Comparative assessment of biomechanics induced by hinge knee prostheses with two different motion axial system.

We aimed to evaluate the biomechanical contact characteristics of rotating hinge knee (RHK) prostheses with different motion axial systems. We performed finite element (FE) analyses to investigate and compare the peak contact stress and contact location on tibial insert and bushing during a gait cycle. The biaxial (BA) system and spherical center axial (SA) system RHK prostheses were included in this study. The comparisons between experimental tests and FE analyses were performed to verify the validation of FE models. Decreased ISO loadings were then applied to the validated FE models to investigate the peak contact stress and contact location on tibial insert and bushing. The contact areas obtained from experimental tests and FE analyses were in a good agreement. The peak contact stresses on tibial insert and bushing of BA prosthesis were higher than those of SA prosthesis. The contact locations on the superior surface of tibial insert in SA and BA prostheses were at the middle-posterior and posterior side, while those on the rotating axial surface were at the medial and lateral sides, respectively. This study indicate that the tibial insert and bushing of an SA prosthesis have lower peak contact stresses and better contact locations than those of a BA prosthesis during a gait cycle, which may decrease the risk of long-term complications of RHK prostheses. Future studies should be performed to confirm the relationship between the contact characteristics and wear in RHK prostheses.

Identification of Abnormal Spindle Microtubule Assembly as a Promising Therapeutic Target for Osteosarcoma.

OBJECTIVE: To demonstrate the expression of abnormal spindle microtubule assembly (ASPM) in clinical osteosarcoma tissue specimens collected in our hospital, and to explore the function of ASPM in osteosarcoma in vitro and in vivo. METHODS: Tissue specimens from 82 cases of osteosarcoma were collected and analyzed by immunohistochemistry assay. We also investigated the relationship between ASPM expression and clinicopathological characteristics in the patients. We transfected shASPM plasmid and the empty control plasmid, respectively, and then used quantitative polymerase chain reaction and western blot analysis to detect ASPM expression. Cell colony assay and MTT were used to observe the proliferation ability. In vivo study was undertaken to explore the ASPM function further. RESULTS: In this study, ASPM showed high expression in osteosarcoma tissue samples compared with non-tumor normal tissues. ASPM was positively correlated with clinical pathological characteristics, including tumor size (P = 0.024) and clinical stage (P = 0.045). Our results further showed that ASPM depletion dramatically inhibited the proliferation of osteosarcoma cells (with fewer cells in the sh-RNA-ASPM group compared with the control group(P < 0.05, respectively), and the in vivo assays further confirmed that ASPM ablation markedly blocked tumor growth compared with control (P < 0.05). CONCLUSION: Our data provides strong evidence that the high expression of ASPM in osteosarcoma promotes proliferation in vitro and in vivo, indicating its potential role as an osteosarcoma therapeutic target.

The effects of length of femoral stem on aseptic loosening following cemented distal femoral endoprosthetic replacement in tumour surgery.

PURPOSE: Aseptic loosening is a common prosthetic failure mode. The purpose of this study was to identify dose-response relationship between length of femoral stem and aseptic loosening. METHODS: We collected data of patients who underwent distal femoral prosthetic replacements at our institution from 2001 to 2017. Cox regression and two-piecewise regression model were used to analyze the associations between stem length and aseptic loosening. RESULTS: Significant association of length of femoral stem with aseptic loosening was observed in multivariate model and a non-linear relationship could be found from the smoothed curve. In two-piecewise model, an inflection point was calculated to be 143 mm. On the left of the inflection point, every 1 mm increase in the length of stem indicated that the risk of aseptic loosening could be reduced by 6%. CONCLUSION: There was a significant non-linear relationship between the length of femoral stem and aseptic loosening, and the inflection point was 143 mm.

Influence of Congruency Design on the Contact Stress of a Novel Hinged Knee Prosthesis Using Finite Element Analysis.

OBJECTIVES: To investigate the contact stress and the contact area o tibial inserts and bushings with respect to different congruency designs in a spherical center axis and rotating bearing hinge knee prosthesis under gait cycle loading conditions using finite element analysis. METHODS: Nine prostheses with different congruency (different degrees of tibiofemoral conformity and different distances between the spherical center and the bushing) designs were developed with the same femoral and tibial components. The models were transferred to finite element software. The peak contact stresses and contact areas on tibial inserts and bushings under the gait cycle loading conditions were investigated and compared. RESULTS: For tibial insert, the peak contact stress was the highest in the low conformity-long group (61.4486 MPa), and it was 1.88 times higher than that in the group with the lowest stress (moderate conformity-short group, 32.754 MPa). The contact area was the largest in the low conformity-long group (420.485 mm2 ), and it was 1.19 times larger than that in the group with the smallest area (moderate conformity-middle group, 352.332 mm2 ). For bushing, the peak contact stress was the highest in the high conformity-long group (72.8093 MPa), and it was 3.21 times higher than that in the group with the lowest stress (high conformity-short group, 22.6928 MPa). The contact area was the largest in the low conformity-short group (2.41 mm2 ), and it was 2.27 times larger than that in the group with the smallest area (high conformity-middle group, 1.063 mm2 ). CONCLUSION: The results of our study showed that the congruency of the tibiofemoral surface and bushing surface should be considered carefully in the design of the spherical center axis and rotating bearing hinge knee prosthesis. Different levels of contact performance were observed with different congruency designs. In addition, the influence of contact stress and contact area on the polyethylene wear of rotating hinge knee prostheses should be confirmed with additional laboratory tests.

Activation of GLP-1 receptor enhances the chemosensitivity of pancreatic cancer cells.

This study aimed to determine whether and how the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide affects the chemoresistance and chemosensitivity of pancreatic cancer cells to gemcitabine in vitro and in vivo. The GLP-1R and protein kinase A (PKA) levels were compared between the human pancreatic cancer cell line PANC-1 and the gemcitabine-resistant cell line PANC-GR. The in vitro effects of liraglutide on the cell proliferation and apoptosis as well as the nuclear factor-kappa B NF-κB expression levels of PANC-GR cells were evaluated. In addition, a mouse xenograft model of human pancreatic cancer was established by s.c. injection of PANC-1 cells, and the effects of liraglutide on the chemosensitivity were evaluated in vitro and in vivo. In contrast to PANC-1 cells, PANC-GR cells exhibited lower expression levels of GLP-1R and PKA. Incubation with liraglutide dose dependently inhibited the growth, promoted the apoptosis, and increased the expression of GLP-1R and PKA of PANC-GR cells. Similar effects of liraglutide were observed in another human pancreatic cancer cell line MiaPaCa-2/MiaPaCa-2-GR. Either the GLP-1R antagonist Ex-9, the PKA inhibitor H89, or the NF-κB activator lipopolysaccharide (LPS) could abolish the antiproliferative and proapoptotic activities of liraglutide. Additionally, each of these agents could reverse the expression of NF-κB and ABCG2, which was decreased by liraglutide treatment. Furthermore, liraglutide treatment increased the chemosensitivity of pancreatic cancer cells to gemcitabine, as evidenced by in vitro and in vivo experiments. Thus, GLP-1R agonists are safe and beneficial for patients complicated with pancreatic cancer and diabetes, especially for gemcitabine-resistant pancreatic cancer.

APLNR promotes the progression of osteosarcoma by stimulating cell proliferation and invasion.

Osteosarcoma is the most common type of bone malignancies with a poor prognosis. In recent years, targeted therapy has shown great potential in the treatment of osteosarcoma, and more effective therapeutic targets for this disease need to be developed. APLNR is a seven transmembrane G-protein-coupled receptor expressed widely in multiple tissues. As has been reported, APLNR is involved in various physiological and pathological processes. Although APLNR plays a role in the development and progression of multiple tumors, the potential role of APLNR in osteosarcoma, a highly malignant tumor, remains unclear. Here, we reported that APLNR expression was correlated positively with clinical features including tumor size and stage of osteosarcoma. We found that APLNR knockdown inhibited the proliferation and invasion of osteosarcoma cells in vitro. In addition, APLNR could promote the progression and metastasis of osteosarcoma in mice. Collectively, this study showed the potential link between APLNR and osteosarcoma and suggested APLNR as a novel therapeutic target for osteosarcoma.

Identification of nine microRNAs as potential biomarkers for lung adenocarcinoma.

Lung cancer is a leading global cause of cancer-related death, and lung adenocarcinoma (LUAD) accounts for ~ 50% of lung cancer. Here, we screened for novel and specific biomarkers of LUAD by searching for differentially expressed mRNAs (DEmRNAs) and microRNAs (DEmiRNAs) in LUAD patient expression data within The Cancer Genome Atlas (TCGA). The identified optimal diagnostic miRNA biomarkers were used to establish classification models (including support vector machine, decision tree, and random forest) to distinguish between LUAD and adjacent tissues. We then predicted the targets of identified optimal diagnostic miRNA biomarkers, functionally annotated these target genes, and performed receiver operating characteristic curve analysis of the respective DEmiRNA biomarkers, their target DEmRNAs, and combinations of DEmiRNA biomarkers. We validated the expression of selected DEmiRNA biomarkers by quantitative real-time PCR (qRT-PCR). In all, we identified a total of 13 DEmiRNAs, 2301 DEmRNAs and 232 DEmiRNA-target DEmRNA pairs between LUAD and adjacent tissues and selected nine DEmiRNAs (hsa-mir-486-1, hsa-mir-486-2, hsa-mir-153, hsa-mir-210, hsa-mir-9-1, hsa-mir-9-2, hsa-mir-9-3, hsa-mir-577, and hsa-mir-4732) as optimal LUAD-specific biomarkers with great diagnostic value. The predicted targets of these nine DEmiRNAs were significantly enriched in transcriptional misregulation in cancer and central carbon metabolism. Our qRT-PCR results were generally consistent with our integrated analysis. In summary, our study identified nine DEmiRNAs that may serve as potential diagnostic biomarkers of LUAD. Functional annotation of their target DEmRNAs may provide information on their roles in LUAD.

Combination of 2-deoxy d-glucose and metformin for synergistic inhibition of non-small cell lung cancer: A reactive oxygen species and P-p38 mediated mechanism.

Targeting metabolism of lung cancer cells is a promising methodology for the treatment of lung cancer. In this regard, 2-Deoxy d-glucose (2-dDG) has been reported to inhibit cell proliferation by intervening the glycolytic pathway. However, phase I clinical trial of 2-dDG demonstrated cardiac side effects at higher dosage. Metformin (Met), on the other hand, has been reported to improve pathological response to chemotherapy in non-small cell lung cancer (NSCLC) patients. In this study, we propose that combination therapy of 2-dDG with Met will demonstrate enhanced cytotoxicity than either compound alone. Our results indicated that inhibition concentration 25 (IC25) for combined treatment of Met and 2-dDG showed more toxicity as compared to individual agents on a NSCLC cell line, A549. This augmented toxicity is associated with increased lipid peroxidation and decreased glutathione level as well as decreased super oxide dismutase and catalase activities. Combination of Met and 2-dDG also demonstrated enhanced DNA damage, DNA adduct formation, intracellular reactive oxygen species (ROS) level, and mitochondrial membrane potential alteration, as well as increased apoptosis, caspase-3 activity, P-p38 and P-AMP-activated protein kinase (AMPK) level. It was also shown that inhibition of caspase-3 and p38 kinase partially (75%-87%) reversed Met and 2-dDG induced cell death, without affecting the ROS levels. On the other hand, pre-treatment of cells with N-acetyl cysteine (NAC) reversed Met and 2-dDG induced cell death to >90%. Taken together, the results of this study demonstrated that combination of Met and 2-dDG showed better toxicity than individual compounds and cell death is ROS, P-p38 and caspase-3 mediated, thereby providing a proof of concept for the combination of Met and 2-dDG as a potential treatment protocol for NSCLC.

Flying high: limits to flight performance by sparrows on the Qinghai-Tibet Plateau.

Limits to flight performance at high altitude potentially reflect variable constraints deriving from the simultaneous challenges of hypobaric, hypodense and cold air. Differences in flight-related morphology and maximum lifting capacity have been well characterized for different hummingbird species across elevational gradients, but relevant within-species variation has not yet been identified in any bird species. Here we evaluate load-lifting capacity for Eurasian tree sparrow (Passer montanus) populations at three different elevations in China, and correlate maximum lifted loads with relevant anatomical features including wing shape, wing size, and heart and lung masses. Sparrows were heavier and possessed more rounded and longer wings at higher elevations; relative heart and lung masses were also greater with altitude, although relative flight muscle mass remained constant. By contrast, maximum lifting capacity relative to body weight declined over the same elevational range, while the effective wing loading in flight (i.e. the ratio of body weight and maximum lifted weight to total wing area) remained constant, suggesting aerodynamic constraints on performance in parallel with enhanced heart and lung masses to offset hypoxic challenge. Mechanical limits to take-off performance may thus be exacerbated at higher elevations, which may in turn result in behavioral differences in escape responses among populations.