KNOCKDOWN OF CIRC_0001379 ATTENUATES HYPOXIA/REOXYGENATION-INDUCED CARDIOMYOCYTE APOPTOSIS AND INFLAMMATORY RESPONSE BY MIR-98-5P/SOX6 AXIS.

ABSTRACT: Background: Aberrant expression of circular RNAs (circRNAs) has been revealed to have crucial roles in the pathological processes of cardiovascular disease. Here, this study aimed to investigate the role and mechanism of circ_0001379 in hypoxia/reoxygenation (H/R)-induced cardiomyocyte injury to explore the potential action of circ_0001379 in acute myocardial infarction (AMI). Methods: Levels of genes and proteins were examined by quantitative real-time polymerase chain reaction and western blot. Cell counting kit-8 assay, 5-ethynyl-2'-deoxyuridine assay, and flow cytometry were used to detect cardiomyocyte proliferation and apoptosis, respectively. The activity of IL-1ß, IL-6, and TNF-α was determined by ELISA analysis. The target relationship between miR-98-5p and circ_0001379 or SOX6 (SRY-Box Transcription Factor 6) was verified by dual-luciferase reporter and RNA immunoprecipitation assays. Results: Circ_0001379 was highly expressed in AMI mouse model and H/R-induced cardiomyocytes. Functionally, circ_0001379 silencing attenuated H/R-evoked cardiomyocyte apoptosis and inflammatory response. Mechanistically, circ_0001379 functioned as a sponge for miR-98-5p, which directly targeted SOX6. Moreover, circ_0001379 could regulate SOX6 expression via sponging miR-98-5p. Further rescue experiments showed that inhibition of miR-98-5p reversed the protective effects of circ_0001379 silencing on H/R-induced cardiomyocytes. Besides that, miR-98-5p overexpression abolished H/R-evoked cardiomyocyte apoptosis and inflammatory response, while this condition was abated by SOX6. Conclusion: Circ_0001379 silencing protects cardiomyocytes from H/R-induced apoptosis and inflammatory response by miR-98-5p/SOX6 axis, suggesting a novel therapeutic strategy for AMI prevention.

Maize PIMT2 repairs damaged 3-METHYLCROTONYL COA CARBOXYLASE in mitochondria, affecting seed vigor.

PROTEIN l-ISOASPARTYL O-METHYLTRANSFERASE (PIMT) affects seed vigor by repairing damaged proteins. While PIMT is capable of isoaspartyl (isoAsp) repair in all proteins, those proteins most susceptible to isoAsp formation have not been well characterized, and the mechanisms by which PIMT affects seed vigor remain largely unknown. Using co-immunoprecipitation and LC-MS/MS, we found that maize (Zea mays) PIMT2 (ZmPIMT2) interacted predominantly with both subunits of maize 3-METHYLCROTONYL COA CARBOXYLASE (ZmMCC). ZmPIMT2 is specifically expressed in the maize embryo. Both mRNA and protein levels of ZmPIMT2 increased during seed maturation and declined during imbibition. Maize seed vigor was decreased in the zmpimt2 mutant line, while overexpression of ZmPIMT2 in maize and Arabidopsis thaliana increased seed vigor upon artificial aging. ZmPIMT2 was localized in the mitochondria, as determined by subcellular localization assays using maize protoplasts. ZmPIMT2 binding to ZmMCCα was confirmed by luciferase complementation tests in both tobacco (Nicotiana benthamiana) leaves and maize protoplasts. Knockdown of ZmMCCα decreased maize seed aging tolerance. Furthermore, overexpression of ZmPIMT2 decreased the accumulation of isoAsp of ZmMCCα protein in seed embryos that underwent accelerated aging treatment. Taken together, our results demonstrate that ZmPIMT2 binds ZmMCCα in mitochondria, repairs isoAsp damage, and positively affects maize seed vigor.

Nomogram for predicting the overall survival and cancer-specific survival of patients with extremity liposarcoma: a population-based study.

BACKGROUND: Extremity liposarcoma represents 25% of extremity soft tissue sarcoma and has a better prognosis than liposarcoma occurring in other anatomic sites. The purpose of this study was to develop two nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with extremity liposarcoma. METHODS: A total of 2170 patients diagnosed with primary extremity liposarcoma between 2004 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to explore the independent prognostic factors and establish two nomograms. The area under the curve (AUC), C-index, calibration curve, decision curve analysis (DCA), Kaplan-Meier analysis, and subgroup analyses were used to evaluate the nomograms. RESULTS: Six variables were identified as independent prognostic factors for both OS and CSS. In the training cohort, the AUCs of the OS nomogram were 0.842, 0.841, and 0.823 for predicting 3-, 5-, and 8-year OS, respectively, while the AUCs of the CSS nomogram were 0.889, 0.884, and 0.859 for predicting 3-, 5-, and 8-year CSS, respectively. Calibration plots and DCA revealed that the nomogram had a satisfactory ability to predict OS and CSS. The above results were also observed in the validation cohort. In addition, the C-indices of both nomograms were significantly higher than those of all independent prognostic factors in both the training and validation cohorts. Stratification of the patients into high- and low-risk groups highlighted the differences in prognosis between the two groups in the training and validation cohorts. CONCLUSION: Age, sex, tumor size, grade, M stage, and surgery status were confirmed as independent prognostic variables for both OS and CSS in extremity liposarcoma patients. Two nomograms based on the above variables were established to provide more accurate individual survival predictions for extremity liposarcoma patients and to help physicians make appropriate clinical decisions.

Short-term outcomes of percutaneous pedicle screw fixation combined with vertebroplasty: A minimally invasive treatment for Kümmell's disease with intravertebral instability.

OBJECTIVE: The aim of this study was to present early clinical and radiological outcomes of percutaneous pedicle screw fixation (PPSF) combined with vertebroplasty (VP) in the treatment of Kümmell's disease with intravertebral instability. METHODS: In this study, 21 consecutive patients (4 male and 17 female; mean age = 75.6 years; age range=65-86 years) who suffered from stage II and III Kümmell's disease with intravertebral instability were prospectively recruited from 2012 to 2016 and treated with PPSF combined with VP. The Cobb angle (CA) or wedge angle (WA) in both flexion and extension positions was measured using lateral radiographs, computed tomography, or magnetic resonance imaging. In addition to these radiological parameters, clinical outcome measures, including the visual analog scale (VAS) and the Oswestry Disability Index (ODI) were collected preoperatively; 1 week and 1, 3, 6, and 12 months postoperatively; and then annually. Complications were also recorded. RESULTS: The mean follow-up was 19.3 (range=12-36) months. The mean operating time was 135.4 (range, 110-175) min, and the mean estimated blood loss was 106.9 (range, 50-165) mL. The mean VAS score and ODI significantly decreased from 7.7±1.1 and 65.3%±7.7% preoperatively to 3.4±0.6 and 30.0%±7.6% postoperatively, respectively (p<0.05). At the final follow-up, the mean VAS score and ODI were 2.5±0.8 and 21.5%±8.8%, respectively (p>0.05). CA and WA significantly decreased from 26.9°±9.7° and 21.3°±6.0° preoperatively to 12.7°±7.2° to 8.6°±4.5° postoperatively, respectively (p<0.05). At the final follow-up, CA was 4.2°±2.0°, and WA was 4.7°±1.8° (p>0.05). No major complications were encountered during the follow-up period. CONCLUSION: PPSF combined with VP seems to be an effective surgical option for the treatment of Kümmell's disease with intravertebral instability. LEVEL OF EVIDENCE: Level IV, Therapeutic study.

Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF-κB signaling pathway.

Current pharmacological intervention for the treatment of osteolytic bone diseases such as osteoporosis focuses on the prevention of excessive osteoclastic bone resorption but does not enhance osteoblast-mediated bone formation. In our study, we have shown that 4-iodo-6-phenylpyrimidine (4-IPP), an irreversible inhibitor of macrophage migration inhibitory factor (MIF), can inhibit receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis and potentiate osteoblast-mediated mineralization and bone nodule formation in vitro. Mechanistically, 4-IPP inhibited RANKL-induced p65 phosphorylation and nuclear translocation by preventing the interaction of MIF with thioredoxin-interacting protein-p65 complexes. This led to the suppression of late osteoclast marker genes such as nuclear factor of activated T cells cytoplasmic 1, resulting in impaired osteoclast formation. In contrast, 4-IPP potentiated osteoblast differentiation and mineralization also through the inhibition of the p65/NF-κB signaling cascade. In the murine model of pathologic osteolysis induced by titanium particles, 4-IPP protected against calvarial bone destruction. Similarly, in the murine model of ovariectomy-induced osteoporosis, 4-IPP treatment ameliorated the bone loss associated with estrogen deficiency by reducing osteoclastic activities and enhancing osteoblastic bone formation. Collectively, these findings provide evidence for the pharmacological targeting of MIF for the treatment of osteolytic bone disorders.-Zheng, L., Gao, J., Jin, K., Chen, Z., Yu, W., Zhu, K., Huang, W., Liu, F., Mei, L., Lou, C., He, D. Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP suppresses osteoclast formation and promotes osteoblast differentiation through the inhibition of the NF-κB signaling pathway.

Cement Distribution Patterns Are Associated with Recompression in Cemented Vertebrae After Percutaneous Vertebroplasty: A Retrospective Study.

OBJECTIVE: To reevaluate the cement distribution patterns and further investigate associations between cement distribution patterns and the occurrence rates of recompression in cemented vertebrae after percutaneous vertebroplasty (PVP) for osteoporotic vertebral compression fractures. METHODS: Two hundred twenty-four patients with a mean age of 71.9 years were enrolled and treated with single-level PVP between June 2012 and July 2015. The mean follow-up time was 16.5 months. Data from medical records and radiographs were collected and analyzed. Cement distribution patterns were divided into 4 cement distribution patterns extending from the traditional 2 patterns: interlocked solid pattern (LS) and uninterlocked solid pattern (ULS); contiguous trabecular pattern (CT) and discontiguous trabecular pattern (DCT). Differences in treatment efficacy and the occurrence rates of recompression in cemented vertebrae were compared for both groups using the Wilcoxon rank sum test and chi-squared test. RESULTS: Thirty-seven patients who underwent PVP developed recompression in cemented vertebrae. Recompression in cemented vertebrae was significantly more frequent in the ULS and DCT groups than in the LS and CT groups (P < 0.05 or 0.001), with the Visual Analogue Scale score at the time of final follow-up was also significantly higher in the ULS and DCT groups (P < 0.001). CONCLUSIONS: Significant associations were found between cement distribution patterns and recompression in cemented vertebrae, which affected the clinical outcome in patients after PVP. A higher incidence of recompression in cemented vertebrae was seen in patients with treated vertebrae exhibiting ULS pattern or DCT pattern.

Anterior reconstruction versus posterior osteotomy in treating Kümmell's disease with neurological deficits: A systematic review.

OBJECTIVE: This study aimed to conduct a systematic review of literature comparing the clinical effectiveness and safety between anterior reconstruction (AR) and posterior osteotomy (PO) in the treatment of Kümmell's disease with neurological deficits. METHODS: We systematically reviewed the literature in PubMed, EMBASE, Cochrane Database of Systematic Reviews, and the Web of Science for "spin*," "surg*," "Kümmell's disease," "Kummell's disease," "Kummell disease," "vertebral osteonecrosis," "vertebral pseudarthrosis," "intravertebral vacuum cleft," "delayed vertebral collapse," and "compression fracture nonunion". Quality was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation method. RESULTS: A total of 10 publications involving 268 Kümmell's disease patients with neurological deficits were included in this review, with 7 studies of low- or very low-quality. There were 37.7% and 62.3% of patients receiving AR and PO, respectively. For clinical outcomes, AR group showed no significant differences in pain, neurological dysfunction, and imaging outcome improvements compared with patients who underwent PO. However, the incidence of implant-related complications including loose screw, screw fracture, screw disconnection, and plate dislodgment, was higher in AR group compared with PO group (21.6% vs. 14.3%). As another major complication, AR group more often required a second surgery. CONCLUSION: This systematic review demonstrated that both AR and PO could improve pain, neurological dysfunction and imaging outcomes. However, serious comorbidities, multilevel corpectomies and/or severe osteoporosis highly required PO. Design discrepancies were found in the current studies, further higher-quality studies are warranted. LEVEL OF EVIDENCE: Level III, therapeutic study.

Association between menopause and lumbar disc degeneration: an MRI study of 1,566 women and 1,382 men.

OBJECTIVE: The aim of this study was to revisit and further investigate the association between menopause and disc degeneration in the lumbar spine using a magnetic resonance imaging-based eight-level grading system. METHODS: This study cohort comprised of 1,566 women and 1,382 age-matched men who were admitted for low back pain from June 2013 to October 2016. Data on age, weight, height, body mass index, age at natural menopause, and years since menopause (YSM) were obtained. Lumbar disc degeneration was assessed using a magnetic resonance imaging-based eight-level grading system. RESULTS: After adjustment for the confounding factors of age, height, and weight, young age-matched men were more susceptible to disc degeneration than premenopausal women (P < 0.05). However, after menopause, postmenopausal women had a significant tendency to develop more severe disc degeneration than their age-matched men (P < 0.05), and also compared with premenopausal and perimenopausal women (P < 0.01). Postmenopausal women were divided into nine subgroups by every 5 YSM. When YSM was less than 15 years, a positive trend was observed between YSM and severity of disc degeneration, respectively, at L1/L2 (r = 0.241), L2/L3 (r = 0.193), L3/L4 (r = 0.191), L4/L5 (r = 0.165), L5/S1 (r = 0.153), and all lumbar discs (r = 0.237) (P < 0.05 or 0.01). The analysis of covariance indicated a significant difference in each disc level (P < 0.05 or 0.01) between every two groups. When YSM was more than 15 years, the significant difference, however, disappeared in each disc level (P > 0.05). CONCLUSIONS: Menopause is associated with lumbar disc degeneration. The association occurred in the first 15 YSM, suggesting estrogen deficiency might be a risk factor of disc degeneration of the lumbar spine. Further studies need to be carried out for deciding whether age or menopause plays a more important role in the progression of disc degeneration in the lumbar spine.

Internal fixation with percutaneous kyphoplasty compared with simple percutaneous kyphoplasty for thoracolumbar burst fractures in elderly patients: a prospective randomized controlled trial.

PURPOSE: The impact of percutaneous internal fixation as a supplement to percutaneous kyphoplasty (PKP) for the management of thoracolumbar burst fractures in elderly patients is unclear. We conducted a clinical controlled trial to investigate the effect and outcomes of this technique in such patients. METHODS: Forty-three patients over 65 years old with thoracolumbar burst fractures without nerve injuries were enrolled. They were randomly assigned to treatment with simple PKP (control group, n = 22) or percutaneous short-segment pedicle screw internal fixation with PKP (treatment group, n = 21). The patients were followed for at least 2 years postoperatively and were assessed with regard to clinical and radiological outcomes. Clinical outcomes were evaluated mainly with use of visual analog scale (VAS) for pain and the Oswestry Disability Index (ODI) questionnaire. Radiological outcomes were assessed mainly on the basis of Cobb kyphosis angle and loss of kyphosis correction. RESULTS: There were no significant differences between the two groups with regard to preoperative indices. The treatment group had better VAS scores and greater postoperative improvement on the ODI compared with the control group (P < 0.05). Postoperative kyphosis angle correction in the treatment group was superior to that in the control group, and loss of correction postoperatively was significantly less (P < 0.05). In the control group, two patients suffered refractures of the injured vertebra postoperatively and one had a fracture in the adjacent vertebra. No postoperative complications needing management were noted in either group. CONCLUSIONS: Compared with simple PKP, percutaneous internal fixation with PKP is a valuable surgical option for the treatment of selected elderly patients with thoracolumbar burst fractures.

Efficacy of infliximab in a rabbit model of osteoarthritis.

The purpose of this study was to investigate the efficacy of intra-articular injection of infliximab in a rabbit model of osteoarthritis. In 30 New Zealand white rabbits, the cruciate ligaments and medial menisci were resected using the Hulth technique. Eight weeks postsurgery, the animals were randomly divided into three groups, and each group was given monthly intra-articular injections (0.5 ml) of 10 mg/ml infliximab, 20 mg/ml infliximab, or saline, respectively. After 3 months, the results were assessed by macroscopic observation, histological evaluation, and measurement of the levels of interleukin-1ß, tumor necrosis factor-α, and nitric oxide in the synovial fluid. In the two groups of rabbits administered infliximab (10 or 20 mg/ml), the pathological changes were more attenuated than in the group administered saline. Mankin scores in the rabbits administered infliximab 10 mg/ml (2.7 ± 0.9) or infliximab 20 mg/ml (2.4 ± 0.7) were significantly lower than in the control group (6.4 ± 1.2) (p <0.05). The tumor necrosis factor-α and nitric oxide contents of the synovial fluid were also decreased significantly in the rabbits administered infliximab at both concentrations compared with the saline-injected rabbits (p <0.05). Administration of infliximab did not change the levels of interleukin-1ß in the synovial fluid. Similar results were obtained for all analyses with the two concentrations of infliximab tested. This study demonstrates that intra-articular injections of infliximab can protect against the development of experimentally induced osteoarthritis.