Ginsenoside Rd Inhibits Glioblastoma Cell Proliferation by Up-Regulating the Expression of miR-144-5p.

miR-144-5p exhibits anti-tumor activities in various cancers. Although treatment for glioblastoma has progressed rapidly, novel targets for glioblastoma are insufficient, particularly those used in precision medicine. In the current study, we found that ginsenoside Rd reduced the proliferation and migration of glioblastoma cells. Ginsenoside Rd up-regulated the tumor-suppressive miR-144-5p in glioblastoma cells. Moreover, Toll-like receptor 2, which is a target of miR-144-5p, was down-regulated. After inhibition of miR-144-5p, the effect of Ginsenoside Rd on proliferation inhibition and down-regulation of Toll-like receptor 2 was reduced. These data demonstrated the ginsenoside Rd/miR-144-5p/Toll-like receptor 2 regulatory nexus that controls the glioblastoma pathogenesis of glioblastoma. Our work provided novel targets for glioblastoma diagnosis and treatment.

Gene expression analysis of primary gingival cancer by whole exome sequencing in thirteen Chinese patients.

OBJECTIVES: Early diagnosis of and markers for gingival oral squamous cell carcinoma (OSCC) is important for effective treatment. METHODS: The current study performed a whole exome sequencing of gingival OSCC tissues in thirteen Chinese patients to explore exonic mutants. RESULTS: Eighty-five genes emerged as mutants in patients with primary gingival OSCC. CCL4L1 presented a G>A transversion at chr17 17q12, position 36212480, exon 3. KDM5B presented a T>TA insertion at chr1 1q32.1, position 202766506, exon 6. ANKRD36C presented a C>G transition at chr2 2q11.1, position 95945175, exon 18. CONCLUSION: These three mutants might be new markers of gingival OSCC. The finding may provide new targets to diagnose and treat gingival OSCC.

Expression of miR-1304 in patients with esophageal carcinoma and risk factors for recurrence.

BACKGROUND: Esophageal carcinoma is a malignant gastrointestinal tumor with a very poor prognosis. MicroRNA (miR)-1304 is a newly discovered non-coding RNA, which shows differential expression in other cancers, and its clinical value in esophageal carcinoma remains unclear. AIM: To explore the expression of miR-1304 in patients with esophageal carcinoma and its clinical value. METHODS: The expression of miR-1304 in patients with esophageal carcinoma was analyzed based on the data on miR in esophageal carcinoma downloaded from The Cancer Genome Atlas database. Quantitative real-time polymerase chain reaction was adopted to determine the expression of miR-1304 in the tissues and serum of patients. The clinical diagnostic value of miR-1304 and independent factors for recurrence and prognosis of esophageal carcinoma were then analyzed. The potential target genes of miR-1304 were predicted, and then analyzed based on gene ontology, Kyoto Encyclopedia of Genes, and Genomes, and protein-protein interaction. RESULTS: The expression of miR-1304 in the tissues and serum of patients with esophageal carcinoma increased, and was also increased according to the database. Patients with high expression of miR-1304 suffered increased rates of tumor ≥ 3 cm, low differentiation and stage II + III. miR-1304 had a diagnostic value in identifying esophageal carcinoma, tumor size, differentiation and TNM stage. Tumor size, differentiation, TNM stage, and miR-1304 were independent risk factors for recurrence of esophageal carcinoma, and they had certain predictive and diagnostic value for the recurrence of esophageal carcinoma. Seventy-eight patients showed a 3-year survival rate of 38.46%, and patients with high expression of miR-1304 had a relatively lower survival rate. Multivariate analysis revealed that tumor size, differentiation, recurrence and miR-1304 were independent factors for the prognosis of patients. MiRTarBase, miRDB, and Targetscan predicted 20 target genes in total. Gene ontology enrichment analysis found 18 functions with a P < 0.05, and Kyoto Encyclopedia of Genes, and Genomes analysis found 11 signal pathways with a P < 0.05. String analysis of protein co-expression found 269 relationship pairs, of which co-expression with epidermal growth factor was the most common. CONCLUSION: miR-1304 can be used as a potential indicator for the diagnosis and recurrence of esophageal carcinoma and for survival of patients with this disease.

RP11-874J12.4 promotes oral squamous cell carcinoma tumorigenesis via the miR-19a-5p/EBF1 axis.

BACKGROUND: Oral squamous cell carcinoma (OSCC) ranks as the fifth most frequent cancer worldwide, and the recurrence and migration of OSCC still pose large threats to patients. Long non-coding RNAs (lncRNAs) have recently emerged as crucial players in cancer development, and it is of great significance to understand the regulatory nexus of lncRNAs in OSCC. METHODS: Here, we identified a novel lncRNA, RP11-874J12.4, which is ectopically expressed in OSCC and facilitates OSCC. RESULTS: RP11-874J12.4 directly binds to and regulates miR-19a-5p. Interestingly, RP11-874J12.4 and miR-19a-5p form a negative regulatory loop that inhibits the expression of miR-19a-5p in OSCC. The expression of an oncogenic transcription factor, EBF1, is unleashed in OSCC due to the low expression of miR-19a-5p, which promotes the growth and migration of OSCC. CONCLUSION: Our data illustrate a regulatory axis of RP11-874J12.4/miR-19a-5P/EBF1 and an inhibitory loop with RP11-874J12.4 and miR-19a-5p. These data provide insights into the tumorigenesis of OSCC and the novel drug targets for OSCC.

Comprehensive multi-omics analysis identified core molecular processes in esophageal cancer and revealed GNGT2 as a potential prognostic marker.

BACKGROUND: Esophageal cancer is one of the most poorly diagnosed and fatal cancers in the world. Although a series of studies on esophageal cancer have been reported, the molecular pathogenesis of the disease remains elusive. AIM: To investigate comprehensively the molecular process of esophageal cancer. METHODS: Differential expression analysis was performed to identify differentially expressed genes (DEGs) in different stages of esophageal cancer from The Cancer Genome Atlas data. Exacting gene interaction modules were generated, and hub genes in the module interaction network were found. Further, through survival analysis, methylation analysis, pivot analysis, and enrichment analysis, some important molecules and related functions/pathways were identified to elucidate potential mechanisms in esophageal cancer. RESULTS: A total of 7457 DEGs and 14 gene interaction modules were identified. These module genes were significantly involved in the positive regulation of protein transport, gastric acid secretion, insulin-like growth factor receptor binding, and other biological processes as well as p53 signaling pathway, epidermal growth factor signaling pathway, and epidermal growth factor receptor signaling pathway. Transcription factors (including hypoxia inducible factor 1A) and non-coding RNAs (including colorectal differentially expressed and hsa-miR-330-3p) that significantly regulate dysfunction modules were identified. Survival analysis showed that G protein subunit gamma transducin 2 (GNGT2) was closely related to survival of esophageal cancer. DEGs with strong methylation regulation ability were identified, including SST and SH3GL2. Furthermore, the expression of GNGT2 was evaluated by quantitative real time polymerase chain reaction, and the results showed that GNGT2 expression was significantly upregulated in esophageal cancer patient samples and cell lines. Moreover, cell counting kit-8 assay revealed that GNGT2 could promote the proliferation of esophageal cancer cell lines. CONCLUSION: This study not only revealed the potential regulatory factors involved in the development of esophageal cancer but also deepens our understanding of its underlying mechanism.

Curcumin upregulates S100 expression and improves regeneration of the sciatic nerve following its complete amputation in mice.

The repair of peripheral nerve injury after complete amputation is difficult, and even with anastomosis, the rapid recovery of nerve function remains challenging. Curcumin, extracted from plants of the genus Curcuma, has been shown to have anti-oxidant and anti-inflammatory properties and to improve sciatic nerve crush injury in rats. Here, we determined whether curcumin had neuroprotective effects following complete peripheral nerve amputation injury. BALB/c mice underwent complete sciatic nerve amputation, followed by an immediate epineurium anastomosis. Mice were intragastrically administered curcumin at doses of 40 (high), 20 (moderate), and 10 mg/kg/d (low) for 1 week. We found that myelin in the mice of the high- and moderate-dose curcumin groups appeared with regular shape, uniform thickness, clear boundary, and little hyperplasia surrounding the myelin. High and moderate doses of curcumin markedly improved both action potential amplitude of the sciatic nerves and the conduction velocity of the corresponding motor neurons, and upregulated mRNA and protein expression of S100, a marker for Schwann cell proliferation, in L4-6 spinal cord segments. These results suggest that curcumin is effective in promoting the repair of complete sciatic nerve amputation injury and that the underlying mechanism may be associated with upregulation of S100 expression.

Knockdown of Nogo gene by short hairpin RNA interference promotes functional recovery of spinal cord injury in a rat model.

The specific myelin component Nogo protein is one of the major inhibitory molecules of spinal cord axonal outgrowth following spinal cord injury. The present study aimed to investigate the effects of silencing Nogo protein with shRNA interference on the promotion of functional recovery in a rat model with spinal cord hemisection. Nogo-A short hairpin RNAs (Nogo shRNAs) were constructed and transfected into rats with spinal cord hemisection by adenovirus-mediated transfection. Reverse transcription­polymerase chain reaction and western blotting were performed to analyze the expression of Nogo-A and Growth Associated Protein 43 (GAP-43). In addition, Basso Beattie Bresnahan (BBB) scores were used to assess the functional recovery of rats following spinal cord injury. The results demonstrated that expression of the Nogo­A gene was observed to be downregulated following transfection and GAP­43 expression was observed to increase. The BBB scores were increased following treatment with Nogo shRNAs, indicating functional recovery of the injured nerves. Thus, Nogo-A shRNA interference can knockdown Nogo gene expression and upregulate GAP-43 to promote the functional recovery of spinal cord injury in rats. This finding may advance progress toward assisting the regeneration of injured neurons through the use of Nogo-A shRNA.

Bone morphogenetic protein-2 sustained delivery by hydrogels with microspheres repairs rabbit mandibular defects.

Mandible defect is a difficult issue in dental surgery owing to limited therapeutic options. Recombinant human bone morphogenetic protein-2 (rhBMP2) is osteoinductive in bone regeneration. This article prepared chitosan/collagen hydrogels with rhBMP2-incorporated gelatin microsphere (GMs) for a sustained release of rhBMP2 to induce bone regeneration in rabbits. In experiments, mandibular defects of 8 mm in diameter and 3 mm in depth were surgically prepared on the right cheek of 27 rabbits. Either chitosan/collagen hydrogels alone, rhBMP2-incorporated hydrogels, or hydrogels with rhBMP2-incorporated GMs were implanted to the defect sites. The animals were euthanized at 2, 6, 12 weeks following surgery. In results, scanning electronic microscope images revealled spherical GMs. The complex delivery systems, hydrogels with rhBMP2-incorporated GMs, exhibited ideal release profiles in vitro. The complex delivery systems resulted in apparent new bone formation within 12 weeks, as evidenced by computed tomography and histological observations. All these results demonstrated that the chitosan/collagen hydrogels with rhBMP2-incorporated GMs had a better capacity to heal mandible defects than other two hydrogel scaffolds. Chitosan/collagen hydrogels with rhBMP2-incorporated GMs might be potential carriers of rhBMP2 for accelerating the repair of mandibular defects.

Accelerating Neuroimage Registration through Parallel Computation of Similarity Metric.

Neuroimage registration is crucial for brain morphometric analysis and treatment efficacy evaluation. However, existing advanced registration algorithms such as FLIRT and ANTs are not efficient enough for clinical use. In this paper, a GPU implementation of FLIRT with the correlation ratio (CR) as the similarity metric and a GPU accelerated correlation coefficient (CC) calculation for the symmetric diffeomorphic registration of ANTs have been developed. The comparison with their corresponding original tools shows that our accelerated algorithms can greatly outperform the original algorithm in terms of computational efficiency. This paper demonstrates the great potential of applying these registration tools in clinical applications.

Brain Structure Network Analysis in Patients with Obstructive Sleep Apnea.

Childhood obstructive sleep apnea (OSA) is a sleeping disorder commonly affecting school-aged children and is characterized by repeated episodes of blockage of the upper airway during sleep. In this study, we performed a graph theoretical analysis on the brain morphometric correlation network in 25 OSA patients (OSA group; 5 female; mean age, 10.1 ± 1.8 years) and investigated the topological alterations in global and regional properties compared with 20 healthy control individuals (CON group; 6 females; mean age, 10.4 ± 1.8 years). A structural correlation network based on regional gray matter volume was constructed respectively for each group. Our results revealed a significantly decreased mean local efficiency in the OSA group over the density range of 0.32-0.44 (p < 0.05). Regionally, the OSAs showed a tendency of decreased betweenness centrality in the left angular gyrus, and a tendency of decreased degree in the right lingual and inferior frontal (orbital part) gyrus (p < 0.005, uncorrected). We also found that the network hubs in OSA and controls were distributed differently. To the best of our knowledge, this is the first study that characterizes the brain structure network in OSA patients and invests the alteration of topological properties of gray matter volume structural network. This study may help to provide new evidence for understanding the neuropathophysiology of OSA from a topological perspective.

Myocardial Iron Loading Assessment by Automatic Left Ventricle Segmentation with Morphological Operations and Geodesic Active Contour on T2* images.

Myocardial iron loading thalassemia patients could be identified using T2* magnetic resonance images (MRI). To quantitatively assess cardiac iron loading, we proposed an effective algorithm to segment aligned free induction decay sequential myocardium images based on morphological operations and geodesic active contour (GAC). Nine patients with thalassemia major were recruited (10 male and 16 female) to undergo a thoracic MRI scan in the short axis view. Free induction decay images were registered for T2* mapping. The GAC were utilized to segment aligned MR images with a robust initialization. Segmented myocardium regions were divided into sectors for a region-based quantification of cardiac iron loading. Our proposed automatic segmentation approach achieve a true positive rate at 84.6% and false positive rate at 53.8%. The area difference between manual and automatic segmentation was 25.5% after 1000 iterations. Results from T2* analysis indicated that regions with intensity lower than 20 ms were suffered from heavy iron loading in thalassemia major patients. The proposed method benefited from abundant edge information of the free induction decay sequential MRI. Experiment results demonstrated that the proposed method is feasible in myocardium segmentation and was clinically applicable to measure myocardium iron loading.

Study of bone-screw surface fixation in lumbar dynamic stabilization.

BACKGROUND: We aimed to use the animal model of dynamic fixation to examine the interaction of the pedicle screw surface with surrounding bone, and determine whether pedicle screws achieve good mechanical stability in the vertebrae. METHODS: Twenty-four goats aged 2-3 years had Cosmic ® pedicle screws implanted into both sides of the L2-L5 pedicles. Twelve goats in the bilateral dynamic fixation group had fixation rods implanted in L2-L3 and L4-L5. Twelve goats in the unilateral dynamic fixation group had fixation rods randomly fixed on one side of the lumbar spine. The side that was not implanted with fixation rods was used as a static control group. RESULTS: In the static control group, new bone was formed around the pedicle screw and on the screw surface. In the unilateral and bilateral dynamic fixation groups, large amounts of connective tissue formed between and around the screw threads, with no new bone formation on the screw surface; the pedicle screws were loose after the fixed rods were removed. The bone mineral density and morphological parameters of the region of interest (ROI) in the unilateral and bilateral dynamic fixation group were not significantly different (P > 0.05), but were lower in the fixed groups than the static control group (P < 0.05). This showed the description bone of the ROI in the static control group was greater than in the fixation groups. Under loading conditions, the pedicle screw maximum pull force was not significantly different between the bilateral and unilateral dynamic fixation groups (P > 0.05); however the maximum pull force of the fixation groups was significantly less than the static control group (P < 0.01). CONCLUSIONS: Fibrous connective tissue formed at the bone-screw interface under unilateral and bilateral pedicle dynamic fixation, and the pedicle screws lost mechanical stability in the vertebrae.

Extracellular matrix-coating pedicle screws conduct and induce osteogenesis.

BACKGROUND: The purpose of the present study was to study the effects of the extracellular matrix-coating pedicle screws on the conduction and induction of bone formation in young sheep. METHODS: Pedicle screws [coated with collagen/chondroitin sulfate (coll/CS), hydroxyapatite (HA), and coll/CS/HA or uncoated] were randomly implanted into the L2-L5 pedicles of sheep. In the first stage, a static experiment was performed. In the second stage, a loading test was performed by implanting connecting rods. After 3 months, the lumbar vertebrae with the screws were removed and examined by micro-CT, histological, and biomechanical analyses. RESULTS: Under non-loading conditions, there is bone formation around the surfaces of coated screws. Bone formation on the surface of the coll/CS/HA coating of pedicle screws was the highest. In terms of the trabecular bone morphology parameters of the region of interest around the surface of the pedicle screws, those associated with coll/CS/HA coatings were highest under non-loading conditions, the pullout strength of the coll-/CS-/HA-coated screws was the highest and that of the uncoated screws was minimal. Under loading conditions, the maximum pullout strength of each group of pedicle screws was less than that of the pedicle screws in the non-loading state. CONCLUSIONS: Under non-loading conditions, the organic and inorganic components of the titanium pedicle screw coatings can conduct or induce bone formation around the surface of the screws. The ability of the coll/CS/HA coating to induce bone formation was the strongest. Under loading conditions, a large amount of connective tissue formed around the surface of the screws in each group.

Age-related differences in the biological parameters of vertebral cancellous bone from Chinese women.

BACKGROUND: With aging, the human fracture risks gradually increase. This is mainly due to the corresponding changes of the biomechanical parameters of human bone presents with aging. We measured the microstructural parameters of lumbar bone from women in several age groups by micro-computed tomography and scanning electron microscopy. We observed changes in lumbar cancellous bone mineral density and in biomechanical parameters with aging to elucidate the relationship between age and risk of fracture. We provide theoretical support for human pathology, fracture risk increased with age and the individualized of each age group. METHODS: Thirty-two fresh L3 vertebral bodies were donated from 32 women, aged 20-59 years and were divided into four age groups: 20 to 29 years (group A); 30 to 39 years (group B); 40 to 49 years (group C); and 50 to 59 years (group D). Conventional lumbar separation was performed by removing soft tissue and subsidiary structures, leaving only the vertebral body. The vertebral body was cut into halves along the median sagittal plane, maintaining the upper and lower end-plates of each half, and used for biomechanical, morphological, and density measurements. RESULTS: Comparing group A to B, the rod-like trabecular thickness (Tb.Th) decreased; the trabecular spacing (Tb.Sp) increased; the plate-like Tb.Th decreased; bone mineral density, tissue mineral density, bone volume fraction, and bone surface fraction decreased, and the elastic modulus and the ultimate stress decreased (all changes P < 0.05). Similar significant (P < 0.05) trends were obtained when comparing group C to D. With aging, the collagen cross-linking capacity declined, the thickness of the collagen fibrils was variable (ranging from almost the same to loose, sparse, or disordered), and the finer collagen fibrils between the thick filaments were disorganized. CONCLUSIONS: In women aged 20 to 59 years, the rod-like and plate-like Tb.Th of the vertebral body decreased, while Tb.Sp increased. Additionally, the density, elastic modulus, and ultimate stress of the cancellous bone decreased with age. These associated changes in bone microstructure, density, and biomechanics with age may lead to an increasing risk of osteoporosis and fracture.