Analysis and validation of biomarkers of immune cell-related genes in postmenopausal osteoporosis: An observational study.

Postmenopausal osteoporosis (PMOP) is a common metabolic inflammatory disease. In conditions of estrogen deficiency, chronic activation of the immune system leads to a hypo-inflammatory phenotype and alterations in its cytokine and immune cell profile, although immune cells play an important role in the pathology of osteoporosis, studies on this have been rare. Therefore, it is important to investigate the role of immune cell-related genes in PMOP. PMOP-related datasets were downloaded from the Gene Expression Omnibus database. Immune cells scores between high bone mineral density (BMD) and low BMD samples were assessed based on the single sample gene set enrichment analysis method. Subsequently, weighted gene co-expression network analysis was performed to identify modules highly associated with immune cells and obtain module genes. Differential analysis between high BMD and low BMD was also performed to obtain differentially expressed genes. Module genes are intersected with differentially expressed genes to obtain candidate genes, and functional enrichment analysis was performed. Machine learning methods were used to filter out the signature genes. The receiver operating characteristic (ROC) curves of the signature genes and the nomogram were plotted to determine whether the signature genes can be used as a molecular marker. Gene set enrichment analysis was also performed to explore the potential mechanism of the signature genes. Finally, RNA expression of signature genes was validated in blood samples from PMOP patients and normal control by real-time quantitative polymerase chain reaction. Our study of PMOP patients identified differences in immune cells (activated dendritic cell, CD56 bright natural killer cell, Central memory CD4 T cell, Effector memory CD4 T cell, Mast cell, Natural killer T cell, T follicular helper cell, Type 1 T-helper cell, and Type 17 T-helper cell) between high and low BMD patients. We obtained a total of 73 candidate genes based on modular genes and differential genes, and obtained 5 signature genes by least absolute shrinkage and selection operator and random forest model screening. ROC, principal component analysis, and t-distributed stochastic neighbor embedding down scaling analysis revealed that the 5 signature genes had good discriminatory ability between high and low BMD samples. A logistic regression model was constructed based on 5 signature genes, and both ROC and column line plots indicated that the model accuracy and applicability were good. Five signature genes were found to be associated with proteasome, mitochondria, and lysosome by gene set enrichment analysis. The real-time quantitative polymerase chain reaction results showed that the expression of the signature genes was significantly different between the 2 groups. HIST1H2AG, PYGM, NCKAP1, POMP, and LYPLA1 might play key roles in PMOP and be served as the biomarkers of PMOP.

Improved Immune Response for Colorectal Cancer Therapy Triggered by Multifunctional Nanocomposites with Self-Amplifying Antitumor Ferroptosis.

Ferroptosis, as a type of regulated cell death, can trigger the release of damage-associated molecular patterns from cancer cells and lead to the enhancement of immune recognition. Fenton reaction-mediated chemodynamic therapy could initiate ferroptosis by generating lipid peroxides, but its efficiency would be greatly restricted by the insufficient H2O2 and antioxidant system within the tumor. Herein, this work reports the successful preparation of H2O2 self-supplied and glutathione (GSH)-depletion therapeutic nanocomposites (Cu2O@Au) through in situ growth of Au nanoparticles on the surface of cuprous oxide (Cu2O) nanospheres. Upon delivery into cancer cells, the released Cu2O could consume endogenous H2S within colorectal cancer cells to form Cu31S16 nanoparticles, while the released Au NPs could catalyze glucose to generate H2O2 and gluconic acid. The self-supplying endogenous H2O2 and lower acidity could amplify the Cu ion-induced Fenton-like reaction. Meanwhile, the consumption of glucose would reduce GSH generation by disrupting the pentose phosphate pathway. Additionally, the Cu2+/Cu+ catalytic cycle promotes the depletion of GSH, leading to lipid peroxide accumulation and ferroptosis. It was found that the onset of ferroptosis triggered by Cu2O@Au could initiate immunologic cell death, promote dendritic cell maturation and T-cell infiltration, and finally enhance the antitumor efficacy of the PD-L1 antibody. In summary, this collaborative action produces a remarkable antitumor effect, which provides a promising treatment strategy for colorectal cancer.

Finite element study of the biomechanical effects on the rotator cuff under load.

Rotator cuff injuries account for 50% of shoulder disorders that can cause shoulder pain and reduced mobility. The occurrence of rotator cuff injury is related to the variation in shoulder load, but the mechanical changes in the rotator cuff caused by load remain unclear. Therefore, the mechanical results of the rotator cuff tissue during glenohumeral abduction and adduction were analyzed based on a finite element shoulder model under non-load (0 kg) and load (7.5 kg) conditions. The results showed that the maximum von Mises stress on the supraspinatus muscle was larger than that on the subscapularis, infraspinatus, and teres minor muscles during glenohumeral abduction. Compared with the non-load condition, the maximum von Mises stress on the supraspinatus muscle increased by 75% under the load condition at 30° abduction. Under the load condition, the supraspinatus joint side exhibited an average stress that was 32% greater than that observed on the bursal side. The von Mises stress on the infraspinatus muscle was higher than that in other rotator cuff tissues during adduction. The stress on the infraspinatus muscle increased by 36% in the load condition compared to the non-load condition at 30° adduction. In summary, the increased load changed the mechanical distribution of rotator cuff tissue and increased the stress differential between the joint aspect and the bursal aspect of the supraspinatus tendon.

Associations of trace element levels in paired serum, whole blood, and tissue: an example of esophageal squamous cell carcinoma.

Previous studies have extensively explored impacts of trace elements on human beings and complex relationships with cancers. However, contradictory conclusions may be more challenging to explain due to biological specimen differences. To investigate the distribution of trace elements inside body, we collected serum, whole blood and tissues from 77 patients with esophageal squamous cell carcinoma (ESCC), as well as serum and whole blood from 100 healthy individuals, and determined the concentrations of 13 elements (Al, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Cd, and Pb) with inductively coupled plasma-mass spectrometry (ICP-MS). Al, Ni, Cu, Sr, and Cd variations between patients and controls were found to be inconsistent in serum and blood. Concentrations of Cu, As, Se, and Sr in serum were positively correlated with that in whole blood in both case and control group (rs >0.450, P <0.01). Elements in serum had a higher accuracy (87.0%) than whole blood (74.0%) in classifying ESCC patients and healthy individuals with discriminant analysis. As, Cd, and Pb concentrations in cancerous tissues were positively correlated with those in normal epithelium (rs =0.397, 0.571, and 0.542, respectively), while Mn, Cu, and Se accumulated in malignant tissues, with V, Cr, Co, Ni, Sr, and Cd partitioning in normal epithelium (all P <0.05). Thus, certain elements in blood, such as Cu, As, Se, and Sr, were useful in assessing element exposure burdens and accumulation tendency of some elements (Mn, Cu and Se, etc.) was uncovered in tumors. Our investigation demonstrated the variations in trace element distribution for frequently used specimens and further evidence of etiological mechanism is necessary.

No Difference Unicompartmental Knee Arthroplasty for Medial Knee Osteoarthritis With or Without Anterior Cruciate Ligament Deficiency: A Systematic Review and Meta-analysis.

BACKGROUND: A functional intact anterior cruciate ligament (ACLI) is considered to be a prerequisite for unicompartmental knee arthroplasty (UKA). However, UKA has been shown to have good clinical efficacy in ACL-deficient (ACLD) knees at 3 to 10 years follow-up. Therefore, the role of ACLD in UKA remains controversial, and more evidence is needed to clarify the role of ACLD in UKA. METHODS: PubMed, the Web of Science, EMBASE, and Cochrane Central were queried for articles comparing the results of the ACLD and ACLI groups after UKA. Outcomes of interest included the Tegner Activity Scale, the Oxford Knee Score (OKS), postoperative slope of the implant (PSI), the Knee Injury and Osteoarthritis Outcomes Score (KOOS), the Lysholm score, and revision rate. There were eight studies included. The mean age was 66 years (range 49 to 87 year old) and the mean follow-up time was 6.9 years (range 1.3 to 16.6 years). There was baseline comparability regarding mean age, duration of follow-up, and body mass index (P > .5) between the ACLD and ACLI groups. RESULTS: The ACLD and ACLI groups had improved postoperative functional indicators, and that postoperative revision rate (mean difference [MD], 1.24; 95% confidence interval [CI], 0.75 to 2.04; P = .4), Tegner score (MD, -0.1; 95% CI, -0.26 to 0.05; P = .19), and Lysholm score (95% CI, -2.46 to 7.32; P = .33) were similar between the groups, with no significant differences; however, the ACLD groups had significantly better KOOS Activities of Daily Living scores, with a significant difference (MD, 4.53; 95% CI, 1.75 to 7.3; P = .001). Also, there were no significant differences between two groups in the PSI, OKS, KOOS. CONCLUSION: ACL deficiency is not always a contraindication for UKA. With correct patient selection, UKA could be considered for medial knee osteoarthritis with ACL deficiency without antero-posterior instability, especially these people over 60 years of age.

Synergistic Reinforcing of Immunogenic Cell Death and Transforming Tumor-Associated Macrophages Via a Multifunctional Cascade Bioreactor for Optimizing Cancer Immunotherapy.

Immunogenic cell death (ICD) has aroused widespread attention because it can reconstruct a tumor microenvironment and activate antitumor immunity. This study proposes a two-way enhancement of ICD based on a CaO2 @CuS-MnO2 @HA (CCMH) nanocomposite to overcome the insufficient damage-associated molecular patterns (DAMPs) of conventional ICD-inducers. The near-infrared (NIR) irradiation (1064 nm) of CuS nanoparticles generates 1 O2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca2+ buffer function of mitochondria. Additionally, CaO2 nanoparticles react with H2 O to produce a large amount of O2 and Ca2+ , which respectively lead to enhanced PDT and Ca2+ overload during mitochondrial damage, thereby triggering a robust ICD activation. Moreover, oxidative-damaged mitochondrial DNA, induced by PDT and released from tumor cells, reprograms the immunosuppressive tumor microenvironment by transforming tumor-associated macrophages to the M1 subphenotype. This study shows that CCMH with NIR-II irradiation can elicit adequate DAMPs and an active tumor-immune microenvironment for both 4T1 and CT26 tumor models. Combining this method with an immune checkpoint blockade can realize an improved immunotherapy efficacy and long-term protection effect for body.

Association between Serum Level of Multiple Trace Elements and Esophageal Squamous Cell Carcinoma Risk: A Case-Control Study in China.

We investigated the associations between multiple serum trace element levels and risk for esophageal squamous cell carcinoma (ESCC). A total of 185 ESCC patients and 191 healthy individuals were recruited in our study. The concentration of 13 trace elements (Al, V, Cr, Mn, Co, Ni, Cu, Zn, As, Se, Sr, Cd and Pb) in serum was determined with inductively coupled plasma mass spectrometry (ICP-MS). Logistic regression and the Probit extension of Bayesian Kernel Machine Regression (BKMR) models was established to explore the associations and the cumulative and mixed effects of multiple trace elements on ESCC. Three elements (Zn, Se and Sr) displayed a negative trend with risk for ESCC, and a significant overall effect of the mixture of Al, V, Mn, Ni, Zn, Se and Sr on ESCC was found, with the effects of V, Ni and Sr being nonlinear. Bivariate exposure-response interactions among these trace elements indicated a synergistic effect between Zn and Se, and an impactful difference of V combined with Ni, Sr or Zn. Our results indicate that Ni, V, Al, Mn, Zn, Se and Sr are associated with ESCC risk, providing additional evidence of the complex effects of trace elements disorder during the etiology of EC development.

Deciphering the molecular mechanism underlying the effects of epimedium on osteoporosis through system bioinformatic approach.

Epimedium has gained widespread clinical application in Traditional Chinese Medicine, with the functions of promoting bone reproduction, regulating cell cycle and inhibiting osteoclastic activity. However, its precise cellular pharmacological therapeutic mechanism on osteoporosis (OP) remains elusive. This study aims to elucidate the molecular mechanism of epimedium in the treatment of OP based on system bioinformatic approach. Predicted targets of epimedium were collected from TCMSP, BATMAN-TCM and ETCM databases. Differentially expressed mRNAs of OP patients were obtained from Gene Expression Omnibus database by performing Limma package of R software. Epimedium-OP common targets were obtained by Venn diagram package for further analysis. The protein-protein interaction network was constructed using Cytoscape software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were carried out by using clusterProfiler package. Molecular docking analysis was conducted by AutoDock 4.2 software to validate the binding affinity between epimedium and top 3 proteins based on the result of protein-protein interaction. A total of 241 unique identified epimedium targets were screened from databases, of which 62 overlapped with the targets of OP and were considered potential therapeutic targets. The results of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis revealed that these targets were positive regulation of cell cycle, cellular response to oxidative stress and positive regulation of cell cycle process as well as cellular senescence, FoxO, PI3K-Akt, and NF-kappa B signaling pathways. Molecular docking showed that epimedium have a good binding activity with key targets. Our study demonstrated the multitarget and multi-pathway characteristics of epimedium on OP, which elucidates the potential mechanisms of epimedium against OP and provides theoretical basis for further drug development.

Hypofractionated Radiation Therapy Combined With Weekly Chemotherapy in Patients With Unresectable or Recurrent Thymic Epithelial Tumor: A Prospective, Single-Arm Phase 2 Study (GASTO-1042).

PURPOSE: This prospective phase 2 study aimed to evaluate the efficacy and safety of hypofractionated radiation therapy (HRT) combined with concurrent weekly chemotherapy in patients with unresectable or recurrent thymic epithelial tumors (TETs). METHODS AND MATERIALS: Patients with unresectable or recurrent intrathoracic TETs that could be encompassed within the radiation fields were enrolled. HRT using intensity modulated radiation therapy (IMRT) technique was administered with 3 different levels of radiation doses (51 Gy/17 fractions (fx), 48 Gy/12 fx, and 45 Gy/9 fx; biologically effective dose of 66.3-67.5Gy), combined with weekly docetaxel (25 mg/m2) and nedaplatin (25 mg/m2). Weekly thymosin α1 (1.6 mg) was administered from the start to 2 months after radiation therapy. The objective response rate (ORR), progression-free survival (PFS), overall survival (OS), health-related quality of life (QOL), and toxicity were recorded. RESULTS: Fifty eligible patients enrolled from August 1, 2018, to July 1, 2020, were analyzed. Most patients (82.0%) had stage IVB tumors. Patients had IMRT-HRT (36-51 Gy in 9-17 fx, median biologically effective dose of 67.2 Gy) and concurrent weekly docetaxel/nedaplatin (2-4 cycles). During a median follow-up of 25.0 months (14.0-40.0), the ORR was 83.7%, the 2-year PFS was 59.1%, and the 2-year OS was 90.0%. There was 1 (2.0%) in-field recurrence while 19 (38.0%) patients developed out-of-field recurrence. Grade 3 pneumonitis was observed in 1 patient (2.0%). The ORR, 2-year PFS, 2-year OS, and toxicity were similar among 3 dose levels. Fourteen (28.0%) patients had 2 to 4 courses of radiation therapy because of recurrent diseases. Only 1 suffered from grade 1 pulmonary fibrosis during follow-up. Most patients (88%) maintained a stable QOL within 1 year after radiation therapy. CONCLUSIONS: IMRT-HRT and concurrent weekly docetaxel/nedaplatin was effective and well tolerated in unresectable or recurrent TETs. Considering the common out-of-field recurrence, this combined regimen could be an option for repeated radiation therapy. Thymosin α1 might help lower the incidence of pneumonitis and maintain the QOL.

TGF-Beta Induced Key Genes of Osteogenic and Adipogenic Differentiation in Human Mesenchymal Stem Cells and MiRNA-mRNA Regulatory Networks.

Background: The clinical efficacy of osteoporosis therapy is unsatisfactory. However, there is currently no gold standard for the treatment of osteoporosis. Recent studies have indicated that a switch from osteogenic to adipogenic differentiation in human bone marrow mesenchymal stem cells (hMSCs) induces osteoporosis. This study aimed to provide a more comprehensive understanding of the biological mechanisms involved in this process and to identify key genes involved in osteogenic and adipogenic differentiation in hMSCs to provide new insights for the prevention and treatment of osteoporosis. Methods: Microarray and bioinformatics approaches were used to identify the differentially expressed genes (DEGs) involved in osteogenic and adipogenic differentiation, and the biological functions and pathways of these genes were analyzed. Hub genes were identified, and the miRNA-mRNA interaction networks of these hub genes were constructed. Results: In an optimized microenvironment, transforming growth factor-beta (TGF-beta) could promote osteogenic differentiation and inhibit adipogenic differentiation of hMSCs. According to our study, 98 upregulated genes involved in osteogenic differentiation and 66 downregulated genes involved in adipogenic differentiation were identified, and associated biological functions and pathways were analyzed. Based on the protein-protein interaction (PPI) networks, the hub genes of the upregulated genes (CTGF, IGF1, BMP2, MMP13, TGFB3, MMP3, and SERPINE1) and the hub genes of the downregulated genes (PPARG, TIMP3, ANXA1, ADAMTS5, AGTR1, CXCL12, and CEBPA) were identified, and statistical analysis revealed significant differences. In addition, 36 miRNAs derived from the upregulated hub genes were screened, as were 17 miRNAs derived from the downregulated hub genes. Hub miRNAs (hsa-miR-27a/b-3p, hsa-miR-128-3p, hsa-miR-1-3p, hsa-miR-98-5p, and hsa-miR-130b-3p) coregulated both osteogenic and adipogenic differentiation factors. Conclusion: The upregulated hub genes identified are potential targets for osteogenic differentiation in hMSCs, whereas the downregulated hub genes are potential targets for adipogenic differentiation. These hub genes and miRNAs play important roles in adipogenesis and osteogenesis of hMSCs. They may be related to the prevention and treatment not only of osteoporosis but also of obesity.

Up-frameshift Protein 1 Promotes Tumor Progression by Regulating Apoptosis and Epithelial-Mesenchymal Transition of Colorectal Cancer.

Background: Recently, accumulating evidence confirmed that up-frameshift protein 1 (UPF1) was aberrantly expressed in various cancers. However, the molecular mechanism mediated by UPF1 underlying colorectal carcinogenesis remains unclear. Method: Immunohistochemistry (IHC) and quantitative real-time polymerase chain reaction analysis were used to determine the expression level of UPF1 in colorectal cancer (CRC) tissues. CCK-8, EdU, transwell assay, and flow cytometry were performed to investigate the biological significance of UPF1. Epithelial-mesenchymal transition (EMT) and apoptosis associated markers were detected by western blotting. Results: We found that UPF1 expression was upregulated in CRC tissues and cell lines. Clinical analysis revealed that high UPF1 expression was positively correlated with advanced stage, lymph node metastasis and shorter survival. Knockdown of UPF1 suppressed cell proliferation and cell cycle progression. Functionally, UPF1 promotes tumor metastasis by inducing epithelial to mesenchymal transition. Further investigations revealed that knockdown of UPF1 promoted apoptosis through triggering DNA damage. Conclusions: Taken together, this research revealed that UPF1 plays an oncogenic role in CRC via regulating EMT and apoptosis and may be a potential therapeutic target for CRC.

Identification and Validation of EMT-Related lncRNA Prognostic Signature for Colorectal Cancer.

Background: This study aimed to explore the biological functions and prognostic role of Epithelial-mesenchymal transition (Epithelial-mesenchymal transition)-related lncRNAs in colorectal cancer (CRC). Methods: The Cancer Genome Atlas database was applied to retrieve gene expression data and clinical information. An EMT-related lncRNA risk signature was constructed relying on univariate Cox regression, Least Absolute Shrinkage and Selector Operation (LASSO) and multivariate Cox regression analysis of the EMT-related lncRNA expression data and clinical information. Then, an individualized prognostic prediction model based on the nomogram was developed and the predictive accuracy and discriminative ability of the nomogram were determined by the receiver operating characteristic curve and calibration curve. Finally, a series of analyses, such as functional analysis and unsupervised cluster analysis, were conducted to explore the influence of independent lncRNAs on CRC. Results: A total of 581 patients were enrolled and an eleven-EMT-related lncRNA risk signature was identified relying on the comprehensive analysis of the EMT-related lncRNA expression data and clinical information in the training cohort. Then, risk scores were calculated to divide patients into high and low-risk groups, and the Kaplan-Meier curve analysis showed that low-risk patients tended to have better overall survival (OS). Multivariate Cox regression analysis indicated that the EMT-related lncRNA signature was significantly associated with prognosis. The results were subsequently confirmed in the validation dataset. Then, we constructed and validated a predictive nomogram for overall survival based on the clinical factors and risk signature. Functional characterization confirmed this signature could predict immune-related phenotype and was associated with immune cell infiltration (i.e., macrophages M0, M1, Tregs, CD4 memory resting cells, and neutrophils), tumor mutation burden (TMB). Conclusions: Our study highlighted the value of the 11-EMT-lncRNA signature as a predictor of prognosis and immunotherapeutic response in CRC.

Effect of the amount of correction on posterior tibial slope and patellar height in open-wedge high tibial osteotomy.

Objectives: To evaluate the effect of amount of correction on postoperative changes in PTS (posterior tibial slope), PH (patellar height), and clinical outcomes following biplanar OWHTO (open-wedge high tibial osteotomy). Method: This study included 79 knees (32 left and 47 right) of 79 patients (mean age 60.28 ± 4.2 years, 24 males, 55 females) with varus malalignment and symptomatic isolated medial joint osteoarthritis who underwent OWHTO. According to the amount of correction angles, all patients were divided into three groups: LCA (large correction angle) group (>14°), MCA (medium correction angle) group (10°-14°), and SCA (small correction angle) group (<10°). All patients were clinically assessed according to the Lysholm score, HSS (hospital for special surgery knee score), and KSS (knee society score) prior to and after surgery. For radiographic analysis, we measured the PTS, PH [ISI (Insall-Salvati index), and BPI (Blackburne-Peel index)]. The pre-post difference of PTS, ISI, and BPI was calculated by subtracting the post-OWHTO value to the pre-OWHTO value in three groups, respectively. The preoperative, postoperative, and difference of PTS, ISI, and BPI values were analyzed according to the correction angle. The mean follow-up period was 28.5 months (SD, 4.9; range 18-52 months). Results: Radiologically, PTS increased and PH decreased after surgery on the whole (p < .05). The relationship between amount of correction and slope increase is significant (p < .001). Furthermore, the pairwise difference between the LCA group and SCA group and MCA group is significant respectively (p < .05). In terms of PH, the LCA group yielded ISI and BPI that were significantly different from baseline for the SCA group and MCA group. In addition, the pairwise difference between the SCA group and LCA group in ISI and BPI is significant (p = .031). Clinically, significant improvements were observed in postoperative clinical scores of the Lysholm score, HSS, and KSS (p < .05). Seventy-four patients (93.67%) reported satisfaction with surgery. However, no correlation was found between changes in PTS and PH with postoperative knee score. No severe adverse complications were observed. Conclusions: The amount of correction angle is a significant factor affecting the PTS and PH in OWHTO. With increased correction angle, the likelihood of increasing the PTS and decreasing the PH increases. Special attention should be paid to keep PTS and PH unchanged in cases where large corrections are required. Otherwise, closing wedge osteotomy or other intraoperative effective measures are supposed to be adopted.

Association Between Bone Cement Augmentation and New Vertebral Fractures in Patients with Osteoporotic Vertebral Compression Fractures: A Systematic Review and Meta-Analysis.

PURPOSE: To investigate the association between bone cement augmentation and new vertebral fractures (VF) in patients with osteoporotic vertebral compression fractures (OVCFs). METHODS: A literature search of PubMed, EMBASE, and the Cochrane Library was conducted from 1987 to December 31, 2020, to identify randomized controlled trials that compared bone cement augmentation with non-bone cement treatments in patients with OVCFs. The clinical incidence of new VF and the risk of new adjacent vertebral fractures (AVF) after treatment were calculated. The indexes of the risk ratio or odds ratio, and 95% confidence intervals were determined with RevMan 5.2 software. RESULTS: A total of 13 randomized controlled trials involving 1949 participants were included in the final quantitative analysis. There was no significant association between bone cement augmentation and the clinical incidence of new VF during the 6-month and 12-month follow-ups or the whole follow-up period. However, there was a significantly lower clinical incidence of new VF in patients who received bone cement augmentation compared with non-bone cement treatments during 24 months or more of follow-up. Pooled data from the relevant trials demonstrated that the risk of new AVF in bone cement augmentation was significantly higher than that in non-bone cement treatments. CONCLUSIONS: Although the use of bone cement augmentation in OVCFs significantly increased the risk of new AVF compared with non-bone cement treatments, it was not significantly associated with a higher clinical incidence of new VF.

UPF1: a potential biomarker in human cancers.

Recently, Up-frameshift protein 1 (UPF1) is reported to be downregulated in various cancers and its low expression is closely correlated with poor prognosis. UPF1 is well known as a master regulator of nonsense-mediated mRNA decay (NMD), which serves as a highly conserved mRNA surveillance process protecting cells from aberrant toxic transcripts. Due to dysfunction of UPF1, NMD fails to proceed, which contributes to tumor initiation and progression. This review shows a brief summary of the aberrant expression, functional roles and molecular mechanisms of UPF1 during tumorigenesis. Increasing evidence has indicated that UPF1 could serve as a potential biomarker for cancer diagnosis and treatment for future clinical applications in cancer.

AVL9 is Upregulated in and Could Be a Predictive Biomarker for Colorectal Cancer.

PURPOSE: This study aimed to explore the function and clinical significance of AVL9 in colorectal cancer (CRC). MATERIALS AND METHODS: The GEO, TCGA, and GEPIA databases were searched to evaluate the expression level of AVL9, while the SurvExpress online tool was used to explore its related clinical survival prognosis. The cBioPortal and LinkedOmics databases were used to identify AVL9 expression-related genes. Protein-protein interaction (PPI) networks were analyzed using Cytoscape 3.7.1 and DAVID6.8, which was used to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) signal pathway enrichment. The immunohistochemistry of AVL9 in CRC was detected using an online tool protein atlas. RNA isolation and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to detect AVL9 expression in tissue and plasma samples. RESULTS: Our study confirmed that AVL9 was highly expressed in CRC lesions versus the adjacent normal tissues (P < 0.001). High AVL9 expression was negatively associated with survival outcomes (P < 0.05). GO analysis showed that AVL9 expression-related genes were enriched in single organismal cell-cell adhesion, post-transcriptional regulation of gene expression, and negative regulation of the vascular endothelial growth factor receptor signaling pathway (P < 0.05). On a KEGG pathway analysis, these genes were mainly involved in progesterone-mediated oocyte maturation, axon guidance, the insulin signaling pathway, and the ubiquitin-mediated proteolysis signaling pathways (P < 0.05). In the PPI analysis, the KBTBD2, KIAA1147, EPDR1, and RNF216 genes interacted with AVL9, and GEPIA predicted that their expression levels were all positively correlated with AVL9. Furthermore, a clinicopathological parameter analysis found that high AVL9 expression was positively correlated with differentiation and TNM stage. RT-qPCR analysis further showed that plasma AVL9 expression was upregulated in CRC patients versus healthy controls. CONCLUSION: AVL9 could serve as a potential biomarker and therapeutic target for CRC.

CircRNA_100876 Is Upregulated in Gastric Cancer (GC) and Promotes the GC Cells' Growth, Migration and Invasion via miR-665/YAP1 Signaling.

The present study aimed to investigate the biological function and relative mechanisms of circRNA_100876 in gastric cancer (GC). To this end, quantitative real-time polymerase chain reaction (RT-qPCR) was performed to examine the expression of circRNA_100876 and miR-665 in GC tissues and cells, and circRNA_100876 expression was depleted by the transfection of circ_100876-targeting siRNAs. CCK-8, flow cytometry, and Transwell assays were applied to examine GC cell cycle distribution, proliferation, apoptosis, migration, and invasion abilities. Proteins related to apoptosis and epithelial-mesenchymal transition (EMT) were detected by western blotting. Luciferase reporter assays were conducted to verify the direct target site between circRNA_100876 and miR-665. Our study confirmed that circRNA_100876 was highly expressed in GC lesions compared with the adjacent normal tissues (P < 0.001). High circRNA_100876 expression was negatively associated with survival outcome (P = 0.000). Furthermore, the down-regulation of circRNA_100876 could inhibit GC cell proliferation, invasion, and migration by suppressing the EMT pathway. Further study suggested that circRNA_100876 could act as a competing endogenous RNA by sequestering miR-665, and luciferase activity assay indicated that circRNA_100876 could bind directly with miR-665. Moreover, we found that Yes-associated protein 1 (YAP1) was the downstream target gene of miR-665, miR-665 knockdown could up-regulate YAP1 expression in MKN45 cells, and YAP1 knockdown could inhibit MKN45 cell proliferation, migration and invasion. Therefore, we demonstrated that circRNA_100876 over-expression in GC could promote GC tumor growth, migration and invasion and exert its effects through miR-665/YAP1 signaling.

Effects of Acupoint Application Therapy with TianGui Powder on Osteoporosis in Ovariectomized Rats through TGF-ß1 and Smad2/3 Signaling Pathway.

OBJECTIVES: To explore the effects of acupoint application therapy (AAT) with TianGui Powder (TGP) on the expressions of the transforming growth factor ß1 (TGF-ß1) and Smad-2/3 signaling pathway in ovariectomized osteoporosis rats. METHODS: Sixty rats were randomly divided into four groups: normal group (group A), model group (group B), TGP group (group C), and Western medicine group (group D). Group A had only the corresponding amount of adipose tissue around the ovary removed; rats in the other groups had bilateral ovariectomies. After 1 week, groups A and B were given 1 mL/100 mg normal saline solution by gavage, group C was treated with AAT with TGP on ShenQue acupoint (0.2 piece/rat, 6 h/time, 1 time/d) and group D was given calcium carbonate vitamin D3 (36 mg/kg/d) and alfacalcidol (0.05 µg/kg/d) tablet suspension. In this study, the bone mineral density (BMD) , the levels of BALP, TRAP-5b, and BGP in serum and the changes in bone histomorphology was detected. For acquiring lumbar experimental data, the expression of TGF-ß1, Smad-2/3 proteins and mRNA of TGF-ß1and Smad-2/3 were assessed. After 12 weeks, the data were collected for analysis. RESULTS: Compared with group A, the bone trabecula was thinner and significantly reduced in other groups. The result of BMD improved significantly in both groups C and D compared to group B after intervention (P < 0.05). In contrast, compared to group B, the levels of BALP, TRAP-5b, and BGP significantly declined in both groups C and D. In group C, the results of protein expressions in TGF-ß1, Smad-2/3 were 2.870 ± 0.270, 1.552 ± 0.111, and 1.420 ± 0.079, respectively. In groups C and D, those indications significantly declined compared to group B (P < 0.01). In group C, the level of mRNA expressions of TGF-ß1, Smad-2/3 were 1.872 ± 0.177, 1.672 ± 0.086, and 1.790 ± 0.136, respectively. Compared with group B, those indications had significant difference in groups C and D (P < 0.05). CONCLUSION: Acupoint application therapy with TGP could significantly improve the BMD. The TGF-ß1 and Smad-2/3 signaling pathway could be a therapeutic target of TGP in postmenopausal osteoporosis rats.

Linc00662 Promotes Tumorigenesis and Progression by Regulating miR-497-5p/AVL9 Axis in Colorectal Cancer.

BACKGROUND: Recently, multiple lines of evidence have demonstrated that linc00662 serves as an oncogene in various cancers. However, the exact mechanism of oncogenesis mediated by linc00662 in colorectal cancer (CRC) remains unknown. In this study, we aimed to explore the biological role of linc00662 in the regulation of CRC progression. METHODS: Both gene expression omnibus (GEO) and the cancer genome atlas (TCGA) datasets were used to evaluate the expression of linc00662. RT-qPCR was used to analyze the expression of linc00662, miR-497-5p, and AVL9 in CRC clinical samples and cell lines. Cell Counting Kit-8 (CCK-8), flow cytometry, transwell assay, and xenograft model were used to investigate the effect of linc00662 on CRC cell proliferation, cell cycle, and metastasis. Western blot analysis was used to analyze the expression of the epithelial-mesenchymal transition (EMT)-associated markers. Furthermore, bioinformatics analysis and mechanism assays were used to elucidate the underlying mechanism. Dual-luciferase reporter assays were used to analyze the regulatory relationships among linc00662, miR-497-5p, and AVL9. RESULTS: In this study, we found that the expression of linc00662 was significantly upregulated in CRC tissues compared to normal tissues and positively correlated with tissue differentiation, T stage, and lymphatic metastasis. Further, our data showed that the expression of linc00662 was positively associated with lymph node metastasis, TMN stage, and poor-moderate differentiation. Patients with higher linc00662 expression level were more likely to have poorer overall survival. Knockdown of linc00662 inhibited CRC cell growth, induced cell apoptosis, triggered cell cycle arrest at G2/M phase, and suppressed cell migration and invasion through regulating the EMT pathway. Further, mechanistic studies revealed that knockdown of linc00662 significantly reduced the expression of AVL9, a direct target of miR-497-5p. CONCLUSIONS: Linc00662 was significantly upregulated in CRC, and mediated CRC progression and metastasis by competing with miR-497-5p to modulate the expression of AVL9. Therefore, our result sheds light on the potential application of linc00662 in CRC diagnosis and therapy.