Circulating miR-107 as a diagnostic biomarker of osteoporotic vertebral compression fracture increases bone formation in vitro and in vivo.

AIMS: This study aimed to examine the key circulating microRNAs (miRNAs) in the plasma of patients with osteoporotic vertebral compression fracture and assess their potential role as diagnostic biomarkers and explore their function in vitro and in vivo. METHODS: Weighted gene co-expression network analysis (WGCNA) was applied to identify hub miRNAs for subsequent analysis. The candidate miRNAs were tested using plasma from 144 patients and the results were applied to construct receiver operating characteristic (ROC) curves to assess their diagnostic value. In addition, the function of the target miRNA was validated in MC3T3-E1 cells, human bone marrow-derived mesenchymal stromal cells (BMSCs), and an ovariectomized (OVX) mouse model. KEY FINDINGS: Seven modules were obtained by WGCNA analysis. The expression levels of circulating miR-107 in the red module were significantly lower in osteoporotic patients than in healthy controls. In addition, miR-107 provided discrimination with an AUC > 85 % by ROC analyses to differentiate women osteoporosis patients from healthy controls and differentiate women osteoporotic patients with vertebral compression fractures from osteoporotic patients without vertebral compression fractures. In vitro experiments revealed that miR-107 levels were increased in osteogenically induced MC3T3-E1 cells and BMSCs and transfection with synthetic miR-107 could promote bone formation. Lastly, the bone parameters were improved by miR-107 upregulation in OVX mice. SIGNIFICANCE: Our findings show that circulating miR-107 plays an essential role in facilitating osteogenesis and may be a useful diagnostic biomarker and therapeutic target in osteoporosis.

A Pan-Histone Deacetylase Inhibitor Enhances the Antitumor Activity of B7-H3-Specific CAR T Cells in Solid Tumors.

PURPOSE: The limited efficacy of chimeric antigen receptor (CAR) T-cell therapies with solid malignancies prompted us to test whether epigenetic therapy could enhance the antitumor activity of B7-H3.CAR T cells with several solid cancer types. EXPERIMENTAL DESIGN: We evaluated B7-H3 expression in many human solid cancer and normal tissue samples. The efficacy of the combinatorial therapy with B7-H3.CAR T cells and the deacetylase inhibitor SAHA with several solid cancer types and the potential underlying mechanisms were characterized with in vitro and ex vivo experiments. RESULTS: B7-H3 is expressed in most of the human solid tumor samples tested, but exhibits a restricted expression in normal tissues. B7-H3.CAR T cells selectively killed B7-H3 expressing human cancer cell lines in vitro. A low dose of SAHA upregulated B7-H3 expression in several types of solid cancer cells at the transcriptional level and B7-H3.CAR expression on human transgenic T-cell membrane. In contrast, the expression of immunosuppressive molecules, such as CTLA-4 and TET2, by T cells was downregulated upon SAHA treatment. A low dose of SAHA significantly enhanced the antitumor activity of B7-H3.CAR T cells with solid cancers in vitro and ex vivo, including orthotopic patient-derived xenograft and metastatic models treated with autologous CAR T-cell infusions. CONCLUSIONS: Our results show that our novel strategy which combines SAHA and B7-H3.CAR T cells enhances their therapeutic efficacy with solid cancers and justify its translation to a clinical setting.

Long-term Results Comparing Cervical Disc Arthroplasty to Anterior Cervical Discectomy and Fusion: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: Whether cervical disc arthroplasty (CDA) is superior to anterior cervical discectomy and fusion (ACDF) remains controversial, especially in relation to long-term results. The present study aimed to evaluate the long-term safety and efficiency of CDA and ACDF for cervical disc disease. METHODS: We performed this study according to the Cochrane methodology. An extensive search was undertaken in PubMed, Embase, and Cochrane databases up to 1 June 2019 using the following key words: "anterior cervical fusion," "arthroplasty," "replacement" and "artificial disc". RevMan 5.3 (Cochrane, London, UK) was used to analyze data. Safety and efficiency outcome measures included the success rate, functional outcome measures, adverse events (AE), adjacent segment degeneration (ASD), secondary surgery, and patients' satisfaction and recommendation rates. The OR and MD with 95% confidence interval (CI) were used to evaluate discontinuous and continuous variables, respectively. The statistically significant level was set at P < 0.05. RESULTS: A total of 11 randomized controlled trials with 3505 patients (CDA/ACDF: 1913/1592) were included in this meta-analysis. Compared with ACDF, CDA achieved significantly higher overall success (2.10, 95% CI [1.70, 2.59]), neck disability index (NDI) success (1.73, 95% CI [1.37, 2.18]), neurological success (1.65, 95% CI [1.24, 2.20]), patients' satisfaction (2.14, 95% CI [1.50, 3.05]), and patients' recommendation rates (3.23, 95% CI [1.79, 5.80]). Functional outcome measures such as visual analog score neck pain (-5.50, 95% CI [-8.49, -2.52]) and arm pain (-3.78, 95% CI [-7.04, -0.53]), the Short Form-36 physical component score (SF-36 PCS) (1.93, 95% CI [0.53, 3.32]), and the Short Form-36 mental component score (SF-36 MCS) (2.62, 95% CI [0.95, 4.29]), revealed superiority in the CDA group. CDA also achieved a significantly lower rate of symptomatic ASD (0.46, 95% CI [0.34, 0.63]), total secondary surgery (0.50, 95% CI [0.29, 0.87]), secondary surgery at the index level (0.46, 95% CI [0.29, 0.74]), and secondary surgery at the adjacent level (0.37, 95% CI [0.28, 0.49]). However, no significant difference was found in radiological success (1.35, 95% CI [0.88, 2.08]), NDI score (-2.88, 95% CI [-5.93, 0.17]), total reported AE (1.14, 95% CI [0.92, 1.42]), serious AE (0.89, 95% CI [0.71, 1.11]), device/surgery-related AE (0.90, 95% CI [0.68, 1.18]), radiological superior ASD (0.63, 95% CI [0.28, 1.43]), inferior ASD (0.45, 95% CI [0.19, 1.11]), and work status (1.33, 95% CI [0.78, 2.25]). Furthermore, subgroup analysis showed different results between US and non-US groups. CONCLUSION: Our study provided further evidence that compared to ACDF, CDA had a higher long-term clinical success rate and better functional outcome measurements, and resulted in less symptomatic ASD and fewer secondary surgeries. However, worldwide multicenter RCT with long-term follow up are still needed for further evaluation in the future.

Effect of Particle Size Ratios on the Physical and Chemical Properties of Surgical-Grade Calcium Sulfate Hemihydrate.

OBJECTIVES: To analyze the optimum particle size or formula ratio of surgical-grade calcium sulfate (CS) for appropriate compressive strength, setting time, and vitro degradation rate. METHODS: Three types of calcium sulfate hemihydrate (CSH) particles with diameters of 0-37.5 µm, 37.5-75 µm, and >75 µm were screened. Based on formulation ratio of different particles, this topic is divided into 10 groups by the unconstrained third-order simplex lattice mixing design scheme in formula design experiment. The optimum formulation ratio of particle diameter for compressive strength, solidification time, and degradation rate in vitro was analyzed. RESULTS: When the percentage of the particle diameter of CS with 0-37.5 µm, 37.5-75 µm and >75 µm are 55.0%, 17.4%, and 27.6% respectively, the compressive strength of the test sample is the highest, which is 14.16 MPa. When the percentage of the particle diameter of CS with 0-37.5 µm, 37.5-75 µm, and >75 µm are 0.00%, 0.00%, and 100.00% respectively, the initial setting time of the sample is the longest, which is 410.0 s. When the percentage of the particle diameter of CS with 0-37.5 µm, 37.5-75 µm, and >75 µm are 0.00%, 0.00%, and 100.00% respectively, the final setting time of the sample is the largest, and the final setting time of the sample is 460.00 s. When the percentage of the particle diameter of CS with 0-37.5 µm, 37.5-75 µm, and >75 µm are 0.00%, 0.00%, and 100.00% respectively, the degradation rate of the sample in vitro is the slowest, which is 18.8%. CONCLUSION: The morphological structure of surgical-grade CS can affect compressive strength, setting time, and in vitro degradation rate. Surgical CS should be prepared based on different uses.

Effects of Ho:YAG Laser Ablation on Postoperative Low Back Pain and Functional Status After Transforaminal Endoscopic Lumbar Discectomy: Minimum of 2-Year Follow-Up.

OBJECTIVE: To evaluate effects of holmium:yttrium-aluminum-garnet (Ho:YAG) laser ablation on postoperative low back pain and improving functional status in patients with lumbar disc herniation undergoing transforaminal endoscopic lumbar discectomy (TELD). METHODS: The study enrolled 220 patients with lumbar disc herniation who underwent TELD or TELD with Ho:YAG laser from August 2015 to September 2016. Parameters including operative time, hospitalization, complications, and recurrence were recorded. Clinical outcomes were assessed according to visual analog scale for back pain and leg pain, Oswestry Disability Index for functional status, and modified MacNab criteria for patient satisfaction. RESULTS: Minimal 2-year follow-up was completed by 186 patients: 76 patients who underwent TELD and 110 patients who underwent TELD with Ho:YAG laser. In the group undergoing TELD, clinical outcomes of back pain and functional status exhibited a V-shaped upward trend after surgery; there were no statistically significant differences in visual analog scale for back pain and Oswestry Disability Index scores at final follow-up compared with preoperatively (P > 0.05). In the group undergoing TELD with Ho:YAG laser, postoperative visual analog scale for back pain and Oswestry Disability Index scores significantly improved compared with preoperatively (P < 0.05) exhibiting relatively consistent improvement after surgery. The only laser-related complication was a burning sensation in the ipsilateral lower limb during the thermal procedure in 2 cases. CONCLUSIONS: Performing Ho:YAG laser ablation with TELD prolonged low back pain relief and improved functional outcome during 2-year follow-up compared with TELD alone in patients with symptomatic lumbar disc herniation.

Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing.

PURPOSE: The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing-related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC). EXPERIMENTAL DESIGN: LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL. RESULTS: We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR-483-5p. In exploring the underlying interaction between MPRL and miR-483-5p, we identified that cytoplasmic MPRL directly binds to pre-miR-483 within the loop region and blocks pre-miR-483 recognition and cleavage by TRBP-DICER-complex, thereby inhibiting miR-483-5p generation and upregulating miR-483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre-miR-483, and low expression of miR-483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients' prognosis. CONCLUSIONS: We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC.These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.

Posterior Cervical Foraminotomy Via Full-Endoscopic Versus Microendoscopic Approach for Radiculopathy: A Systematic Review and Meta-analysis.

BACKGROUND: Recently posterior cervical foraminotomy (PCF) performed using a minimally-invasive surgery (MIS) approach for cervical radiculopathy due to lateral disc herniation or osseous foraminal stenosis has gained popularity. As 2 dominating MIS techniques, whether FE-PCF or MI-PCF provides superior clinical outcomes remains controversial. OBJECTIVES: To compare clinical success rate, overall incidence of complications and reoperation rate between full-endoscopic posterior cervical foraminotomy (FE-PCF) and microendoscopic posterior cervical foraminotomy (MI-PCF) for cervical radiculopathy. STUDY DESIGN: A systematic review and meta-analysis. METHODS: A literature search of Pubmed, Embase and Web of Science was conducted to identify comparative or single-arm studies concerning FE-PCF or MI-PCF. The pooled results were performed by calculating the effect size based on the logit event rate and reported with 95% confidence intervals (CI). RESULTS: A total of 26 articles with 2003 patients (FE-PCF, 377; MI-PCF, 1626) were included. The pooled clinical success rate was 93.6% (CI: 90.0%-95.9%) for the FE group and 89.9% (CI: 86.6%-92.5%) for the MI group, which was not statistically significant (P = 0.908). Overall complication rates were 6.1% (CI: 3.2%-11.3%) and 3.5% (CI: 2.7%-4.6%) for the FE group and the MI group, respectively, with no significant difference (P = 0.128). Nevertheless, the specific constituents showed apparent disparity, with transient nerve root palsy in the FE group (12/16, 75.0%) and dural tear in the MI group (20/47, 42.6%) being the most commonly reported. the pooled reoperation rate, the FE group (4.8%, CI: 2.9%-7.8%) and the MI group (5.3%, CI: 3.4%-8.2%), also demonstrated no statistical difference (P = 0.741). LIMITATIONS: The indirect comparison eroded the reliability of results inevitably due to the paucity of randomized clinical trials or high quality prospective cohort studies. CONCLUSIONS: Both FE-PCF and MI-PCF can offer an effective and relatively secure treatment for cervical radiculopathy. There was no significant difference in the pooled outcomes of clinical success rate, complication rate and reoperation rate between the 2 approaches. KEY WORDS: Cervical radiculopathy, full-endoscopic, microendoscopic, posterior cervical foraminotomy, clinical outcome, complication, reoperation, meta-analysis.

Mitochondrial miRNA Determines Chemoresistance by Reprogramming Metabolism and Regulating Mitochondrial Transcription.

miRNAs that translocate from the nucleus to mitochondria are referred to as mitochondrial microRNAs (mitomiR). mitomiRs have been shown to modulate the translational activity of the mitochondrial genome, yet their role in mitochondrial DNA (mtDNA) transcription remains to be determined. Here we report that the mitomiR-2392 regulates chemoresistance in tongue squamous cell carcinoma (TSCC) cells by reprogramming metabolism via downregulation of oxidative phosphorylation and upregulation of glycolysis. These effects were mediated through partial inhibition of mtDNA transcription by mitomiR-2392 rather than through translational regulation. This repression required specific miRNA-mtDNA base pairing and Argonaute 2. mitomiR-2392 recognized target sequences in the H-strand and partially inhibited polycistronic mtDNA transcription in a cell-specific manner. A retrospective analysis of TSCC patient tumors revealed a significant association of miR-2392 and regulated mitochondrial gene expression with chemosensitivity and overall survival. The clinical relevance of targeted mitochondrial genes was consistently validated by The Cancer Genome Atlas RNA sequencing in multiple types of cancer. Our study revealed for the first time the role of mitomiR in mtDNA transcription and its contribution to the molecular basis of tumor cell metabolism and chemoresistance.Significance: These findings uncover a novel mechanism by which mitomiRNA regulates mitochondrial transcription and provide rationale for use of mitomiRNA and mtDNA-encoded genes to predict chemosensitivity and patient clinical prognosis.

Full-Endoscopic Lumbar Discectomy for Lumbar Disc Herniation with Posterior Ring Apophysis Fracture: A Retrospective Study.

OBJECTIVE: The present retrospective study evaluated the clinical results of full-endoscopic lumbar discectomy (FELD) for the treatment of lumbar disc herniation (LDH) with lumbar posterior ring apophysis fracture (PRAF) using an interlaminar or a transforaminal approach at an inpatient surgery center. METHODS: Patients with single-level LDH with type III PRAF who had undergone FELD using an interlaminar or a transforaminal approach from January 2010 to December 2015 were enrolled. The general data recorded included sex, age, location, surgical approach, operative time, hospital stay, perioperative complications, and recurrence. The presence of mobile and immobile fragments was documented. The clinical outcomes were evaluated using a visual analog scale for low back and leg pain. The Oswestry Disability Index was used for the functional assessment and the modified MacNab criteria for patient satisfaction. RESULTS: FELD was performed successfully in all cases and no serious perioperative complications were observed. A mobile fragment of PRAS was present in 18 patients and an immobile fragment in 15 patients. Complications occurred in 2 of the 33 included patients; 1 dual tear (3.0%) and 1 transient dysesthesia (3.0%) that did not require further treatment. Recurrence developed in 1 patient (3.0%) and required reoperation. The visual analog scale and Oswestry Disability Index scores had significantly improved postoperatively at 3, 6, and 12 months and the final follow-up visit (P < 0.05). Using the modified MacNab criteria, an excellent or good rate of 93.4% was achieved. CONCLUSIONS: FELD is a safe and effective minimally invasive approach for the treatment of LDH with type III PRAF. Sufficient preparation and experience are required to achieve satisfactory results.

Stand-Alone Anterolateral Interbody Fusion Versus Extended Posterior Fusion for Symptomatic Adjacent-Segment Degeneration: A Retrospective Study of 2 Years' Follow-up.

OBJECTIVE: To evaluate the clinical and radiologic outcome of stand-alone anterolateral lumbar interbody fusion (ALLIF) using self-locked cages in comparison with extended posterior lumbar interbody fusion (PLIF) for symptomatic adjacent-segment degeneration (ASD) after posterior lumbar fusion. METHODS: This retrospective study enrolled 40 symptomatic patients with ASD who were treated with ALLIF (n = 13) or extended PLIF (n = 27) between January 2011 and January 2015. Evaluations were performed preoperatively, at 3, 12, and 24 months postoperatively. Clinical outcome measurements included visual analog scale scores for low-back and leg pain, Oswestry Disability Index score for function assessment, Short-Form 36 Questionnaire for quality of life, and modified Macnab criteria for patient satisfaction. Radiologic outcome measurements included fusion rate, cage subsidence, disc height, and lumbar lordosis. RESULTS: There were no significant differences in the baseline data for the ALLIF and PLIF groups (P > 0.05). Mean operative time, blood loss, and length of hospital stay were significantly decreased for the ALLIF group (P < 0.05). Postoperatively, low back and leg pain was relieved, function and quality of life were improved in both groups (P < 0.05), whereas disc height and lumbar lordosis were restored (P < 0.05). At 24-month follow-up, fusion was observed in 13 of 13 patients (100%), with 3 of 13 (23.1%) patients developing cage subsidence in the ALLIF group. CONCLUSIONS: Stand-alone ALLIF could achieve satisfactory safety and efficacy for the treatment of symptomatic ASD with less trauma and faster recovery, and it may serve as an alternative surgical treatment for symptomatic ASD with appropriate indication.

Early Experience of Full-Endoscopic Interlaminar Discectomy for Adolescent Lumbar Disc Herniation with Sciatic Scoliosis.

BACKGROUND: Full-endoscopic interlaminar discectomy (FEID) has achieved satisfactory outcome in adolescent lumbar disc herniation (ALDH). Sciatic scoliosis is found to be a common presentation in ALDH. However, few reports are focused on the influences of sciatic scoliosis on ALDH and the prognosis of sciatic scoliosis after FEID. OBJECTIVE: This study aims to evaluate the clinical and radiological results of FEID in the treatment of ALDH with sciatic scoliosis and to identify the effects of sciatic scoliosis on complication and recurrence. STUDY DESIGN: A retrospective study. SETTING: An inpatient surgery center. METHODS: A series of cases of patients under age 20 with single-level ALDH that underwent FEID between January 2010 and December 2014 were retrospectively analyzed. The patients were divided into 2 groups according to if they had scoliosis or not. Clinical outcomes were evaluated using a visual analog scale (VAS) for low back and leg pain, Oswestry Disability Index (ODI) for the functional assessment, and modified Macnab criteria for the patient satisfaction. Radiological parameters of the scoliosis group such as Cobb angle, CVSL-max, and CVSL-C7 were statistically analyzed. RESULTS: No significant differences were found between both groups in terms of the mean operative time, the mean length of hospital stay, complications, and recurrences (P > 0.05). VAS and ODI scores were significantly improved in both groups (P < 0.05). However, there were no statistically significant differences between the 2 groups in VAS, ODI, and modified MacNab criteria (P > 0.05). For the scoliosis group, significant improvements were observed in the postoperative sagittal and coronal alignment parameters (P < 0.05). LIMITATIONS: This was a retrospective study with a relatively small sample size. Additionally, the length of follow-up was short. CONCLUSIONS: The application of FEID in the treatment of ALDH could achieve satisfactory clinical and radiological outcomes. Sciatic scoliosis was corrected spontaneously without increasing the risk of complication and recurrence. KEY WORDS: Adolescent lumbar disc herniation, full-endoscopic interlaminar discectomy, sciatic scoliosis, recurrence.

Familial lumbar Scheuermann disease with idiopathic scoliosis in China: First case report.

RATIONALE: Given that Scheuermann disease rarely occurs in the lumbar region and that the co-occurrence of Scheuermann disease and idiopathic scoliosis (IS) has not been reported-the etiology of Scheuermann disease and IS is not clear. In this case report, we present familaiar lumbar Scheuermann disease with IS, in a Chinese proband, who was successfully treated with surgery. PATIENT CONCERNS: A 16-year-old boy presented at the Second XiangYa Hospital of Central South University with a chief complaint of kyphotic deformity in the lower back for 4 years and obvious lower back pain. In addition, he complained of limited lumbar activity. And The proband's family history was obtained by routine inquiring. In this Chinese family with 17 members over 3 generations. The 3 patients (proband, proband's sister and father) shared the characteristics of vertebral wedging from L1 to L3 and a kyphosis Cobb angle of 37°, 70°, or 73°, respectively. The main deformity of the proband's mother was at T7-L1 with a Cobb angle of 102° in the coronal plane at T7-L1, thoracic kyphosis of 73°, and lumbar lordosis of 62°. DIAGNOSES: Scheuermann's disease. INTERVENTIONS: Clinical history, physical examination, laboratory tests, and radiographs of those in the pedigree were recorded, and the related literature was reviewed. The proband accepted osteotomy and orthopedic surgery for treatment. OUTCOMES: After 3 months of treatment, postoperative lateral radiographs showed a significantly improved sagittal vertical axis (SVA). The other patients were continued to be seen in follow-up visits. LESSONS: This series of lumbar Scheuermann patients with IS in a pedigree support the genetic contribution to Scheuermann disease. Therefore, this study provides some insight into the genetic etiology of Scheuermann disease with IS.

MiR-140/BDNF axis regulates normal human astrocyte proliferation and LPS-induced IL-6 and TNF-α secretion.

Reactive astrocyte proliferation after spinal cord injury (SCI) contributes to glial scar formation that impedes axonal regeneration. The mechanisms underlying astrocyte proliferation upon injury remain partially understood. MicroRNAs (miRNAs) function as a major class of post-transcriptional gene expression regulators that participate in many biological processes. In this study, we focused on the functional role of miR-140 in normal human astrocyte (NHA) cell proliferation. Ectopic miR-140 expression significantly inhibited NHA cell viability and proliferation; miR-140 inhibition exerted the opposite function. Commonly, miRNAs exert functions through targeting downstream genes to inhibit their expression. In the present study, brain-derived neurotrophic factor (BDNF), a regulator of astrocyte proliferation and differentiation, confirmed as a direct target of miR-140 in NHA. Through binding to the 3'UTR of BDNF, miR-140 inhibited BDNF expression. BDNF overexpression significantly promoted NHA cell viability and proliferation; the regulatory effect of miR-140/BDNF on NHA proliferation was mediated by PI3K/AKT pathway. Moreover, we evaluated the functional role of miR-140 in Lipopolysaccharide (LPS)-induced in vitro injury model of astroglial cultures; a significantly up-regulated BDNF, interleukin (IL)-6 and tumor necrosis factor (TNF)-α expression in response to LPS stimulation was observed. After ectopic miR-140 expression, the promotive effect of LPS on BDNF, IL-6 and TGF-α expression was partially restored. Taken together, miR-140/BDNF axis regulates NHA proliferation through PI3K/AKT pathway; miR-140 could inhibit BDNF, IL-6 and TGF-α expression in LPS-induced in vitro injury model. MiR-140/BDNF might serve as a promising target in strategy against reactive astrocyte proliferation after SCI.

Clinical Outcome of Full-endoscopic Interlaminar Discectomy for Single-level Lumbar Disc Herniation: A Minimum of 5-year Follow-up.

BACKGROUND: Full-endoscopic interlaminar discectomy (FEID) is widely applied for the treatment of lumbar disc herniation (LDH) and satisfactory short-term outcomes have been achieved. However, the long-term evaluation for this technique is still lacking, especially the comparison between FEID and microendoscopic discectomy (MED). OBJECTIVE: To evaluate the clinical outcome of FEID technique in comparison with MED for single-level LDH with a minimum of 5-year follow-up. STUDY DESIGN: Retrospective study. SETTING: Inpatient surgery center. METHODS: A total of 152 patients with single-level LDH located at either L4-L5 or L5-S1 who underwent either FEID or MED from August 2008 to April 2011 at our hospital were enrolled in this study. General parameters including operative time, length of hospital stay, mean time to return to work, complications, and recurrences were recorded. Clinical outcomes were evaluated using visual analog scale (VAS) for low back and leg pain, Oswestry Disability Index (ODI) for functional assessment, and modified MacNab criteria for patient satisfaction. RESULTS: At the final follow-up, the VAS of leg and back pain decreased from 7.6 ± 1.6 and 3.1 ± 2.2 points preoperatively to 1.6 ± 1.2 and 1.7 ± 0.9 at the final follow-up, respectively (P < 0.05). The ODI score was 69.5% ± 10.5% preoperatively, and declined to 21.8% ± 7.0% at the final follow-up (P < 0.05). VAS, ODI, and modified MacNab criteria of the FEID group were improved compared to the control group though there were no statistically significant differences between the 2 groups. LIMITATIONS: This was a retrospective study with a relatively small sample size. Additionally, this study contained only clinical outcomes, without long-term radiological outcomes. CONCLUSIONS: The application of FEID achieved similar satisfactory long-term clinical outcomes for the surgical treatment of LDH as MED. However, compared with MED, FEID exhibits advantages including less operation time, shorter hospital stay, and faster postoperative recovery.Key words: Lumbar disc herniation, full-endoscopic interlaminar discectomy, microendoscopic disectomy, long-term.

Amorphous ZnO Quantum Dot/Mesoporous Carbon Bubble Composites for a High-Performance Lithium-Ion Battery Anode.

Due to its high theoretical capacity (978 mA h g-1), natural abundance, environmental friendliness, and low cost, zinc oxide is regarded as one of the most promising anode materials for lithium-ion batteries (LIBs). A lot of research has been done in the past few years on this topic. However, hardly any research on amorphous ZnO for LIB anodes has been reported despite the fact that the amorphous type could have superior electrochemical performance due to its isotropic nature, abundant active sites, better buffer effect, and different electrochemical reaction details. In this work, we develop a simple route to prepare an amorphous ZnO quantum dot (QDs)/mesoporous carbon bubble composite. The composite consists of two parts: mesoporous carbon bubbles as a flexible skeleton and monodisperse amorphous zinc oxide QDs (smaller than 3 nm) encapsulated in an amorphous carbon matrix as a continuous coating tightly anchored on the surface of mesoporous carbon bubbles. With the benefits of abundant active sites, amorphous nature, high specific surface area, buffer effect, hierarchical pores, stable interconnected conductive network, and multidimensional electron transport pathways, the amorphous ZnO QD/mesoporous carbon bubble composite delivers a high reversible capacity of nearly 930 mA h g-1 (at current density of 100 mA g-1) with almost 90% retention for 85 cycles and possesses a good rate performance. This work opens the possibility to fabricate high-performance electrode materials for LIBs, especially for amorphous metal oxide-based materials.

Characterization of FRM-36143 as a new γ-secretase modulator for the potential treatment of familial Alzheimer's disease.

BACKGROUND: Familial Alzheimer's disease (FAD) is caused by mutations in the amyloid precursor protein (APP) or presenilin (PS). Most PS mutations, which account for the majority of FAD cases, lead to an increased ratio of longer to shorter forms of the amyloid beta (Aß) peptide. The therapeutic rationale of γ-secretase modulators (GSMs) for Alzheimer's disease is based on this genetic evidence as well as on enzyme kinetics measurements showing changes in the processivity of the γ-secretase complex. This analysis suggests that GSMs could potentially offset some of the effects of PS mutations on APP processing, thereby addressing the root cause of early onset FAD. Unfortunately, the field has generated few, if any, molecules with good central nervous system (CNS) drug-like properties to enable proof-of-mechanism studies. METHOD: We characterized the novel GSM FRM-36143 using multiple cellular assays to determine its in vitro potency and off-target activity as well as its potential to reverse the effect of PS mutations. We also tested its efficacy in vivo in wild-type mice and rats. RESULTS: FRM-36143 has much improved CNS drug-like properties compared to published GSMs. It has an in vitro EC50 for Aß42 of 35 nM in H4 cells, can reduce Aß42 to 58 % of the baseline in rat cerebrospinal fluid, and also increases the non-amyloidogenic peptides Aß37 and Aß38. It does not inhibit Notch processing, nor does it inhibit 24-dehydrocholesterol reductase (DHCR24) activity. Most interestingly, it can reverse the effects of presenilin mutations on APP processing in vitro. CONCLUSIONS: FRM-36143 possesses all the characteristics of a GSM in terms of Aß modulation Because FRM-36143 was able to reverse the effect of PS mutations, we suggest that targeting patients with this genetic defect would be the best approach at testing the efficacy of a GSM in the clinic. While the amyloid hypothesis is still being tested with ß-site APP-cleaving enzyme inhibitors and monoclonal antibodies in sporadic AD, we believe it is not a hypothesis for FAD. Since GSMs can correct the molecular defect caused by PS mutations, they have the promise to provide benefits to the patients when treated early enough in the course of the disease.

Concentration-response relationship of the α7 nicotinic acetylcholine receptor agonist FRM-17874 across multiple in vitro and in vivo assays.

Pharmacological activation of α7 nicotinic acetylcholine receptors (α7 nAChRs) may improve cognition in schizophrenia and Alzheimer's disease. The present studies describe an integrated pharmacological analysis of the effects of FRM-17874, an analogue of encenicline, on α7 nAChRs in vitro and in behavioral and neurophysiological assays relevant to cognitive function. FRM-17874 demonstrated high affinity binding to human α7 nAChRs, displacing [(3)H]-methyllacaconitine (Ki=4.3nM). In Xenopus laevis oocytes expressing human α7 nAChRs, FRM-17874 acted as an agonist, evoking inward currents with an EC50 of 0.42µM. Lower concentrations of FRM-17874 (0.01-3nM) elicited no detectable current, but primed receptors to respond to sub-maximal concentrations of acetylcholine. FRM-17874 improved novel object recognition in rats, and enhanced memory acquisition and reversal learning in the mouse water T-maze. Neurophysiological correlates of cognitive effects of drug treatment, such as synaptic transmission, long-term potentiation, and hippocampal theta oscillation were also evaluated. Modulation of synaptic transmission and plasticity was observed in rat hippocampal slices at concentrations of 3.2 and 5nM. FRM-17874 showed a dose-dependent facilitation of stimulation-induced hippocampal theta oscillation in mice and rats. The FRM-17874 unbound brain concentration-response relationship for increased theta oscillation power was similar in both species, exhibited a biphasic pattern peaking around 3nM, and overlapped with active doses and exposures observed in cognition assays. In summary, behavioral and neurophysiological assays indicate a bell-shaped effective concentration range and this report represents the first attempt to explain the concentration-response function of α7 nAChR-mediated pro-cognitive effects in terms of receptor pharmacology.

Modulation of γ-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice.

BACKGROUND: A hallmark of Alzheimer's disease is the presence of senile plaques in human brain primarily containing the amyloid peptides Aß42 and Aß40. Many drug discovery efforts have focused on decreasing the production of Aß42 through γ-secretase inhibition. However, identification of γ-secretase inhibitors has also uncovered mechanism-based side effects. One approach to circumvent these side effects has been modulation of γ-secretase to shift Aß production to favor shorter, less amyloidogenic peptides than Aß42, without affecting the overall cleavage efficiency of the enzyme. This approach, frequently called γ-secretase modulation, appears more promising and has lead to the development of new therapeutic candidates for disease modification in Alzheimer's disease. RESULTS: Here we describe EVP-0015962, a novel small molecule γ-secretase modulator. EVP-0015962 decreased Aß42 in H4 cells (IC50 = 67 nM) and increased the shorter Aß38 by 1.7 fold at the IC50 for lowering of Aß42. AßTotal, as well as other carboxyl-terminal fragments of amyloid precursor protein, were not changed. EVP-0015962 did not cause the accumulation of other γ-secretase substrates, such as the Notch and ephrin A4 receptors, whereas a γ-secretase inhibitor reduced processing of both. A single oral dose of EVP-0015962 (30 mg/kg) decreased Aß42 and did not alter AßTotal peptide levels in a dose-dependent manner in Tg2576 mouse brain at an age when overt Aß deposition was not present. In Tg2576 mice, chronic treatment with EVP-0015962 (20 or 60 mg/kg/day in a food formulation) reduced Aß aggregates, amyloid plaques, inflammatory markers, and cognitive deficits. CONCLUSIONS: EVP-0015962 is orally bioavailable, detected in brain, and a potent, selective γ-secretase modulator in vitro and in vivo. Chronic treatment with EVP-0015962 was well tolerated in mice and lowered the production of Aß42, attenuated memory deficits, and reduced Aß plaque formation and inflammation in Tg2576 transgenic animals. In summary, these data suggest that γ-secretase modulation with EVP-0015962 represents a viable therapeutic alternative for disease modification in Alzheimer's disease.

Characterization of alkaline phosphatase labeled UidA(Gus) probe and its application in testing of transgenic tritordeum.

Hybridization is a very important molecular biology technique to measure the degree of genetic similarity between DNA sequences, and detect the foreign genes in transgenic organisms. To label a DNA or RNA probe plays a key role in hybridization. A method using nonradioactive material alkaline phosphatase to label UidA(Gus) DNA as probe has been studied. On that basis of Renz and our previous work, alkaline phosphatase-labeled DNA was used as a probe to examine the transformation of the foreign UidA(Gus) gene in transgenic tritordeum. Such DNA-enzyme complexes were characterized and examined carefully, the results showed that it was a sensitive, specific, safe and economical probe. For dot hybridization and Southern blot under full-stringency conditions with alkaline phosphatase as the detector and 5-bromo-4-chloro-3-indolyl phosphate (BCIP)-Nitro Blue Tetrazolium (NBT) as the substrate, dot hybridization showed that the UidA(Gus) gene was transformed into the target plants and inherited stable, Southern blot showed that at least two copies of UidA(Gus) gene were inserted into one line of our transgenic tritordeum. Histochemical staining with X-Gluc of transgenic tritordeum also certified that the foreign UidA(Gus) DNA were transformed into the transgenic tritordeum.