Intelligent and Bioactive Osseointegration of the Implanted Piezoelectric Bone Cement with the Host Bone Is Realized by Biomechanical Energy.

Poly methyl methacrylate (PMMA) bone cement is widely used in orthopedic surgeries, including total hip/knee arthroplasty and vertebral compression fracture treatment. However, loosening due to bone resorption is a common mid-to-late complication. Therefore, developing bioactive bone cement that promotes bone growth and integration is key to reducing aseptic loosening. In this study, we developed a piezoelectric bone cement comprising PMMA and BaTiO3 with excellent electrobioactivity and further analyzed its ability to promote bone integration. Experiments demonstrate that the PMMA and 15 wt % BaTiO3 cement generated an open-circuit voltage of 37.109 V under biomimetic mechanical stress, which effectively promoted bone regeneration and interfacial bone integration. In vitro experiments showed that the protein expression levels of ALP and RUNX-2 in the 0.65 Hz and 20 min group increased by 1.74 times and 2.31 times. In vivo experiments confirmed the osteogenic ability of PMMA and 15 wt % BaTiO3, with the increment of bone growth in the non-movement and movement groups being 4.67 and 4.64 times, respectively, at the second month after surgery. Additionally, Fluo-4 AM fluorescence staining and protein blotting experiments verified that PMMA and 15 wt % BaTiO3 electrical stimulation promoted osteogenic differentiation of BMSCs by activating calcium-sensitive receptors and increasing calcium ion inflow by 1.41 times when the stimulation reached 30 min. Therefore, piezoelectric bioactive PMMA and 15 wt % BaTiO3 cement has excellent application value in orthopedic surgery systems where stress transmission is prevalent.

Serine/threonine kinase 36 induced epithelial-mesenchymal transition promotes docetaxel resistance in prostate cancer.

To investigate the role and potential mechanism of serine/threonine kinase 36 (STK36) in docetaxel resistance-prostate cancer (PCa). The expression of STK36 in PCa and the correlation with clinicopathological characteristics of PCa patients were analyzed using the data from different databases and tissue microarrays. To investigate the role of STK36 on cell proliferation, invasion, and migration, STK36 was overexpressed and silenced in DU-145 and PC-3 cell lines. Cell counting kit-8 (CCK8) was used to test cell proliferation. Cell invasion and migration were detected by cell wound scratch assay and trans well, respectively. The expression profile of STK36, E-Cadherin, and Vimentin was analyzed by Western blot. Cell apoptosis was detected by the TUNEL assay. STK36 expression was upregulated in PCa tissue compared with adjacent benign PCa tissue; it was higher in patients with advanced stages compared with lower stages and was significantly correlated with decreased overall survival. Up-regulation of STK36 significantly promoted the proliferation, invasion, and migration of DU-145 and PC-3 cells and compensated for the suppression caused by docetaxel treatment in vitro. A striking apoptosis inhibition could be observed when dealing with docetaxel, although the apoptosis of DU-145 and PC-3 cells was not affected by the STK36 exclusive overexpression. Besides, E-Cadherin expression was restrained while the expression levels of vimentin were all enhanced. The knockdown of STK36 reversed the above process. STK36 up-regulation could accelerate the biological behavior and docetaxel resistance of PCa by epithelial-mesenchymal transition (EMT) activation. STK36 may be potentially used as a target in PCa resolvent with docetaxel.

Hsa_circ_0063329 inhibits prostate cancer growth and metastasis by modulating the miR-605-5p/tgif2 axis.

Circular RNAs play crucial regulatory roles in the progression of various cancers. Nevertheless, the underlying mechanisms of circRNAs in prostate cancer (PCa) proliferation and metastasis remain largely uncertain. Here, we performed circRNA microarray analyses to identify differentially expressed circRNAs in a normal prostate epithelial cell line and PCa cell lines. We found that hsa_circ_0063329 was significantly downregulated in PCa. A series of in vitro and in vivo functional assays showed that overexpression of hsa_circ_0063329 inhibits PCa cell progression, while silencing of hsa_circ_0063329 achieved the opposite effects. Mechanistically, bioinformatics analysis, RNA pulldown, RNA-seq and dual-luciferase reporter assays demonstrated that hsa_circ_0063329 exerts its effect by sponging miR-605-5p to derepress TG-interacting factor 2 (TGIF2) and inactivate the TGF-ß pathway. In conclusion, hsa_circ_0063329 inhibits the proliferation and metastasis of PCa via modulation of the miR-605-5p/TGIF2 axis, and targeting hsa_circ_0063329 may provide a promising treatment strategy for aggressive PCa.

Grim-19 plays a key role in mitochondrial steroidogenic acute regulatory protein stability and ligand-binding properties in Leydig cells.

Grim-19 (gene associated with retinoid-IFN-induced mortality 19), the essential component of complex I of mitochondrial respiratory chain, functions as a noncanonical tumor suppressor by controlling apoptosis and energy metabolism. However, additional biological actions of Grim-19 have been recently suggested in male reproduction. We investigated here the expression and functional role of Grim-19 in murine testis. Testicular Grim-19 expression was detected from mouse puberty and increased progressively thereafter, and GRIM-19 protein was observed to be expressed exclusively in interstitial Leydig cells (LCs), with a prominent mitochondrial localization. In vivo lentiviral vector-mediated knockdown of Grim-19 resulted in a significant decrease in testosterone production and triggered aberrant oxidative stress in testis, thus impairing male fertility by inducing germ cell apoptosis and oligozoospermia. The control of testicular steroidogenesis by GRIM-19 was validated using the in vivo knockdown model with isolated primary LCs and in vitro experiments with MA-10 mouse Leydig tumor cells. Mechanistically, we suggest that the negative regulation exerted by GRIM-19 deficiency-induced oxidative stress on steroidogenesis may be the result of two phenomena: a direct effect through inhibition of phosphorylation of steroidogenic acute regulatory protein (StAR) and subsequent impediment to StAR localization in mitochondria and an indirect pathway that is to facilitate the inhibiting role exerted by the extracellular matrix on the steroidogenic capacity of LCs via promotion of integrin activation. Altogether, our observations suggest that Grim-19 plays a potent role in testicular steroidogenesis and that its alterations may contribute to testosterone deficiency-related disorders linked to metabolic stress and male infertility.

Impact of Femoral Neck Cortical Bone Defect Induced by Core Decompression on Postoperative Stability: A Finite Element Analysis.

Objective: To analyze the impact of femoral neck cortical bone defect induced by core decompression on postoperative biomechanical stability using the finite element method. Methods: Five finite element models (FEMs) were established, including the standard operating model and four models of cortical bone defects at different portions of the femoral neck (anterior, posterior, superior, and inferior). The maximum stress of the proximal femur was evaluated during normal walking and walking downstairs. Results: Under both weight-bearing conditions, the maximum stress values of the five models were as follows: femoral neck (inferior) > femoral neck (superior) > femoral neck (posterior) > femoral neck (anterior) > standard operation. Stress concentration occurred in the areas of femoral neck cortical bone defect. Under normal walking, the maximum stress of four bone defect models and its increased percentage comparing the standard operation were as follows: anterior (17.17%), posterior (39.02%), superior (57.48%), and inferior (76.42%). The maximum stress was less than the cortical bone yield strength under normal walking conditions. Under walking downstairs, the maximum stress of four bone defect models and its increased percentage comparing the standard operation under normal walking were as follows: anterior (36.75%), posterior (67.82%), superior (83.31%), and inferior (103.65%). Under walking downstairs conditions, the maximum stress of bone defect models (anterior, posterior, and superior) was less than the yield strength of cortical bone, while the maximum stress of bone defect model (inferior) excessed yield strength value. Conclusions: The femoral neck cortical bone defect induced by core decompression can carry out normal walking after surgery. To avoid an increased risk of fracture after surgery, walking downstairs should be avoided when the cortical bone defect is inferior to the femoral neck except for the other three positions (anterior, posterior, and superior).

Exosomal miR-1275 Secreted by Prostate Cancer Cells Modulates Osteoblast Proliferation and Activity by Targeting the SIRT2/RUNX2 Cascade.

Prostate cancer (PCa) is one of the most frequently diagnosed malignancies and the second leading cause of cancer mortality among men worldwide. Modulation of osteoblast activity is involved in PCa metastasis, and miR-1275 is also reported to regulate PCa metastasis; however, the association between cancer-derived exosomal miR-1275 and osteoblast activity is unclear. Here, we isolated exosomes from PC3-derived conditioned medium by ultracentrifugation. We found that miR-1275 could be transferred from PCa cells to osteoblasts via exosomes. Exosomal miR-1275 significantly accelerated the proliferation of osteoblasts and the expression levels of osteoblast-specific genes, such as osteocalcin (OCN), type I collagen (COL-1), and osteopontin (OPN). Moreover, exosomal miR-1275 increased the expression of RUNX2, a master modulator of osteoblast activity, by down-regulation of SIRT2, which in turn influenced the growth and activity of osteoblasts. Our findings indicate that PCa-derived exosomal miR-1275 promotes the proliferation and activity of osteoblasts via modulation of SIRT2/Runx2 signaling.

MicroRNA-126 engineered muscle-derived stem cells attenuates cavernosa injury-induced erectile dysfunction in rats.

BACKGROUND: Cavernosa injury is a common cause of organic erectile dysfunction (ED), which requires safe and effective treatments. In the present study, the therapeutic efficiency of muscle-derived stem cells (MDSCs) modified with microRNA-126 (miR-126) was determined in rats with cavernosa injury. METHODS: MDSCs were transfected with miR-126 and then were transplanted into rats with cavernosa injury. Erectile function, vascular function (western blot and immunofluorescence), extraction, and detection of exosomes were then undertaken. RESULTS: On the 28th day after transplantation, the highest value of intra-cavernous pressure (ICP)/mean arterial pressure (MAP) in rats of miRNA-126 group (0.84 ± 0.14) was observed (Control: 0.38 ± 0.07; MDSC: 0.54 ± 0.11, Vector: 0.60 ± 0.02; respectively). Treatment of miRNA-126-modified-MDSCs remarkably strengthened vascular structure, supported by hematoxylin-eosin staining. The expression of CD31, von Willebrand Factor and vascular endothelial factors were higher than those in other groups, indicating improved vascular function. In vitro mechanism studies showed that exosomes containing miR-126 isolated from MDSCs promoted angiogenesis and attenuated apoptosis of human umbilical venous endothelial cells. Finally, insulin receptor substrate 1 and Krüppel-like factor 10 were determined as the direct target genes of miR-126. CONCLUSIONS: MiR-126 engineered MDSCs notably repaired cavernosa injury in rats via vascular reconstruction by directly targeting IRS1 and KLF10, in which the exosomes secreted by MDSCs played a critical role.

Comparative Analysis of Paper-Based and Web-Based Versions of the National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) Questionnaire in Breast Cancer Patients: Randomized Crossover Study.

BACKGROUND: Breast cancer remains the most common neoplasm diagnosed among women in China and globally. Health-related questionnaire assessments in research and clinical oncology settings have gained prominence. The National Comprehensive Cancer Network-Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) is a rapid and powerful tool to help evaluate disease- or treatment-related symptoms, both physical and emotional, in patients with breast cancer for clinical and research purposes. Prevalence of individual smartphones provides a potential web-based approach to administrating the questionnaire; however, the reliability of the NFBSI-16 in electronic format has not been assessed. OBJECTIVE: This study aimed to assess the reliability of a web-based NFBSI-16 questionnaire in breast cancer patients undergoing systematic treatment with a prospective open-label randomized crossover study design. METHODS: We recruited random patients with breast cancer under systematic treatment from the central hospital registry to complete both paper- and web-based versions of the questionnaires. Both versions of the questionnaires were self-assessed. Patients were randomly assigned to group A (paper-based first and web-based second) or group B (web-based first and paper-based second). A total of 354 patients were included in the analysis (group A: n=177, group B: n=177). Descriptive sociodemographic characteristics, reliability and agreement rates for single items, subscales, and total score were analyzed using the Wilcoxon test. The Lin concordance correlation coefficient (CCC) and Spearman and Kendall τ rank correlations were used to assess test-retest reliability. RESULTS: Test-retest reliability measured with CCCs was 0.94 for the total NFBSI-16 score. Significant correlations (Spearman ρ) were documented for all 4 subscales-Disease-Related Symptoms Subscale-Physical (ρ=0.93), Disease-Related Symptoms Subscale-Emotional (ρ=0.85), Treatment Side Effects Subscale (ρ=0.95), and Function and Well-Being Subscale (ρ=0.91)-and total NFBSI-16 score (ρ=0.94). Mean differences of the test and retest were all close to zero (≤0.06). The parallel test-retest reliability of subscales with the Wilcoxon test comparing individual items found GP3 (item 5) to be significantly different (P=.02). A majority of the participants in this study (255/354, 72.0%) preferred the web-based over the paper-based version. CONCLUSIONS: The web-based version of the NFBSI-16 questionnaire is an excellent tool for monitoring individual breast cancer patients under treatment, with the majority of participants preferring it over the paper-based version.

Prevalence of symptomatic dry eye in breast cancer patients undergoing systemic adjuvant treatment: A cross-sectional study.

OBJECTIVES: To investigate the prevalence of symptomatic dry eye (SDE) on women undergoing systemic adjuvant therapy for breast cancer and its association with treatment settings. METHODS: Woman undergoing breast cancer systemic adjuvant therapy were included in exposure group. An age-matched non-treatment control group was recruited. This cross-sectional questionnaire-based study utilised validated Ocular Surface Disease Index (OSDI) and NCCN-FACT-Breast Cancer Symptom Index (NFBSI-16) questionnaires to determine the presence of SDE and investigate other breast cancer treatment complications. Additionally, demographic data and medical histories were collected. RESULTS: Of 423 eligible participants, 200 in each of the control group and the exposure group were included in the final analysis. The prevalence of SDE was 59.0% in breast cancer patients with adjuvant treatment, statistically significantly higher than 25.5% in the control group (P < 0.01). Additionally, exposure group experienced higher prevalence of moderate and severe SDE, which were 20.0% and 19.5% respectively compared with 9.0% and 4.0% in the control group (P = 0.002, P < 0.001). There was a significantly high prevalence of SDE among patients who had received over four cycles of systemic therapy (71.0%, P < 0.001) and the application of targeted therapy (71.2%, P = 0.014). The severity of SDE positively correlated with the cycles of treatment administered. CONCLUSION: SDE was significantly predominant in women with breast cancer undergoing systemic adjuvant treatment. Our findings suggest dry eye assessments among patients receiving more than four cycles of chemotherapy or targeted therapy, thus early revealing possible dry eye conditions to both patients and clinicians for further specialized examination and treatment.

Lnc-MUC20-9 binds to ROCK1 and functions as a tumor suppressor in bladder cancer.

The study aimed to investigate the expression and function of bladder cancer (BC) long noncoding RNAs (lncRNAs) using a high-throughput platform. High-throughput sequencing was used to compare the expression profiles of lncRNA in BC and adjacent normal tissues. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR), in situ hybridization, gene ontology, and Kyoto Encyclopedia of Genes and Genomes analysis were performed to verify differential expression of lncRNA. The effect of lncRNA overexpression on cellular proliferation, apoptosis, migration, and invasion was analyzed following the transfection of lncRNA overexpressing lentivirus into 5637 and T24 cell lines. The overexpressing cells were subcutaneously injected into nude mice to evaluate their effects on tumor growth. Tumor-associated RNA-binding proteins of lncRNA were analyzed by RNA pull-down combined with mass spectrometry. A total of 93 lncRNA genes were upregulated and 352 lncRNA genes were downregulated in the tissues of patients with BC. Of which, we investigated the function of downregulated lnc-MUC20-9. Overexpression of lnc-MUC20-9 in 5637 and T24 cells resulted in decreased tumor cell viability and cell clones, decreased migration and invasion, and increased apoptosis. Similarly, nude mice bearing lnc-MUC20-9 overexpressing tumor cells exhibited smaller tumor size and volume than that of mice bearing control cells. Mass spectrometry analysis showed that lnc-MUC20-9 binds to ROCK1, an oncogene whose expression was decreased in lnc-MUC20-9 overexpressing cells. The study revealed that lnc-MUC20-9 has the function of inhibiting tumor growth, migration, and invasion. In BC cells, lnc-MUC20-9 binds to ROCK1 and may be involved in lnc-MUC20-9-mediated tumor suppressor function, which might be potential therapeutic targets for BC.

Systematic analysis of survival-associated alternative splicing signatures in clear cell renal cell carcinoma.

Alternative splicing (AS) constitutes a major reason for messenger RNA (mRNA) and protein diversity. Increasing studies have shown a link to splicing dysfunction associated with malignant neoplasia. Systematic analysis of AS events in kidney cancer remains poorly reported. Therefore, we generated AS profiles in 533 kidney renal clear cell carcinoma (KIRC) patients in The Cancer Genome Atlas (TCGA) database using RNA-seq data. Then, prognostic models were developed in a primary cohort (N = 351) and validated in a validation cohort (N = 182). In addition, splicing networks were built by integrating bioinformatics analyses. A total of 11 268 and 8083 AS variants were significantly associated with patient overall survival time in the primary and validation KIRC cohorts, respectively, including STAT1, DAZAP1, IDS, NUDT7, and KLHDC4. The AS events in the primary KIRC cohorts served as candidate AS events to screen the independent risk factors associated with survival in the primary cohort and to develop prognostic models. The area under the curve of the receiver-operator characteristic curve for prognostic prediction in the primary and validation KIRC cohorts was 0.84 and 0.82 at 2500 days of overall survival, respectively. In addition, splicing correlation networks revealed key splicing factors (SFs) in KIRC, such as HNRNPH1, HNRNPU, KHDBS1, KHDBS3, SRSF9, RBMX, SFQ, SRP54, HNRNPA0, and SRSF6. In this study, we analyzed the AS landscape in the TCGA KIRC cohort and detected predictors (prognostic) based on AS variants with high performance for risk stratification of the KIRC cohort and revealed key SFs in splicing networks, which could act as underlying mechanisms.

The analysis of a ceRNA network and the correlation between lncRNA, miRNA, and mRNA in bladder cancer.

BACKGROUND: To explore the correlation between the lncRNA-miRNA-mRNA and ceRNA network through the differential expression analysis of lncRNAs, miRNAs and mRNAs in bladder cancer based on The Cancer Genome Atlas (TCGA) database combined with Gene Ontology (GO) and Kyoto Encyclopedia of Genes Genomes (KEGG) enrichment analysis. METHODS: Firstly, the expression profile data and corresponding clinical data of RNAs in bladder cancer were searched and downloaded from TCGA database, and aberrantly expressed long non-coding RNA (lncRNA), microRNA (miRNA), and messenger RNA (mRNA) were screened and found by using TCGA database. The relationship between lncRNA-miRNA-mRNA was established by comparing these lncRNAs, miRNAs, and mRNAs, while the ceRNA network was constructed. Combined with the analysis of the GO annotation and KEGG pathway, the effects of lncRNA-miRNA-mRNA interaction on the development of bladder cancer were explored. RESULTS: A total of 1,742 differentially expressed lncRNA, 511 differentially expressed miRNAs, and 4,373 differentially expressed mRNAs were identified, and 328 lncRNAs, 73 miRNAs, and 677 mRNAs were screened by survival analysis. With the lncRNA-miRNA-mRNA correlation analysis, a ceRNA network consisting of 45 lncRNAs, 14 miRNAs, and 29 mRNAs was successfully constructed. The GO annotation and functional enrichment of target gene mRNAs in the network are mainly concentrated in the signal pathways and include fatty acid biosynthesis, gap junction, insulin signaling pathway, and the MAPK signaling pathway biological processes such as positive regulation of cellular process and system development. CONCLUSIONS: We successfully identified the target gene correlating lncRNA, miRNA, and mRNA, and constructed a ceRNA network. Our findings can provide a potential target for the study of the occurrence, development, diagnosis, treatment, and prognosis of bladder cancer.

IL-7/IL-7 receptor axis stimulates prostate cancer cell invasion and migration via AKT/NF-κB pathway.

IL-7, acting via IL-7 receptor (IL-7R), plays an important role in tumor progression. Elevated IL-7 expression has been reported to be observed in prostate cancer tissues and closely associated with poor prognosis. However, the biological functions of IL-7 and its receptor in prostate cancer cell invasiveness remain unclear. In our study, we found that the expressions of IL-7 and IL-7R were both upregulated in prostate cancer cells. IL-7 dose-dependently promoted the invasion and migration of prostate cancer cells, whereas knockdown of IL-7R attenuated the effect of IL-7. Further, IL-7/IL-7R axis induced the activation of AKT and NF-κB, whereas blocking of AKT suppressed IL-7-mediated NF-κB activity. Moreover, IL-7/IL-7R axis increased MMP-3 and MMP-7 expression of prostate cancer cells, whereas inhibition of NF-κB as well as MMPs activity suppressed IL-7-mediated cell invasion and migration. Together, these data identify IL-7/IL-7R axis to be involved in prostate cancer cell invasion and migration, probably via activating AKT/NF-κB pathway and upregulating MMP-3 and MMP-7 expression. Therefore, blocking IL-7/IL-7R axis may provide a potential therapeutic strategy to treat prostate cancer.

The GSTT1 null genotype contributes to increased risk of prostate cancer in Asians: a meta-analysis.

BACKGROUND: Many studies have investigated the association between glutathione S-transferase T 1 (GSTT1) null genotype and risk of prostate cancer, but the impact of GSTT1 null genotype in Asians is still unclear owing to inconsistencies across results. Thie present meta-analysis aimed to quantify the strength of the association between GSTT1 null genotype and risk of prostate cancer. METHODS: We searched the PubMed, Embase and Wangfang databases for studies of associations between the GSTT1 null genotype and risk of prostate cancer in Asians and estimated summary odds ratio (OR) with their 95% confidence interval (95% CI). RESULTS: A total of 11 case-control studies with 3,118 subjects were included in this meta-analysis, which showed the GSTT1 null genotype to be significantly associated with increased risk of prostate cancer in Asians (random-effects OR = 1.49, 95% CI 1.15-1.92, P = 0.002), also after adjustment for heterogeneity (fixed-effects OR = 1.45, 95% CI 1.23-1.70, P< 0.001). No evidence of publication bias was observed. CONCLUSIONS: This meta-analysis of available data suggested the GSTT1 null genotype does contribute to increased risk of prostate cancer in Asians.