UBC9-mediated SUMOylation of Lamin B1 enhances DNA-damage-induced nuclear DNA leakage and autophagy after spinal cord injury.

Recent studies have shown that nucleophagy can mitigate DNA damage by selectively degrading nuclear components protruding from the nucleus. However, little is known about the role of nucleophagy in neurons after spinal cord injury (SCI). Western blot analysis and immunofluorescence were performed to evaluate the nucleophagy after nuclear DNA damage and leakage in SCI neurons in vivo and NSC34 expression in primary neurons cultured with oxygen-glucose deprivation (OGD) in vitro, as well as the interaction and colocalization of autophagy protein LC3 with nuclear lamina protein Lamin B1. The effect of UBC9, a Small ubiquitin-related modifier (SUMO) E2 ligase, on Lamin B1 SUMOylation and nucleophagy was examined by siRNA transfection or 2-D08 (a small-molecule inhibitor of UBC9), immunoprecipitation, and immunofluorescence. In SCI and OGD injured NSC34 or primary cultured neurons, neuronal nuclear DNA damage induced the SUMOylation of Lamin B1, which was required by the nuclear Lamina accumulation of UBC9. Furthermore, LC3/Atg8, an autophagy-related protein, directly bound to SUMOylated Lamin B1, and delivered Lamin B1 to the lysosome. Knockdown or suppression of UBC9 with siRNA or 2-D08 inhibited SUMOylation of Lamin B1 and subsequent nucleophagy and protected against neuronal death. Upon neuronal DNA damage and leakage after SCI, SUMOylation of Lamin B1 is induced by nuclear Lamina accumulation of UBC9. Furthermore, it promotes LC3-Lamin B1 interaction to trigger nucleophagy that protects against neuronal DNA damage.

Ezrin inhibition alleviates oxidative stress and pyroptosis via regulating TRPML1-calcineurin axis mediated enhancement of autophagy in spinal cord injury.

Spinal cord injury (SCI) presents profound ramifications for patients, leading to diminished motor and sensory capabilities distal to the lesion site. Once SCI occurs, it not only causes great physical and psychological problems for patients but also imposes a heavy economic burden. Ezrin is involved in various cellular processes, including signal transduction, cell death, inflammation, chemotherapy resistance and the stress response. However, whether Ezrin regulates functional repair after SCI and its underlying mechanism has not been elucidated. Here, our results showed that there is a marked augmentation of Ezrin levels within neurons and Ezrin inhibition markedly diminished glial scarring and bolstered functional recuperation after SCI. RNA sequencing indicated the potential involvement of pyroptosis, oxidative stress and autophagy in the enhancement of functional recovery upon reduced Ezrin expression. Moreover, the inhibition of Ezrin expression curtailed pyroptosis and oxidative stress by amplifying autophagy. Our studies further demonstrated that Ezrin inhibition promoted autophagy by increasing TFEB activity via the Akt-TRPML1-calcineurin pathway. Finally, we concluded that inhibiting Ezrin expression alleviates pyroptosis and oxidative stress by enhancing TFEB-driven autophagy, thereby promoting functional recovery after SCI, which may be a promising therapeutic target for SCI treatment.

Frequency and Type of Ponticulus Posticus and Lateralis in a Chinese Population: A CT-Based Analysis of 4047 Cases.

AIM: To investigate the prevalence and type of ponticulus posticus (PP) and ponticulus lateralis (PL) in the Chinese population by analyzing computed tomography (CT) scans, and to uncover the pathogenesis of PP and PL. MATERIAL AND METHODS: A total of 4,047 cases were included in this study. We evaluated cervical spine CT scans with three dimensional reconstructions and collected age, gender, and presence of PP and PL in each case. If either or both were present, location and type were recorded. RESULTS: The overall prevalence of PP was 8.01%. The age of patients with PP was significantly higher than those without. Men had a higher prevalence of PP than women. The presence of PP was more common on the left side than the right. According to our previous classification, the most common type of a PP was AC (32.41%), followed by CC (20.06%) and CA (16.98%). The overall prevalence of PL was 4.67%, with no differences between age groups, genders or by location. The most common type of PL was AC (43.92%), followed by CA (35.98%) and CC (20.11%). The prevalence of PP and PL occurring in the same patient was 1.26%. CONCLUSION: Based on cervical spine CT scans of 4,047 Chinese patients, we found that the prevalence of PP and PL were 8.01% and 4.67%, respectively. PP was more common in older patients, which strongly suggests that PP may be a congenital osseous anomaly of the atlas that mineralizes during aging.

Forest gaps regulate seed germination rate and radicle growth of an endangered plant species in a subtropical natural forest.

The survival rate of Castanopsis kawakamii from seed to seedling is relatively low, leading to difficulties in the regeneration of its natural forests. Forest gaps play a vital role in plant regeneration and biodiversity maintenance in forest ecosystems. Unfortunately, our understanding of the effects of gap size and within-gap position on the seed germination and radicle growth of C. kawakamii is still limited. In particular, our knowledge on the relationship between gap size and environmental factors and their influence on seed germination and radicle growth is incomplete. In the present study, we studied the influences of forest gaps and within-gap position on seed regeneration on the germination and radicle growth of an endangered species C. kawakamii in a subtropical natural forest in China. We selected three large gaps (LG, gap size above 200 m2), three medium gaps (MG, gap size 50-100 m2), three small gaps (SG, gap size 30-50 m2), and non-gap (NG), and planted the seeds of C. kawakamii in five positions within each gap. The results showed that (1) the influence of forest gaps on seed germination rate was, from highest to lowest, medium gaps (51%), non-gap (47%), small gaps (40%) and large gaps (17%), and the seed germination rate was the highest in all positions in medium gaps, with the exception of the east position. (2) Radicle length in forest gaps was, from highest to lowest, medium gaps, small gaps, large gaps and non-gap, and it was the highest in the east, south, west and north positions of medium gaps. (3) Canopy openness (gap size) and air temperature were the main factors influencing seed germination and radicle growth of C. kawakamii. We concluded that medium-sized gaps were the most suitable for seed germination and radicle growth of C. kawakamii, and they promote the regeneration of this endangered species in the investigated natural forest.

Clinical and Radiologic Outcomes of Robot-Assisted Kyphoplasty versus Fluoroscopy-Assisted Kyphoplasty in the Treatment of Osteoporotic Vertebral Compression Fractures: A Retrospective Comparative Study.

BACKGROUND: Making surgery as less aggressive as possible is best for elderly patients with osteoporotic vertebral compression fractures (OVCFs). Recently, we attempted a more precise, minimally invasive, and robot-assisted kyphoplasty in our clinical setting. OBJECTIVE: We sought to compare the clinical and radiologic outcomes of robot-assisted percutaneous kyphoplasty (rPKP) with those of fluoroscopy-assisted percutaneous kyphoplasty (fPKP) in treating OVCFs. METHODS: We retrospectively reviewed the clinical and radiologic data of patients with single-segment OVCF who received either rPKP or fPKP between January 2020 and December 2020 at our institution. The operation time, injected volume of cement, length of hospital stays, visual analog scale for back pain, Oswestry Disability Index, local kyphosis angle (LKA), height of fractured vertebra (HFV), and perioperative complications were compared between the 2 groups. RESULTS: A total of 212 cases were included in this study, among whom 81 cases received rPKP and 131 cases received fPKP. Both techniques exhibited satisfying improvement in pain relief and radiologic outcomes. Specifically, the rPKP costed less operation time and achieved better correction and maintenance regarding LKA, HFV, and instant pain relief (P < 0.05). The length of hospital stays, incidence of cement leakage, visual analog scale for back pain, and Oswestry Disability Index at final follow-up were comparable between 2 groups. CONCLUSIONS: rPKP provides a precise puncture and exhibits superiority in the correction and maintenance of LKA and HFV when compared with traditional fPKP. The cost-effectiveness and specific application scenarios of this technique shall be confirmed via further extensive studies.

Identification and comparison of novel circular RNAs with associated co-expression and competing endogenous RNA networks in postmenopausal osteoporosis.

BACKGROUND: Circular RNAs (circRNAs) are emerging as crucial regulators in various human diseases. So far, the expression profile and regulatory mechanism of circRNAs in postmenopausal osteoporosis (PMOP) are less studied and should be deciphered urgently. Herein, we aimed to reveal key circRNAs affecting PMOP and clarify their compounding regulatory actions. METHODS: To reveal key circRNAs affecting PMOP and clarify their compounding regulatory actions, whole transcriptome sequencing and bioinformatics analysis were performed to identify differentially expressed circRNAs (DECs). The expression pattern and regulatory networks of DECs in peripheral blood mononuclear cells (PBMCs) were unearthed. RESULTS: A total of 373 DECs comprising 123 intronic, 100 antisense, 70 exonic, 55 intergenic, and 25 sense-overlapping circRNAs were identified. Among these, 73 circRNAs were upregulated and 300 were downregulated. These DECs exerted pivotal functions in the pathogenesis of PMOP as demonstrated by Gene Ontology (GO) annotation and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. The circRNA-miRNA-mRNA co-expression network comprising 28 DECs, 145 miRNAs, and 175 differentially expressed mRNAs predicted the possible mechanism of the pathogenesis and progression of PMOP. CONCLUSION: The results of the present study provided a further comprehension of circRNA-associated competing endogenous RNA regulatory mechanism in PMOP. The steadily expressed and disease-specific DECs may serve as promising diagnostic and prognostic biomarkers for PMOP.

Identification and Validation of the Prognostic Stemness Biomarkers in Bladder Cancer Bone Metastasis.

BACKGROUND: Bladder urothelial carcinoma (BLCA) is one of the most common urinary system malignancies with a high metastasis rate. Cancer stem cells (CSCs) play an important role in the occurrence and progression of BLCA, however, its roles in bone metastasis and the prognostic stemness biomarkers have not been identified in BLCA. METHOD: In order to identify the roles of CSC in the tumorigenesis, bone metastasis and prognosis of BLCA, the RNA sequencing data of patients with BLCA were retrieved from The Cancer Genome Atlas (TCGA) databases. The mRNA expression-based stemness index (mRNAsi) and the differential expressed genes (DEGs) were evaluated and identified. The associations between mRNAsi and the tumorigenesis, bone metastasis, clinical stage and overall survival (OS) were also established. The key prognostic stemness-related genes (PSRGs) were screened by Lasso regression, and based on them, the predict model was constructed. Its accuracy was tested by the area under the curve (AUC) of the receiver operator characteristic (ROC) curve and the risk score. Additionally, in order to explore the key regulatory network, the relationship among differentially expressing TFs, PSRGs, and absolute quantification of 50 hallmarks of cancer were also identified by Pearson correlation analysis. To verify the identified key TFs and PSRGs, their expression levels were identified by our clinical samples via immunohistochemistry (IHC). RESULTS: A total of 8,647 DEGs were identified between 411 primary BLCAs and 19 normal solid tissue samples. According to the clinical stage, mRNAsi and bone metastasis of BLCA, 2,383 stage-related DEGs, 3,680 stemness-related DEGs and 716 bone metastasis-associated DEGs were uncovered, respectively. Additionally, compared with normal tissue, mRNAsi was significantly upregulated in the primary BLCA and also associated with the prognosis (P = 0.016), bone metastasis (P < 0.001) and AJCC clinical stage (P < 0.001) of BLCA patients. A total of 20 PSRGs were further screened by Lasso regression, and based on them, we constructed the predict model with a relatively high accuracy (AUC: 0.699). Moreover, we found two key TFs (EPO, ARID3A), four key PRSGs (CACNA1E, LINC01356, CGA and SSX3) and five key hallmarks of cancer gene sets (DNA repair, myc targets, E2F targets, mTORC1 signaling and unfolded protein response) in the regulatory network. The tissue microarray of BLCA and BLCA bone metastasis also revealed high expression of the key TFs (EPO, ARID3A) and PRSGs (SSX3) in BLCA. CONCLUSION: Our study identifies mRNAsi as a reliable index in predicting the tumorigenesis, bone metastasis and prognosis of patients with BLCA and provides a well-applied model for predicting the OS for patients with BLCA based on 20 PSRGs. Besides, we also identified the regulatory network between key PSRGs and cancer gene sets in mediating the BLCA bone metastasis.

Does Robot Navigation and Intraoperative Computed Tomography Guidance Help with Percutaneous Endoscopic Lumbar Discectomy? A Match-Paired Study.

OBJECTIVE: To evaluate the efficacy and safety of robot-assisted percutaneous endoscopic lumbar discectomy (rPELD) using a specially designed orthopaedic robot with an intraoperative computed tomography-equipped suite for treatment of symptomatic lumbar disc herniation and compare rPELD with fluoroscopy-assisted percutaneous endoscopic lumbar discectomy (fPELD). METHODS: We retrospectively reviewed and compared demographic data, radiologic workups, and patient-reported outcomes of 39 patients treated with rPELD and 78 patients treated with fPELD at our institution between January 2019 and December 2019. RESULTS: Our data showed that a single-shot puncture in the rPELD group was significantly more precise compared with 4.12 ± 1.71 trials in the fPELD group (P < 0.001). There was an overall reduction of fluoroscopy (21.33 ± 3.89 times vs. 33.06 ± 2.92 times, P < 0.001), puncture-channel time (13.34 ± 3.03 minutes vs. 15.03 ± 4.5 minutes, P = 0.038), and total operative time (57.46 ± 7.49 minutes vs. 69.40 ± 12.59 minutes, P < 0.001) using the rPELD technique versus the fPELD technique. However, there were no significant differences in patient-reported outcomes, length of hospital stay, and complication rate between the 2 groups (P > 0.05). CONCLUSIONS: Taken together, our data indicate that rPELD provides a precise skin entry point and optimal trajectory for puncture, which increases the success rate of PELD, negating the need for revision surgery. However, further studies are required to confirm the superiority and application of the rPELD technique.

The 100 Most-Cited Publications in Endoscopic Spine Surgery Research.

STUDY DESIGN: A bibliometric review of the literature. OBJECTIVE: Our objective was to identify and analyze the 100 most-cited publications in the field of endoscopic spine surgery (ESS). METHODS: In order to determine the top cited 100 articles, a 3-step approach was employed. First, the 100 most-cited ESS studies were identified using the key phrase "endoscopic spine surgery." Then, 8 keywords were identified from the 100 studies of step 1 were used to conduct a second round searching in all databases of the Web of Science. Finally, when the results of the first and second steps were overlapped, duplicated studies were removed. The 100 top-cited articles were used for further analysis. RESULTS: The citation number of the top 100 most-cited articles ranged from 44 to 236 with a mean value of 84.4. The most productive periods were from 2001 to 2010. The majority of publications came from Spine and Neurosurgery, where Spine holds the largest number of 35 articles, followed by Neurosurgery with 13 articles. Overall, 10 countries contributed to the 100 articles, with the most productive country being the United States, followed by Germany and Korea. CONCLUSION: This bibliometric study is meant to produce a list of intellectual milestones in the field of ESS. This article's identification of the most influential articles in the field of ESS gives us a unique and comprehensive insight into the development of ESS in the past several decades.

Minimally invasive surgery for low-grade spondylolisthesis: percutaneous endoscopic or oblique lumbar interbody fusion.

Aim: To compare the clinical and radiographic outcomes of percutaneous endoscopic-assisted lumbar interbody fusion (PELIF) versus oblique lumbar interbody fusion (OLIF) for the treatment of symptomatic low-grade lumbar spondylolisthesis. Material & methods: The clinical and radiographic records of 48 patients underwent single-level minimally invasive lumbar fusion with a PELIF (n = 16) or OLIF (n = 32) were reviewed. Results: The clinical and radiographic outcomes were similar in both groups. PELIF procedure exhibited superior capability of the enlargement of foraminal width, but inferior capability of the restoration of foraminal height than OLIF procedure. Conclusion: PELIF minimizes the iatrogenic damages and perioperative risks to a great extent, and seems to be a promising option for the treatment of symptomatic low-grade lumbar spondylolisthesis.

Percutaneous endoscopic-assisted direct repair of pars defect without general anesthesia could be a satisfying treatment alternative for young patient with symptomatic lumbar spondylolysis: a technique note with case series.

BACKGROUND: Multiple surgical procedures are applied in young patients with symptomatic lumbar spondylolysis when conservative treatments fail. Although the optimal surgical procedure option is controversial, the treatment paradigm has shifted from open surgery to minimally invasive spine surgery. To date, a limited number of studies on the feasibility of percutaneous endoscopic-assisted direct repair of pars defect have been carried out. Herein, for the first time, we retrospectively explore the outcomes of pars defect via percutaneous endoscopy. METHODS: We retrospectively examined young patients with spondylolysis treated using the percutaneous endoscopic-assisted direct repair of pars defect supplemented with autograft as well as percutaneous pedicle screw fixation between September 2014 and December 2018. Six patients with a mean age of 18.8 years were enrolled in the study. We used preoperatively computed tomographic (CT) scans to evaluate the size of pars defect, and graded disc degeneration using Pfirrmann's classification through magnetic resonance images (MRI). We assessed the clinical outcomes using the Oswestry Disability Index (ODI), 36-Item Short-Form Health Survey (SF-36) as well as Visual Analogue Scale for back pain (VAS-B). RESULTS: Our findings revealed that pain intensity and function outcomes, including VAS-B, ODI, and SF-36 (PCS and MCS) scores, were markedly improved after surgery and at the final follow-up visit. The change in the gap distance of the pars defect was remarkably significant after surgery and during the follow-up period. Only one of the 12 pars repaired was reported as a non-union at the final follow-up visit. Moreover, no surgery-related complications were reported in any of the cases. CONCLUSION: Percutaneous endoscopic-assisted direct repair of pars defect without general anesthesia, a minimally invasive treatment option, supplemented with autograft and percutaneous pedicle screw fixation, could be a satisfying treatment alternative for young patients with symptomatic lumbar spondylolysis.

Percutaneous Transforaminal Endoscopic Lumbar Interbody Fusion for Degenerative Lumbar Diseases: A Consecutive Case Series with Mean 2-Year Follow-Up.

BACKGROUND: Conventional open surgical procedures may cause massive dissections of the spine, higher perioperative complications, prolonged hospitalization, protracted rehabilitation programs and recovery. Percutaneous endoscopic lumbar interbody fusion (PELIF) is an evolving treatment option. OBJECTIVES: To present the detailed procedure and preliminary clinical and radiologic results of PELIF for degenerative lumbar diseases. STUDY DESIGN: A retrospective cohort study. SETTING: A university affiliated tertiary hospital. METHODS: The medical records of patients with degenerative lumbar diseases who underwent PELIF between January 2016 and December 2017 were retrospectively reviewed. Surgical level, surgical time, blood loss, hospital length of stay, and perioperative complications were discussed. Patients were also evaluated for pain by the Visual Analog Scale (VAS), and functional assessment by the Oswestry Disability Index (ODI) and the 36-Item Short Form Health Survey (SF-36), including Physical Component Summary (PCS) and Mental Component Summary (MCS) preoperatively, postoperatively, and during the follow-up period. RESULTS: Thirty-nine consecutive patients (25 men and 14 women) with a mean age of 59.0 years (range, 39-77 years) were enrolled. The average surgical time was 213.8 ± 31.7 minutes (range, 185-324 minutes). Mean estimated blood loss was 25.0 ± 12.6 mL (range, 15-50 mL). At the latest follow-up visit, the VAS scores for back pain, leg pain, ODI, and SF-36 (MCS/PCS) scores improved 89.5%, 95.0%, 71.2%, and 37.5%/58%, respectively. Reoperations were performed in one patient for residual disc mass and one for misplacement of pedicle screw. Fusion was achieved in all patients. LIMITATIONS: The presented results are preliminary and should be interpreted taking the limitations into account, including nonrandomized design, relatively small sample size, and less intensive follow-up period. CONCLUSIONS: The presented PELIF technique seems to be a promising surgical alternative for the treatment of patients with specific degenerative lumbar diseases. Randomized studies with larger sample size and long-term follow-up duration are needed to validate the superiorities of this versatile surgery. KEY WORDS: Endoscopic, minimally invasive spine surgery, lumbar interbody fusion, disc herniation, spondylolisthesis.

The Top 100 Most-Cited Articles on Kyphoplasty and Vertebroplasty.

INTRODUCTION: Over the last several decades, both percutaneous kyphoplasty (PKP) and percutaneous vertebroplasty (PVP) have been used for pain relief in patients with osteoporotic vertebral compression fractures. The purpose of our study was to use citation analysis to identify and review the top 100 most-cited publications regarding PKP and PVP. METHODS: All databases of the Web of Science were searched using the keywords "kyphoplasty" and "vertebroplasty." All publications with >100 citations were identified and the results were ranked in descending order of citations. The 100 most-cited publications were included for analysis. RESULTS: A total of 6271 publications on PKP and PVP were identified. The number of citations of the 100 most-cited studies ranged from 735 to 109, with a mean of 225.3 citations per study. The most productive period was 2001-2010, which produced 79 of the top 100 publications. Thirteen journals published these 100 studies, with Spine publishing the largest number (23) of studies. Most of the identified articles originated in the United States, with France and Switzerland found to be the next most heavily represented countries of origin of the 11 countries that produced them. Most of the studies focused on treatment of osteoporotic vertebral compression fractures, followed by pathologic fractures caused by tumors. CONCLUSIONS: We identified the 100 most-cited publications on PKP and PVP and performed a bibliometric analysis characterizing distinguishing features of these studies. This list can help guide clinical decision making and future research directions as clinicians and researchers continue to explore these controversial therapeutic techniques.

[Clinical application of percutaneous transforaminal endoscope-assisted lumbar interbody fusion].

OBJECTIVE: To conclude of the technical notes of percutaneous transforaminal endoscope-assisted lumbar interbody fusion (PT-Endo-LIF), and to investigate its safety and efficacy for treatment of degenerative lumbar disease. METHODS: Twenty-four patients were treated by PT-Endo-LIF combined with posterior percutaneous pedicle screws fixation from October 2017 to April 2018. There were 16 males and 8 females, ranging in age from 39 to 72 years old, with a mean of (59.6±9.5) years old. There were 15 cases diagnosed with lumbar intervertebral disc herniation combined with degenerative disc, the other 9 cases were diagnosed as low level lumbar spondylolistheses w/o segmental instability. Single segmental fusion was performed for 22 cases(one for L2,3, 3 for L3,4 and 18 for L4,5) and 2 segmental fusion was performed for the other 2 cases (both for L3,4 and L4,5). PT-Endo-LIF was performed under local anesthesia with conscious sedation, followed by decompression through endoscopic technics. After that, end-plate preparation and autogenous bone and expandable cage implantation were performed. Finally, percutaneous screws and rod instrumentation were used. The visual analogue scale (VAS) and Oswestry Disability Index (ODI) were used to evaluate the clinical efficacy. The operation time, intraoperative bleeding volume, intraoperative and postoperative complications were recorded. All patients underwent X-ray, CT plain scan, three-dimensional reconstruction and MRI examination to evaluate the stability of the implants and fusion rate before 3 days and 1, 3, 6, 12 and 18 months after operation. RESULTS: All patients were followed up, and the duration ranged from 12 to 18 months. The operation time of single-segment fusion was (192.3±22.7) min, and that of double-segment fusion was (272.5±24.7) min. The estimated intraoperative bleeding volume was less than 50 ml per segment, and no blood transfusion was performed in all patients. The VAS improved from preoperative 7.4±1.1 to postoperative 2.3±0.8 (t=-19.65, P<0.000 5). The ODI improved from preoperative (41.2±3.3)% to the final follow-up (12.3±2.5)%(t=-35.76, P<0.000 5). Postoperative complications occurred in 4 cases, and contralateral radicular symptoms occurred in 2 cases. After contralateral foraminoscopic decompression, the symptoms were completely alleviated. One case had neurological symptoms related to percutaneous screw placement, and the symptoms were alleviated after removal of the lateral screw rod internal fixation. The other cases had surgical incision infection and improved after debridement and suture. At the latest follow-up, no displacement or loosening of the fusion cage and screw rod system occurred in all patients, and 14 cases showed signs of fusion. CONCLUSIONS: PT-Endo-LIF is a minimal invasive, safe and efficient surgical procedure for treatment of degenerative lumbar disease. Nevertheless, the long-term results still need to be confirmed by a multi-center and lagre sample follow-up study.

Cauda Equina Syndrome as First Manifestation of von Hippel-Lindau Disease.

BACKGROUND: Von-Hippel Lindau (VHL) disease is rare neurocutaneous disorder arising from an inactivating mutation of the VHL gene on chromosome 3p35. The disease is inherited in an autosomal dominant fashion and predominantly involves tissues originating from the ectodermal germ layer. Although hemangioblastomas of retina and cerebellum are the most common clinical features, multiple-organ involvement in the form of renal cell carcinomas, spinal hemangioblastomas, renal cysts, and pancreatic cysts have also been reported. Hemangioblastomas of the spinal canal could present as cauda equina syndrome. CASE DESCRIPTION: We describe the case of a 55-year-old man with cauda equina syndrome as his first manifestation. An initial magnetic resonance imaging scan uncovered hemangiomas in the spinal canal. A thorough family history strongly suggested an autosomal dominant pattern of disease inheritance. Further physical examination and imaging revealed additional organ involvement consistent with VHL. We performed laminectomy and partial resection of hemangioblastoma for decompression. He recovered satisfactorily with his cauda equina syndrome resolving quickly post operation. No deterioration was apparent by the 12-month follow-up visit. CONCLUSIONS: To the best of our knowledge, this is the first case with cauda equina syndrome as the first manifestation of VHL disease. Laminectomy and partial resection of hemangioblastoma are safe and effective treatments to resolve impingement of the spinal cord. VHL disease resulting in hemangioblastoma in the spinal canal is rarely seen but should be included in the differential diagnosis of cauda equina syndrome to facilitate genetic counseling for the proband and offspring.

miR-33a Mediates the Anti-Tumor Effect of Lovastatin in Osteosarcoma by Targeting CYR61.

BACKGROUND/AIMS: Preventing cell metastasis is an effective therapeutic strategy to treat osteosarcoma and improve prognosis. Statins have been found to have anticancer effects in addition to their cholesterol-lowering action. As a new target of statins, cysteine-rich 61 (CYR61) was recently identified to promote cell migration and metastasis in osteosarcoma. However, the underlying mechanisms mediating the regulation of CYR61 expression by statins remain unknown. METHODS: Human osteosarcoma cell lines MG63 and SaOS2 were used to clarify the effect of lovastatin on CYR61 expression. Real-time PCR was performed to detect mRNA or microRNA (miRNA) levels and western blot was performed to detect protein levels. Cell invasive ability was determined using Transwell assays. Lentivirus encoding CYR61 cDNA or sterol regulatory element-binding protein 2 (SREBP-2) shRNA was used to upregulate CYR61 expression or downregulate SREBP-2 expression. Binding of the CYR61 3' untranslated region (UTR) and miR-33a was analyzed by luciferase reporter assay. RESULTS: We found that lovastatin treatment decreased CYR61 expression, inhibited cell invasion and altered epithelial-to-mesenchymal-transition (EMT)-related protein expression, while CYR61 overexpression abolished the effect of lovastatin. Moreover, lovastatin increased the expression of SREBP-2 and miR-33a, which were then downregulated by SREBP-2 silencing. Bioinformatics analysis indicated that the CYR61 3'UTR harbored a potential miR-33a binding site and luciferase reporter assay demonstrated that CYR61 was a target of miR-33a in osteosarcoma cells. Furthermore, miR-33a could inhibit cell invasion and alter EMT-related protein expression. SREBP-2 silencing or miR-33a inhibitor upregulated CYR61 expression and reversed the effects of lovastatin on cell invasion and EMT-related proteins. CONCLUSION: Our findings suggest lovastatin suppresses osteosarcoma cell invasion through the SREBP-2/miR-33a/CYR61 pathway.

Erratum to: Transforming Growth Factor b1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression.

[This corrects the article on p. 211 in vol. 40.].

miRNA-340 inhibits osteoclast differentiation via repression of MITF.

Many miRNAs play critical roles in modulating various biological processes of osteoclast differentiation and function. Microphthalmia-associated transcription factor (MITF), a target of miR-340, served as pivotal transcription factor involved in osteoclast differentiation. However, the role of miR-340 and MITF during osteoclast differentiation has not yet been clearly established. Tartrate-resistant acid phosphatase (TRAP) staining assay was performed to identify osteoclasts differentiated from bone marrow-derived macrophages (BMMs). Quantitative reverse transcription PCR (qRT-PCR) or Western blotting was undertaken to examine the mRNA or protein expression respectively. Luciferase reporter assay was performed to investigate the interaction between miR-340 and MITF. MITF was knocked down and miR-340 was overexpressed and transfected into BMMs to detect their effects on osteoclast differentiation. Firstly, qRT-PCR analysis showed that miR-340 was down-regulated during osteoclast differentiation stimulated by macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-κB (RANK) ligand (RANKL). Besides, we found that overexpression of miRNA-340 inhibited osteoclast differentiation and suppressed both the mRNA and protein level of MITF. Finally, Western blot and qRT-PCR analysis revealed that silencing MITF inhibited TRAP, calcitonin receptor, V-ATPase d2, and cathepsin K. miR-340 suppresses osteoclast differentiation by inhibiting MITF. Our findings may provide promising therapeutic targets for osteoclast-associated diseases.

Transforming Growth Factor ß1/Smad4 Signaling Affects Osteoclast Differentiation via Regulation of miR-155 Expression.

Transforming growth factor ß1 (TGFß1)/Smad4 signaling plays a pivotal role in maintenance of the dynamic balance between bone formation and resorption. The microRNA miR-155 has been reported to exert a significant role in the differentiation of macrophage and dendritic cells. The goal of this study was to determine whether miR-155 regulates osteoclast differentiation through TGFß1/Smad4 signaling. Here, we present that TGFß1 elevated miR-155 levels during osteoclast differentiation through the stimulation of M-CSF and RANKL. Additionally, we found that silencing Smad4 attenuated the upregulation of miR-155 induced by TGFß1. The results of luciferase reporter experiments and ChIP assays demonstrated that TGFß1 promoted the binding of Smad4 to the miR-155 promoter at a site located in 454 bp from the transcription start site in vivo, further verifying that miR-155 is a transcriptional target of the TGFß1/Smad4 pathway. Subsequently, TRAP staining and qRT-PCR analysis revealed that silencing Smad4 impaired the TGFß1-mediated inhibition on osteoclast differentiation. Finally, we found that miR-155 may target SOCS1 and MITF to suppress osteoclast differentiation. Taken together, we provide the first evidence that TGFß1/Smad4 signaling affects osteoclast differentiation by regulation of miR-155 expression and the use of miR-155 as a potential therapeutic target for osteoclast-related diseases shows great promise.