patients with mCRC showed anti-tumor activity and safety profile, which is worth further investigation. Clinical Trial Registration: chictr.org.cn, identifier ChiCTR1900028417.

KDM2A plays a dual role in regulating the expression of malignancy-related genes in esophageal squamous cell carcinoma.

KDM2A is a histone demethylase, which primarily catalyzes the demethylation of H3K36me2. Abnormal expression of KDM2A is observed in many types of cancers; however, the molecular events connected to KDM2A expression remain unclear. We report that KDM2A performs an oncogenic function in esophageal squamous cell carcinoma (ESCC) and is robustly expressed in ESCC cells. ShRNA-mediated knockdown of KDM2A resulted in a significant inhibition of the malignant phenotype of ESCC cell lines, whereas ectopic expression of KDM2A showed the opposite effect. We also analyzed the function of KDM2A using a CRISPR-CAS9 depletion system and subsequent rescue experiment, which also indicated a cancerous role of KDM2A. Interestingly, analysis of the gene expression network controlled by KDM2A using RNA-seq revealed an unexpected feature: KDM2A could induce expression of a set of well-documented oncogenic genes, including IL6 and LAT2, while simultaneously suppressing another set of oncogenes, including MAT2A and HMGCS1. Targeted inhibition of the upregulated oncogene in the KDM2A-depleted cells led to a synergistic suppressive effect on the malignant phenotype of ESCC cells. Our results revealed the dual role of KDM2A in ESCC cells, which may have therapeutic implications.

Acceleration of dermal wound healing by using electrospun curcumin-loaded poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) fibrous mats.

This study prepared a composite scaffold composed of curcumin and poly(ε-caprolactone)-poly(ethylene glycol)-poly(ε-caprolactone) (PCL-PEG-PCL, PCEC) copolymer using coelectrospinning technology. Incorporation of curcumin into the polymeric matrix had an obvious effect on the morphology and dimension of PCEC/curcumin fibers. The results of in vitro anti-oxidant tests and of the cytotoxicity assay demonstrated that the curcumin-loaded PCEC fibrous mats had significant anti-oxidant efficacy and low cytotoxicity. Curcumin could be sustainably released from the fibrous scaffolds. More importantly, in vivo efficacy in enhancing wound repair was also investigated based on a full-thickness dermal defect model for Wistar rats. The results indicated that the PCEC/curcumin fibrous mats had a significant advantage in promoting wound healing. At 21 days post-operation, the dermal defect was basically recovered to its normal condition. A percentage of wound closure reached up to 93.3 ± 5.6% compared with 76.9 ± 4.9% of the untreated control (p < 0.05). Therefore, the as-prepared PCEC/curcumin composite mats are a promising candidate for use as wound dressing.

Effect of Fraxiparine, a type of low molecular weight heparin, on the invasion and metastasis of lung adenocarcinoma A549 cells.

Lung cancer is one of the most highly malignant tumors, and a significant threat to human health. Lung cancer patients often exhibit tumor cell invasion and metastasis, which often render current treatments ineffective. Recently, the beneficial effects of low molecular weight heparin (LMWH) on cancer metastasis were reported in pre-clinical research studies. LMWH may be a potential drug for cancer therapy. However, the mechanism of LMWH on the invasion and metastasis of cancer has yet to be determined. This study investigated the effects of Fraxiparine on the proliferation, invasion and metastasis of the human lung adenocarcinoma A549 cell line. MTT assay and flow cytometry showed that Fraxiparine slightly inhibited the cell viability dose- and time-dependently, but did not arrest the A549 cells in the G1 phase nor induce early apoptosis. The transwell chamber assay showed that Fraxiparine significantly suppressed the invasion and migration of the A549 cells in vitro. Fraxiparine also markedly inhibited the adhesion of the A549 cells to Matrigel. The RT-PCR assay demonstrated that the reduction in invasion and metastasis may be related to the up-regulation of nm23-H1 and the down-regulation of the heparanase expression. Moreover, the RT-PCR assay and Western blot analysis demonstrated that down-regulation of the expression of integrin ß1 and ß3, as well as that of matrix metalloproteinase-2 and -9 may be responsible for the inhibition of the invasion and metastasis of A549 cells by Fraxiparine.

[Study on invasion and metastasis-associated genes of lung cancer related with NM23-H1 gene].

OBJECTIVE: To study on invasion and metastasis-associated genes of lung cancer related with NM23-H1 gene. METHODS: Human gene expression chip based on the subtracted cDNA libraries was constructed. After microarray hybridization, clones sequencing, sequence homology search, the information of differently expressed genes in human large cell lung cancer cell line of L9981 and L9981-nm23-H1 were obtained and then further confirmed by real-time quantitative PCR. RESULTS: Gene expression profiling chips of differently expressed genes in human large cell lung cancer cell line L9981 and L9981-nm23-H1 were successfully constructed. After microarray hybridization, sequence homology search, 19 differentially expressed genes were observed. After real-time quantitative PCR evaluation, we found that the mRNA of 8 genes including PSMA7, SBDS, ODC1, YARS, CSDA, PTP4A1, SHPRH and TOMM7 was up-regulated in the cell line of L9981 after transfected with NM23-H1 gene, whereas the mRNA of PKM2 and GMNN was down-regulated. CONCLUSION: NM23-H1 gene may be the upstream regulator of metastasis-associated genes, which can regulate the downstream genes to achieve a series of lung cancer metastatic potential.