Ultrastrong nanotwinned titanium alloys through additive manufacturing.

Titanium alloys, widely used in the aerospace, automotive and energy sectors, require complex casting and thermomechanical processing to achieve the high strengths required for load-bearing applications. Here we reveal that additive manufacturing can exploit thermal cycling and rapid solidification to create ultrastrong and thermally stable titanium alloys, which may be directly implemented in service. As demonstrated in a commercial titanium alloy, after simple post-heat treatment, adequate elongation and tensile strengths over 1,600 MPa are achieved. The excellent properties are attributed to the unusual formation of dense, stable and internally twinned nanoprecipitates, which are rarely observed in traditionally processed titanium alloys. These nanotwinned precipitates are shown to originate from a high density of dislocations with a dominant screw character and formed from the additive manufacturing process. The work here paves the way to fabricate structural materials with unique microstructures and excellent properties for broad applications.

Clinicopathological value of the upregulation of cyclin-dependent kinases regulatory subunit 2 in osteosarcoma.

BACKGROUND: Cyclin-dependent kinase subunit 2 (CKS2) is a member of cyclin dependent kinase subfamily and the relationship between CKS2 and osteosarcoma (OS) remains to be further analyzed. METHODS: 80 OS and 41 non-tumor tissue samples were arranged to perform immunohistochemistry (IHC) to evaluate CKS2 expression between OS and non-tumor samples. The standard mean deviation (SMD) was calculated based on in-house IHC and tissue microarrays, and exterior high-throughput datasets for further verification of CKS2 expression trend in OS. The effect of CKS2 expression on clinicopathological parameters of OS patients, and single-cell in OS tissues was analyzed through public high-throughput datasets and functional enrichment analysis was conducted for co-expression genes of CKS2 in accordance with weighted correlation network analysis. RESULTS: A total of 217 OS samples and 87 non-tumor samples (including tissue and cell line) were obtained from in-house IHC, microarrays and exterior high-throughput datasets. The analysis of integrated expression status demonstrated up-regulation of CKS2 in OS (SMD = 1.57, 95%CI [0.27-2.86]) and the significant power of CKS2 expression in distinguishing OS samples from non-tumor samples (AUC = 0.97 95%CI [0.95-0.98]). Clinicopathological analysis of GSE21257 indicated that OS patients with higher CKS2 expression was more likely to suffer OS metastasis. Although Kaplan-Meier curves showed no remarkable difference of overall survival rate between OS patients with high and low-CKS2, CKS2 was found up-regulated in proliferating osteosarcoma cells. Co-expression genes of CKS2 were mainly assembled in function and pathways such as cell cycle, cell adhesion, and intercellular material transport. CONCLUSIONS: In summary, up-regulation of CKS2 expression in OS tissue was found through multiple technical approaches. In addition, scRNA-seq and co-expression analysis showed that CKS2 may have an impact on important biological process linked with cell cycle, cell adhesion, and intercellular material transport. Present study on CKS2 in OS indicated a promising prospect for CKS2 as a biomarker for OS.

The Clinical Significance and Potential Molecular Mechanism of Upregulated CDC28 Protein Kinase Regulatory Subunit 1B in Osteosarcoma.

BACKGROUND: CDC28 Protein Kinase Regulatory Subunit 1B (CKS1B) is a member of cyclin-dependent kinase subfamily and the relationship between CKS1B and osteosarcoma (OS) remains to be explored. METHODS: 80 OS and 41 nontumor tissue samples were arranged to conduct immunohistochemistry (IHC) to evaluate CKS1B expression between OS and nontumor samples. The standard mean deviation (SMD) was calculated based on in-house IHC and tissue microarrays and exterior high-throughput datasets for further verification of CKS1B expression in OS. The effect of CKS1B expression on clinicopathological and overall survival of OS patients was measured through public high-throughput datasets, and analysis of immune infiltration and single-cell RNA-seq was applied to ascertain molecular mechanism of CKS1B in OS. RESULTS: A total of 197 OS samples and 83 nontumor samples (including tissue and cell line) were obtained from in-house IHC, microarrays, and exterior high-throughput datasets. The analysis of integrated expression status demonstrated upregulation of CKS1B in OS (SMD = 1.38, 95% CI [0.52-2.25]) and the significant power of CKS1B expression in distinguishing OS samples from nontumor samples (Area under the Curve (AUC) = 0.89, 95% CI [0.86-0.91]). Clinicopathological and prognosis analysis indicated no remarkable significance but inference of immune infiltration and single-cell RNA-seq prompted that OS patients with overexpressed CKS1B were more likely to suffer OS metastasis while MYC Protooncogene may be the upstream regulon of CKS1B in proliferating osteoblastic OS cells. CONCLUSIONS: In this study, sufficient evidence was provided for upregulation of CKS1B in OS. The advanced effect of CKS1B on OS progression indicates a foreground of CKS1B as a biomarker for OS.

miR-199a-3p negatively regulates the progression of osteosarcoma through targeting AXL.

Dysregulation of micro-RNAs has been shown to contribute to multiple tumorigenic processes, as well as to correlate with tumor progression and prognosis. miR-199a has been shown to be dysregulated in many different tumor types; however, the association between miR-199a and the clinicopathological features of osteosarcoma is unknown, and the target gene for miR-199a and the regulatory mechanism are also unknown. In this study, we demonstrated that miR-199a-3p is expressed at low levels in osteosarcoma cells, which may inhibit the migration and invasion of these tumor cells. The downregulation of miR-199a-3p expression is significantly correlated with the recurrence and lung metastasis of patients with osteosarcoma. Using multivariate Cox regression analysis, low level of expression of miR-199a-3p was shown to be an independent predictor for worse prognosis in osteosarcoma. Furthermore, we showed that miR-199a-3p mimics can decrease the expression of the mRNA and protein of the receptor tyrosine kinase AXL, and miR-199a-3p targets directly the 3'-UTR of AXL mRNA, suggesting that miR-199a-3p may downregulate the expression of the AXL gene to inhibit the progression of osteosarcoma. In patients' osteosarcoma samples, we also showed a statistically significant inverse relation between the levels of miR-199a-3p and AXL, which is consistent with the results in osteosarcoma cell lines. Interestingly, miR-199a-3p mimics reduced the level of phosphorylation of AKT. Together with the previous data, we conclude that miR-199a-3p negatively contributes to the progression of osteosarcoma by downregulating the expression of AXL mRNA and protein. By this mechanism, a regulatory pathway comprised of miR-199a-3p and AXL may exist in osteosarcoma cells, which may as a result regulate the progression of osteosarcoma through the AKT pathway.

LCH-7749944, a novel and potent p21-activated kinase 4 inhibitor, suppresses proliferation and invasion in human gastric cancer cells.

P21-activated kinase 4 (PAK4), a serine/threonine protein kinase, has involved in the regulation of cytoskeletal reorganization, cell proliferation, gene transcription, oncogenic transformation and cell invasion. Moreover, PAK4 overexpression, genetic amplification and mutations were detected in a variety of human tumors, which make it potential therapeutic target. In this paper we found that LCH-7749944, a novel and potent PAK4 inhibitor, effectively suppressed the proliferation of human gastric cancer cells through downregulation of PAK4/c-Src/EGFR/cyclin D1 pathway. In addition, LCH-7749944 significantly inhibited the migration and invasion of human gastric cancer cells in conjunction with concomitant blockage of PAK4/LIMK1/cofilin and PAK4/MEK-1/ERK1/2/MMP2 pathways. Interestingly, LCH-7749944 also inhibited the formation of filopodia and induced cell elongation in SGC7901 cells. Importantly, LCH-7749944 caused successful inhibition of EGFR activity due to its inhibitory effect on PAK4. Taken together, these results provided novel insights into the development of PAK4 inhibitor and potential therapeutic strategies for gastric cancer.