OGR1 mediates the inhibitory effects of acidic environment on proliferation and angiogenesis of endothelial progenitor cells.

Ovarian cancer G-protein-coupled receptor 1 (OGR1), an acid-sensitive receptor, plays a key proton-sensing role through stimulation of inositol phosphate formation. Avascular necrosis of the femoral head is characterized by apoptosis of bone cells mainly resulting from deficient local blood perfusion, eventually leading to acidification with disruption of endothelial progenitor cells' (EPCs) function. However, whether EPCs express OGR1 has not been demonstrated. This study attempted to whether OGR1 mediates the effects of acid on proliferation, migration, and angiogenesis in EPCs. FITC-UEA-I and Dil-Ac-LDL double-staining methods were used to identify EPCs. Expression of OGR1 was analyzed by RT-PCR (reverse transcription PCR) and western blot after incubation in media ranging in pH, cell counting kit-8 and cell cycle analysis were used to analyze proliferation and cell cycle distribution. Scratch test, transwell migration assay, and tube formation experiments were performed to analyze migration and vascularization of EPCs after silencing OGR1 with small interfering RNA (siRNA). The result show EPCs were positive for FITC-UEA-I and Dil-Ac-LDL double-staining and expressed OGR1. The expression of OGR1 increased gradually with decreased pH and was highest in pH 6.4 medium. Incubation in pH 6.4 medium inhibited proliferation of EPCs and caused cell cycle arrest. Silencing of OGR1 using siRNA partially reversed the effect of acidic environment on EPCs. Migration and angiogenesis of EPCs were inhibited in pH 6.4 medium, and silencing of OGR1 partially reversed this effect. The results demonstrated expression of OGR1 in EPCs, and the OGR1 mediated the effects of acidic environment on proliferation, migration, and angiogenesis of EPCs.

Lipid-polymer nanoparticles with CD133 aptamers for targeted delivery of all-trans retinoic acid to osteosarcoma initiating cells.

Osteosarcoma, a common type of bone cancer in children, and represents an aggressive and fetal cancer worldwide. Osteosarcoma initiating cells are considered to be a subpopulation of cancer cells which contribute to the progression, recurrence, metastasis and multi-drug resistance of osteosarcoma. CD133 is considered to be one marker for osteosarcoma initiating cells. All-trans retinoic acid (ATRA), an active metabolite of vitamin A under the family retinoid, is an up-and-coming drug which was able to effectively treat various cancer initiating cells. Nevertheless, there have been no research that reported the activity of ATRA against osteosarcoma initiating cells. In this research, we hereby examined the potential activity of ATRA in osteosarcoma initiating cells, and developed lipid-polymer nanoparticles with CD133 aptamers for targeted ATRA delivery to osteosarcoma initiating cells. Using the cytotoxicity assay, colony formation assay, tumorsphere formation assay and flow cytometry, the therapeutic effect of ATRA and ATRA-loaded lipid-polymer nanoparticles conjugated with CD133 aptamers (ATRA-PLNP-CD133) against osteosarcoma initiating cells were investigated. The results showed that ATRA exerted potent activity towards osteosarcoma initiating cells. ATRA-PLNP-CD133, which showed a size of 129.9 nm and a sustained release of ATRA during 144 h, was demonstrated to efficiently and specifically promote the ATRA delivery to osteosarcoma initiating cells, and achieve superior therapeutic efficacy in osteosarcoma compared with ATRA and non-targeted nanoparticles. This is the first report of the therapeutic efficacy of ATRA towards osteosarcoma initiating cells, and the increased ATRA delivery by nanoparticles to osteosarcoma initiating cells using CD133 aptamers. ATRA-PLNP-CD133 represent an up-and coming approach for the therapy of osteosarcoma initiating cells.

Beraprost sodium versus clopidogrel for preventing vascular thromboembolic events of arteriovenous fistula in uraemic patients: a retrospective study with a mean 3-year follow-up.

OBJECTIVE: This study aimed to evaluate the efficacy of beraprost sodium (BPS) or clopidogrel (CL) using vascular thromboembolic events (VTEs) of arteriovenous fistula as a primary endpoint in patients with end-stage renal disease (ESRD) undergoing arteriovenous fistula surgery. METHODS: We performed a multicentre, retrospective cohort study from August 2012 to August 2016. We studied patients with ESRD who underwent arteriovenous fistula surgery and received peroral administration of 40 µg BPS, three times per day, for 1 month, or 75 mg CL (initial dose of 300 mg), one time per day, for 1 month. The time to first on-study VTE was the primary endpoint. RESULTS: The BPS-treated cohort had a significantly delayed time to first VTE compared with the CL-treated cohort (hazard ratio 0.33, 95% confidence interval 0.18-0.56). An increased incidence of VTEs was detected in the 1-month follow-up, with rates of 2.4% and 8.7% for BPS and CL, respectively. This difference persisted over time, with rates of 8.0% and 18.1% at the final follow-up, respectively. CONCLUSION: CL-treated patients with ESRD have a greater risk of VTEs compared with BPS-treated patients. CL-treated patients also tend to experience a VTE within the first month after cessation of oral administration.

Denosumab versus zoledronic acid for preventing symptomatic skeletal events in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer: an outcome analyses with a mean follow-up of 3 years.

BACKGROUND: The purpose of this study was to evaluate the efficacy of denosumab or zoledronic acid (ZA) using symptomatic skeletal events (SSEs) as the primary endpoint in Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer. METHODS: Asian postmenopausal women with oestrogen-receptor-positive advanced breast cancer receiving subcutaneous denosumab 120 mg Q4W, or intravenous ZA 4 mg Q4W until the primary analysis cut-off date were retrospectively analysed in the Hong Kong Practice-Based Cancer Research Center(HKCRC) from March 2011 to March 2013. The time to first on-study SSE that was assessed either clinically or through routine radiographic scans was the primary endpoint. RESULTS: 242 patients received denosumab or ZA treatment (n = 120, mean age of 64.9 years (SD 3.01) and n = 122, 65.4 years (3.44), respectively). The median times to first on-study SSE were 14.7 months (12.9-45.6) and 11.7 months (9.9-45.6) for denosumab and ZA, respectively (hazard ratio, HR 0.44, 95% CI 0.71-2.95; p = 0·0002). Compared with the ZA group, denosumab-treated patients had a significantly delayed time to first SSE (HR 0.65 [95% CI 0.29-1.45], p < 0.0001). An increased incidence of SSE was found in the 16-month follow-up with rates of 2.1 and 10.7% for denosumab and ZA, respectively (P = 0.033). The difference persisted with time with rates of 8.3 and 17.2% at the final follow-up, respectively (P < 0.05). CONCLUSION: In postmenopausal women aged ≥60 years with oestrogen-receptor-positive advanced breast cancer, denosumab significantly reduced the risk of developing SSEs compared with ZA. The findings of this pilot trial justify a larger study to determine whether the result is more generally applicable to a broader population.

Cyclophosphamide versus cyclosporine A therapy in steroid-resistant nephrotic syndrome: a retrospective study with a mean 5-year follow-up.

OBJECTIVE: To compare the clinical efficacy of cyclophosphamide (CTX) and cyclosporine A (CSA) in initial treatment of children with steroid-resistant nephrotic syndrome (SRNS). METHODS: Prospectively maintained databases were reviewed to retrospectively compare two cohorts with SRNS that received peroral administration of 2 to 2.5 mg/kg/d CTX for 3 to 6 months or 1 to 5 mg/kg/d CSA for 2 years until the primary analysis cut-off date during 2007 to 2011. The time to first on-study relapse of SRNS was the primary endpoint. The effective rate was the second endpoint. RESULTS: A total of 127 children with SRNS were included (CTX-treated cohort: n = 62; CSA-treated cohort: n = 65), with a mean 5-year follow-up. CTX-treated children showed a significantly delayed time to first on-study relapse of SRNS compared with CSA-treated children (hazard ratio 0.66, 95% confidence interval 0.32-1.75). The relapse rate (rate/year) in CTX-treated children (1.1 ± 0.1) at the 24-month follow-up was significantly higher than that with CSA (0.4 ± 0.2). This difference persisted until the final follow-up. CONCLUSIONS: CSA is associated with a significantly lower relapse rate and significantly higher effective rate compared with CTX, especially in children with minimal change disease.

[Effectiveness analysis of surgical treatment of Schatzker type â £ tibial plateau fractures].

Objective: To introduce a surgical protocol based on the location and orientation of the apex of the medial condylar fracture line for the treatment of Schatzker type Ⅳ tibial plateau fractures and report the preliminary effectiveness. Methods: The clinical data of 18 patients with Schatzker type Ⅳ tibial plateau fractures underwent open reduction and internal fixation between March 2012 and April 2016 were retrospectively analysed. There were 6 males and 12 females, aged 36-74 years (mean, 45 years). The causes of injury included traffic accident in 2 cases, falling in 14 cases, bruise injury in 1 case, and crush injury of heavy object in 1 case. All cases were fresh closed fractures, without injury of nerves and blood vessels. According to sub type of Wahlquist tibial plateau type Ⅳ fracture classification, there were 1 case of type A, 5 cases of type B, and 12 cases of type C. The interval of injury and operation was 6-16 days (mean, 9.5 days). The location of the apex of the medial condylar fracture line was determined the surgical approach. After operation, reduction of tibial plateau fractures was evaluated by the DeCoster score evaluation criteria. The knee joint function was assessed by short Musculoskeletal Function Assessment (SMFA) score and Hospital for Special Surgery (HSS) score. Results: The incisions all healed by first intension after operation without surgery related complications. All the patients obtained satisfactory exposure and reduction during operation. According to DeCoster score evaluation criteria, the results were excellent in 13 cases and fair in 5 cases. All the patients were followed up 12-30 months (mean, 18 months). X-ray films showed that all fractures healed at 10-16 weeks (mean, 12 weeks) after operation. There was no plate displacement, screw loosening, and other complications occurred during follow-up. At last follow-up, the SMFA score was 15-48 (mean, 28.5). The HSS score was 52-94 (mean, 81.1), and the results were excellent in 10 cases, good in 5 cases, fair in 2 cases, and poor in 1 case with an excellent and good rate of 83.3%; the main clinical manifestation was severe traumatic osteoarthritis symptom in 1 case with the fair result. Conclusion: The surgical program should be developed based on the location and orientation of the apex of the medial condylar fracture line. Open reduction and internal fixation for treating Schatzker type Ⅳ fractures can achieve satisfactory effectiveness.

Construction of Radial Defect Models in Rabbits to Determine the Critical Size Defects.

Many studies aimed at investigating bone repair have been conducted through animal models in recent years. However, limitations do exist in these models due to varying regeneration potential among different animal species. Even using the same animal, big differences exist in the size of critical size defects (CSD) involving the same region. This study aimed to investigate the standardization of radial bone defect models in rabbits and further establish more reliable CSD data. A total of 40 6-month-old New Zealand white rabbits of clean grade totaling 80 radial bones were prepared for bone defect models, according to the principle of randomization. Five different sizes (1.0, 1.2, 1.4, 1.7 and 2.0 cm) of complete periosteal defects were introduced under anesthesia. At 12 weeks postoperatively, with the gradual increase in defect size, the grades of bone growth were significantly decreased in all 5 groups. X-ray, CT scans and H&E staining of the 1.4, 1.7, and 2.0-cm groups showed lower grades of bone growth than that of the 1.0 and 1.2-cm groups respectively (P < 0.05). Using rabbit radial defect model involving 6-month-old healthy New Zealand white rabbits, this study indicates that in order to be critical sized, defects must be greater than 1.4 cm.

[RESEARCH STATUS ON MOLECULAR BASIS OF INTERVERTEBRAL DISC DEGENERATION AND REPAIRING EFFECT OF PLATELET-RICH PLASMA].

OBJECTIVE: To review the research status on the molecular basis of intervertebral disc degeneration and the repairing effect of platelet-rich plasma. METHODS: The related literature about the molecular basis of intervertebral disc degeneration and the repairing effect of platelet-rich plasma was reviewed, analyzed, and summarized. RESULTS: The molecular basis of intervertebral disc degeneration includes genetic influences, cell senescence, decreased matrix production, increased degradative enzyme production, proinflammatory cytokine expression, apoptosis, and neural ingrowth. Platelet-rich plasma can release a series of growth factors to promote intervertebral disc cells proliferation, differentiation, and extracellular matrix synthesis. It can also inhibit proinflammatory effect and apoptosis. CONCLUSION: Although the prospect of using platelet-rich plasma to repair intervertebral disc degeneration is encouraging, further studies are still needed.

Inhibitory effects of platelet-rich plasma on intervertebral disc degeneration: a preclinical study in a rabbit model.

BACKGROUND: Platelet-rich plasma (PRP) contains multiple growth hormones that may stimulate tissue repair. This study aimed to assess the effects of PRP in a rabbit model of IDD (annulus fibrosus puncture). MATERIAL/METHODS: Thirty-six adult New Zealand white rabbits were randomly divided into 3 groups: 0.1 mL PRP (group A), 0.1 mL phosphate-buffered saline (group B), and control (group C) (n=12/group). Annulus fibrosus puncture was performed to establish L4/5 and L5/6 IDD models. Two and 4 weeks later, 6 rabbits from each group were given an IVD injection at L4/5 and L5/6. Two or 4 weeks after injection, rabbits were scanned with X-ray and MRI before being sacrificed. IVDs were collected for hematoxylin and eosin, Masson's trichrome, and Safranin O staining, and type II collagen immunohistochemistry. RESULTS: Over time, IVD height and disc imaging signal intensity decreased gradually in groups B and C, but only slightly in group A (baseline: 100% for all groups; A: 95.9±4.2% at 4 weeks, 90.1±8.4 at 6 weeks; B: 75.3±5.7% at 4 weeks, 70.8±6.4% at 6 weeks; C: 74.7±5.5% at 4 weeks, 69.9±6.2% at 6 weeks; all P<0.001, P<0.01 between A vs. B and C). Degenerative histological changes in IVDs in groups B and C were more severe compared with group A. CONCLUSIONS: Platelet-rich plasma interventions can effectively attenuate the IDD process in rabbits.

The downregulation of miR-144 is associated with the growth and invasion of osteosarcoma cells through the regulation of TAGLN expression.

Alterations in the expression of microRNAs (miRNAs or miRS) have been implicated in the pathogenesis of the majority of human malignancies, and the dysregulation of microRNA-144 (miR-144) has been associated with several diseases. However, the potential involvement of miR-144 in osteosarcoma, a common malignant bone tumor in children and adolescents with a high risk of relapse and metastasis, has not yet been fully investigated. In the present study, we examined the expression and roles of miRNAs in osteosarcoma as potential diagnostic markers and therapeutic targets, and we focused on miR-144 due to its known involvement in osteogenesis. We demonstrate that miR-144 is downregulated in osteosarcoma cell lines and primary human osteosarcoma tissue samples and that its ectopic expression inhibits osteosarcoma cell proliferation and invasion. We identified TAGLN as a downstream target of miR-144 and demonstrated that its expression is upregulated in osteosarcoma cell lines and tumor tissue and is inversely correlated with miR-144 expression. Our results indicate that miR-144 may regulate osteosarcoma cell proliferation and invasion by downregulating its target gene, TAGLN, suggesting that miR-144 may be a potential therapeutic target for the treatment of osteosarcoma.