First-Line Anlotinib Treatment for Soft Tissue Sarcoma in Chemotherapy-Ineligible Patients: An Open-label, Single-arm, Phase 2 Clinical Trial.

PURPOSE: Standard treatment for patients with unresectable locally advanced or metastatic soft-tissue sarcoma (LA/M STS) is chemotherapy based on anthracyclines, but patient tolerance of chemotherapy is limited. The present trial (NCT03792542) investigated the use of anlotinib as first-line treatment for patients with advanced STS, in particular liposarcoma (LPS). PATIENTS AND METHODS: Eligible patients were previously untreated, pathologically confirmed, unresectable LA/M STS cases. Anlotinib was given orally at a dose of 12 mg once daily from day 1 to day 14 every 3 weeks until disease progression or intolerable adverse events (AEs) occurred. The primary endpoint was progression-free survival (PFS) and the secondary endpoints overall survival (OS), the objective response rate and the disease control rate (DCR). The safety profile was also evaluated. RESULTS: Forty patients were enrolled from April 2019 to Jun 2022 and are included in the intention-to-treat analysis. The median PFS was 6.83 months [95% confidence interval (CI): 4.17-8.71] and the median OS 27.40 months (95% CI: 16.43-not evaluable); 1 patient reached partial response and 26 attained stable disease, with a DCR of 67.5% (27/40). Median PFS and OS times for LPS patients were 8.71 and 16.23 months, respectively. Ten (25.0%) patients had treatment-related AEs ≥ grade 3, with in particular a higher incidence of hypertension (15.0%) and proteinuria (7.5%). CONCLUSIONS: The findings suggest a potential benefit in employing front-line anlotinib to treat patients with STS, who are not eligible for cytotoxic chemotherapy. Of note, the clinical outcomes for the LPS subgroup of patients were encouraging.

miR-652 Inhibits the Proliferation, Migration, and Invasion of Osteosarcoma Cells by Targeting HOXA9 and Regulating the PI3K/Akt Signaling Pathway.

OBJECTIVE: The aim of this study was to investigate the abnormal expression of miR-652 in osteosarcoma and its related mechanism. MATERIALS AND METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the expression of miR-652 and HOXA9 in osteosarcoma tissues and normal tissues. A bioinformatics method was used to predict target genes of miR-652, and then luciferase reporter genes and western blot tests were used to verify expression of target genes. The miR-652 overexpression models were established by transfecting miR-652 mimics into osteosarcoma U-2OS cells, and HOXA9 overexpression models were simultaneously established by transfecting pcDNA3.1-HOXA9 into osteosarcoma U-2OS cells. Cell proliferation ability was detected by the CCK-8 assay, cell migration ability was detected by the scratch test, and cell invasion ability was detected by the Transwell invasion assay. Western blot tests were used to verify the expression of HOXA9, p-PI3K, p-AKT, MMP2 and MMP9. RESULTS: miR-652 and HOXA9 showed low expression and overexpression, respectively, in osteosarcoma tissues. Proliferation, invasion, and migration abilities of osteosarcoma cells and the level of protein expression of p-PI3K, p-Akt, MMP2, and MMP9 were significantly decreased with enhanced miR-652 expression (P < 0.01), while overexpression of HOXA9 reversed this situation. The results of dual-luciferase reporter gene showed that expression and activity of HOXA9 were downregulated accordingly, and the level of HOXA9 protein was decreased with enhancing miR-652 expression (P < 0.01). CONCLUSION: miR-652 may negatively regulate HOXA9 expression and inhibit the proliferation, migration, and invasion abilities of osteosarcoma cells through the PI3K/Akt signaling pathway.

MicroRNA-106b serves as a prognostic biomarker and is associated with cell proliferation, migration, and invasion in osteosarcoma.

MicroRNAs (miRNAs) have been demonstrated to be involved in tumor progression of various human malignancies. The purpose of this study was to investigate the expression patterns and prognostic value of microRNA-106b (miR-106b) in osteosarcoma (OS) and to examine its functional role in OS progression. Reverse transcription-quantitative PCR (RT-qPCR) was used to estimate the expression of miR-106b in OS tissues and cells. The prognostic value of miR-106b in OS was evaluated by plotting Kaplan-Meier survival curves and performing Cox analyses. Cell experiments were carried out to examine the effects of miR-106b on OS cell proliferation, migration, and invasion. The expression of miR-106b was elevated in both OS tissues and cells compared with the expression in normal control tissues and cells (P<0.001). miR-106b expression was associated with metastasis (P=0.028) and Tumor-Node-Metastasis stage (P=0.017). Patients with high miR-106b expression levels had a poorer overall survival rate compared with those with low miR-106b expression levels (log-rank P=0.001). Multivariate Cox analyses indicated that miR-106b expression was an independent prognostic factor for patients with OS (hazard ratio=2.769; 95% confidence interval=1.369-5.599; P=0.005). The results of cell experiments implied that the upregulation of miR-106b could promote OS cell proliferation, migration and invasion, whereas the downregulation of miR-106b could suppress these functions (P<0.05). Taken together, this study's results indicated that the overexpression of miR-106b is associated with a poor prognosis for patients with OS and that overexpression promotes OS cell proliferation, migration, and invasion. This study may provide a novel prognostic biomarker and a candidate therapeutic target for OS treatment.

Effect of maternal food restriction during gestation on early development of F1 and F2 offspring in the rat-like hamster (Cricetulus triton).

Maternal food restriction (FR) may have strong and long-term effects on body weight, brain and behavior development of offspring. However, it is still not well understood whether such an effect is carried over to the next generation. Our objective was to examine the differences of maternal behavior, body growth, cranial growth and early development of F1 and F2 offspring of rat-like hamsters between a FR group and a control group. Results show that FR has a significant influence on maternal gathering behavior. The body weight of F1 offspring was significantly lower in the food-restricted group compared with that of the control animals, while the body weight of food-restricted F2 offspring was not significantly different from that of the control group. The physical development and neurodevelopment of food-restricted F1 and F2 offspring were significantly delayed compared to the controls. These results suggest that FR in female rat-like hamsters affected negatively the body growth of F1 offspring, and the physical and neurodevelopment of both F1 and F2 offspring. The effect of maternal FR on F2 offspring was smaller than that on F1 offspring. These factors may, in turn, play an important role in the population regulation of this species.

[Regulation of differentiation and proliferation of epiphysis stem cells by Notch1 signaling system].

OBJECTIVE: To investigate the regulation of differentiation and proliferation of epiphysis stem cells by Notch1 signaling system. METHODS: Costocostal cartilage was taken from a SD rat. Epiphysis stem cells were isolated and cultured. Recombinant human nuclear factor-kappaB (rhNF-kappaB), an activator of the Notch signaling system, and gamma-secretase inhibitor (MW167), an inhibitor of the Notch signaling system, were added into the culture medium respectively. The cells cultured in the medium added with phosphate-buffered saline were used as control group. Then the cultured cells were collected. The expression of the homologous Notch receptors and homologous Notch ligands was detected by RT-PCR. Immunohistochemistry was used to detect the levels of collagen II, collagen X, and proliferating cell nuclear antigen (PCNA). MTT method was used to calculate the growth curve. The cell phase was examined by flow cytometry. The level of alkaline phosphatase (AP) was measured. Western blotting was used to detect the protein expression of collagen II, collagen X, and stathmin, a signaling protein of proliferation. RESULTS: Only 2 the expression of the receptor Notch1 and the ligand Jagged1 was found. The expression of PCNA was stronger in the rhNF-kappaB group than in the other 2 groups. rhNF-kappaB remarkably promoted the expression of collagen II and inhibited the expression of collagen X and MW167 remarkably promoted the expression of collagen X and did not remarkably influence the expression of collagen II. MTT method showed that rhNF-kappaB significantly promote the proliferation of the cells (P = 0.027), and MW167 did not significantly promote the cell proliferation (P > 0.05). The percentage of cells at S phase of the rhNF-kappaB group was 26.54%, significantly higher than those of the MW167 group and control group (8.22% and 6.15%). AP was significantly expressed in the MW167 group, and less expressed in the other groups. Western blotting showed a significantly increased expression of collagen X protein and decreased expression of collagen II protein and stathmin. CONCLUSION: When the Notch signaling system is activated the epiphysis stem cells proliferate, and when the Notch signaling system is suppressed the epiphysis stem cells differentiate.