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Objective. This study aims to explore circ_0058063 effect on multiple myeloma cells malignant phenotype and its feasible mechanism. Methods. We selected 47 cases of multiple myeloma tissues and 47 cases of normal bone marrow tissues and then used RT-qPCR method to test circ_0058063 and miR-635 expression in the tissues. Myeloma cells RPMI8226 were transfected with si-circ_0058063, miR-635 mimic, and si-circ_0058063 + anti-miR-635, respectively. Then, we adopt CCK-8 method, flow cytometry method, and Transwell and western blot methods to detect the influences of knockdown of circ_0058063 or miR-635 overexpression on RPMI8226 cell proliferation, apoptosis, migration, and invasion and also Ki-67, Bax, Bcl-2, MMP-2, and MMP-9 protein expression. The dual luciferase reporter gene assay experiment proved that it has regulatory relationship between circ_0058063 and miR-635. Results. circ_0058063 expression of multiple myeloma was higher than that in normal bone marrow tissue ( P < 0.05 ), while miR-635 expression was lower than that in normal bone marrow tissue ( P < 0.05 ). Knockdown of circ_0058063 or overexpression of miR-635 could reduce proliferation capacity, migration, invasion cell quantities, and Ki-67, MMP-2, MMP-9, and Bcl-2 protein expression ( P < 0.05 ), while increasing apoptosis rate together with Bax protein expression ( P < 0.05 ). circ_0058063 targets to negatively regulate miR-635, while knocking down miR-635 reverses the influences of knocking down circ_0058063 on RPMI8226 proliferation, apoptosis, migration, and invasion. Conclusion. circ_0058063 expression increased in multiple myeloma tissues. Knocking down its expression may inhibit myeloma proliferation, migration, and invasion by targeting and upregulating miR-635 and also promote cell apoptosis. As for multiple myeloma treatment, circ_0058063/miR-635 may provide new molecular targets.

BACKGROUND Mounting studies have emerged indicating that patients with peptic ulcer disease (PUD) are at a high risk of developing osteoporosis, but the evidence has not been previously synthesized. The present study aims to examine whether patients with PUD have a significantly higher prevalence of osteoporosis than the healthy normal subjects. METHODS Four electronic databases were systematically searched for eligible studies up to February 2020. The association between PUD and osteoporosis was evaluated by calculating the relative risk (RR) with a 95% confidence interval (CI). RESULTS Six observational studies were finally included, enrolling a total of 216 122 individuals. Synthetic results from the six included studies providing the number of cases for both sexes demonstrated that PUD was significantly associated with an increased risk of osteoporosis (95% CI, 1.37-1.89; P

Phosphorylated AKT is highly expressed or overexpressed in chemoresistant tumor samples. However, the precise molecular mechanism involved in AKT phosphorylation-related chemoresistance in breast cancer is still elusive. The present research was designed to estimate the effect of AKT phosphorylation on cell viability and chemoresistance in breast cancer. We utilized MCF-7 and MDA-MB468 human breast cancer cell lines and developed multidrug-resistant MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells. Immunofluorescence analysis and Western blotting were employed to test the level of glycogen synthase kinase 3 beta (GSK3β), phosphorylated phosphatase and tension homologue (p-PTEN) and phosphorylated AKT (p-AKT) in MCF-7/MDR and MDA-MB468 cells. Xenograft assays in nude mice were performed with MCF-7/MDR cells to verify chemoresistance and the signaling pathway upstream of phosphatidylinositide 3-kinase (PI3K)/AKT. An increase in GSK3β, p-PTEN and p-AKT expression was strongly induced in MCF-7/MDR and cisplatin-resistant MDA-MB-468 cells, and augmented GSK3β phosphorylation and PTEN inactivation enhanced AKT signaling. The elevation in GSK3β, p-PTEN and p-AKT was associated with cell viability based on a CCK-8 assay. The results of in vivo and in vitro assays indicated that GSK3β knockdown with lentiviral shRNA (shRNA-GSK3β) promoted apoptosis and suppressed the migration of cisplatin-resistant MCF-7/MDR cells, while these effects were reversed by activating p-AKT with the PTEN inhibitor bpV(pic). AKT phosphorylation mediated by GSK3β and PTEN were correlated with cell viability, migration and apoptosis, which may promote chemoresistance in breast cancer. Furthermore, GSK3β can regulate cell viability through the PTEN/PI3K/AKT signaling pathway and induce chemoresistance, serving as a valuable molecular strategy for breast cancer therapy.

Demyelination in white matter is the end product of numerous pathological processes. This study was designed to evaluate the neuroprotective effect of l -serine and the underlying mechanisms against the demyelinating injury of white matter. A model of focal demyelinating lesions (FDL) was established using the two-point stereotactic injection of 0.25% lysophosphatidylcholine (LPC, 10 μg per point) into the corpus callosum of mice. Mice were then intraperitoneally injected with one of three doses of l -serine (114, 342, or 1026 mg/kg) 2 h after FDL, and then twice daily for the next five days. Behavior tests and histological analysis were assessed for up to twenty-eight days post-FDL induction. Electron microscopy was used for ultrastructural investigation. In vitro, we applied primary co-cultures of microglia and oligodendrocytes for oxygen glucose deprivation (OGD). After establishing FDL, l -serine treatment: 1) improved spatial learning, memory and cognitive ability in mice, and relieved anxiety for 4 weeks post-FDL induction; 2) reduced abnormally dephosphorylated neurofilament proteins, increased myelin basic protein, and preserved anatomic myelinated axons; 3) inhibited microglia activation and reduced the release of inflammatory factors; 4) promoted recruitment and proliferation of oligodendrocyte progenitor cells, and the efficiency of subsequent remyelination on day twenty-eight post-FDL induction. In vitro experiments, showed that l -serine not only directly protected against oligodendrocytes from OGD damage, but also provided an indirect protective effect by regulating microglia. In our study, l -serine offered long-lasting behavioral and oligodendrocyte protection and promoted remyelination. Therefore, l -serine may be an effective clinical treatment aganist white matter injury.

Objective Traumatic brain injury (TBI) results not only in gray matter damage, but also in severe white matter injury (WMI). Previous findings support hypoxic preconditioning (HP) could augment the efficacy of bone marrow stromal cell (BMSC) transplantation in a TBI mouse model. However, whether HP‐treated BMSCs (H‐BMSCs) could overcome remyelination failure after WMI is unclear, and the molecular mechanisms remain to be explored. Here, we focused on the therapeutic benefits of H‐BMSC transplantation for treating WMI, as well as its underlying mechanisms. Methods In vitro, BMSCs were incubated at passage 4 in the hypoxic preconditioning (1.0% oxygen) for 8 hr. In vivo, a TBI mouse model was established, and DMEM cell culture medium (control), normal cultured BMSCs (N‐BMSCs), or H‐BMSCs were transplanted to mice 24 hr afterward. Neurobehavioral function, histopathological changes, and oligodendrogenesis were assessed for up to 35 days post‐TBI. Results Compared with the control group, improvement of cognitive functions and smaller lesion volumes was observed in the two BMSC‐transplanted groups, especially the H‐BMSC group. H‐BMSC transplantation resulted in a greater number of neural/glial antigen 2 (NG2)–positive and adenomatous polyposis coli (APC)–positive cells than N‐BMSC transplantation in both the corpus callosum and the striatum. In addition, we observed that the expression levels of hypoxia‐inducible factor‐1a (HIF‐1α), phosphorylated mechanistic target of rapamycin (p‐mTOR), and vascular endothelial growth factor (VEGF) were all increased in H‐BMSC–transplanted mice. Furthermore, the mTOR pathway inhibitor rapamycin attenuated the impact of HP both in vivo and in vitro. Conclusion The results provided mechanistic evidences suggesting that HP‐treated BMSCs promoted remyelination partly by modulating the pro‐survival mTOR/HIF‐1α/VEGF signaling pathway., The aim of the present study was to assess the effects of HP‐treated BMSCs (H‐BMSCs) on neuronal behavior and the differentiation of cells in the white matter area following TBI in mice. H‐BMSC transplantation not only ameliorated neurological deficits, but also enhanced axonal regeneration and remyelination in mice after TBI, which may involve the mTOR/HIF‐1α/VEGF pathway. This study provided novel biological and histopathological evidences for TBI treatment that H‐BMSC transplantation may serve as a promising therapeutic option for both gray matter and white matter.

Disruption of remyelination contributes to neurodegeneration and cognitive impairment in chronically disabled patients. Valproic acid (VPA) inhibits histone deacetylase (HDAC) function and probably promotes oligodendrocyte progenitor cell (OPC) proliferation and differentiation; however, the relevant molecular mechanisms remain unknown. Here, focal demyelinating lesions (FDLs) were generated in mice by two-point stereotactic injection of lysophosphatidylcholine (LPC) into the corpus callosum. Cognitive functions, sensorimotor abilities and histopathological changes were assessed for up to 28 days post-injury with or without VPA treatment. Primary OPCs were harvested and used to study the effect of VPA on OPC differentiation under inflammatory conditions. VPA dose-dependently attenuated learning and memory deficits and robustly protected white matter after FDL induction, as demonstrated by reductions in SMI-32 and increases in myelin basic protein staining. VPA also promoted OPC proliferation and differentiation and increased subsequent remyelination efficiency by day 28 post-FDL induction. VPA treatment did not affect HDAC1, HDAC2 or HDAC8 expression but reduced HDAC3 protein levels. In vitro, VPA improved the survival of mouse OPCs and promoted their differentiation into oligodendrocytes following lipopolysaccharide (LPS) stimulation. LPS caused OPCs to overexpress HDAC3, which translocated from the cytoplasm into the nucleus, where it directly interacted with the nuclear transcription factor PPAR-γ and negatively regulated PPAR-γ expression. VPA decreased the expression of HDAC3 and promoted remyelination and functional neurological recovery after FDL. These findings may support the use of strategies modulating HDAC3-mediated regulation of protein acetylation for the treatment of demyelination-related cognitive dysfunction.

Herniated disc (HD) is one of the most common causes of lower back pain. Treatment for HD includes conservative therapy and surgical intervention. Following conservative treatment, spontaneous absorption of HD occurs in some patients. To assess whether modic changes are associated with spontaneous absorption of HD, 85 patients with or without modic changes were followed up after 6 months of conservative treatment. As result, we found modic changes of lumbar endplates are associated with poor absorption of HD after conservative treatment. In addition, patients with modic changes exhibit significantly increased cartilage content and decreased neovascularization and macrophage infiltration in HD tissues, all of which are known to impair spontaneous absorption of herniated tissues. At molecular level, modic changes are associated with decreased expression of matrix metalloproteinase-3 gene, which is a key matrix-degrading enzyme for tissue absorption. Our study established a strong association between modic changes of lumbar endplates and spontaneous absorption of lumbar HD, which provided a potential novel method for prediction of spontaneous absorption.

Herniated disc (HD) is one of the most common causes of lower back pain. Treatment for HD includes conservative therapy and surgical intervention. Following conservative treatment, spontaneous absorption of HD occurs in some patients. To assess whether modic changes are associated with spontaneous absorption of HD, 85 patients with or without modic changes were followed up after 6 months of conservative treatment. As result, we found modic changes of lumbar endplates are associated with poor absorption of HD after conservative treatment. In addition, patients with modic changes exhibit significantly increased cartilage content and decreased neovascularization and macrophage infiltration in HD tissues, all of which are known to impair spontaneous absorption of herniated tissues. At molecular level, modic changes are associated with decreased expression of matrix metalloproteinase-3 gene, which is a key matrix-degrading enzyme for tissue absorption. Our study established a strong association between modic changes of lumbar endplates and spontaneous absorption of lumbar HD, which provided a potential novel method for prediction of spontaneous absorption.

Background Demyelination is the end product of numerous pathological processes, and also is one of the main causes of neurological disability in Multiple sclerosis (MS). Research into the pathogenesis of MS is hampered by the conventional rodent models’ inability to produce stable demyelination. New method Focal demyelinating lesions were stereotactically targeted to the corpus callosum with a two-point injection of lysophosphatidylcholine (LPC-2) in mice. Three groups were analyzed (n = 8, each) and water maze, sensorimotor test, and compound action potential were included in functional tests. Electron microscopy was used for morphological analyses while western blot and immunohistochemistry were included for molecular detection. Results Ten days after the LPC-2 injection, the expression of myelin basic protein (MBP) was reduced, while non-phosphorylated neurofilament (SMI-32) was increased. The amplitude of the N1 segment decreased and less well-defined myelin sheaths was found. Behavioral tests showed increased latency to escape and reduced time spent in target quadrant. Four weeks later, MBP expression still reduced, SMI-32 expression was increased, both spatial learning (D24-D27) and spatial memory (D28) were still significantly impaired in LPC-2 injection mice. Comparison with existing method(s) Compared with the classic single-point LPC-injection model, our studies showed that the two-point LPC-injection not only could induce demyelination in a short-term manner, but also could cause demyelination in a long-term manner with little remyelination in the mouse corpus callosum. Conclusions We established a simple, reliable, and inexpensive model of demyelination in the corpus callosum in mice, with functional and morphological reproducibility, and good validity.

e15512 Background: Programmed death ligand 1 (PD-L1) expression has become a promising biomarker in predicting the efficacy of immune checkpoint inhibitors in various advanced cancers, including gastric cancer (GC). However, the prognostic value and clinicopathological significance of PD-L1 in GC is still not clearly identified. Hence, we carried out a meta-analysis to investigate the potential role of PD-L1 in GC, expecting to provide new clues for the judgement of prognosis in resected gastric cancer. Methods: A literature search strategy was performed from the PubMed, Web of Science, EMBASE, and the Cochrane Library database as of December 1, 2018. Relevant data was rigorously extracted from the included literatures. Hazard ratios (HRs) and Odds ratios (ORs) along with 95% confidence intervals (95% CIs) were used to evaluate the prognostic value or clinicopathological significance of PD-L1 expression in GC. Results: A total of 21 studies containing 6021 patients fitted into our meta-analysis. The pooled HRs indicated that PD-L1 high-expression accompanied with a worse overall survival (OS) (HR=1.28, 95% CI: 1.01-1.62, P=0.04) in GC, while no correlation with disease-free survival (DFS) (HR=0.88, 95%CI: 0.53-1.45, P=0.61). Subgroup analysis showed that PD-L1 high-expression was negatively associated with distant metastasis groups (OR=0.66, 95%CI:0.48-0.89, P=0.01), but was positively related to elderly(OR=1.19, 95%CI: 1.01-1.40, P=0.04), lymph-node metastasis(OR=1.63, 95%CI: 1.08-2.46, P=0.02), deeper tumor infiltration(OR=1.73, 95%CI: 1.08-2.79, P=0.02), Epstein-Barr virus infection positive (EBV+) (OR=8.01, 95%CI: 3.10-20.72, P

Herniated disc (HD) is one of the most common causes of lower back pain. Treatment for HD includes conservative therapy and surgical intervention. Following conservative treatment, spontaneous absorption of HD occurs in some patients. To assess whether modic changes are associated with spontaneous absorption of HD, 85 patients with or without modic changes were followed up after 6 months of conservative treatment. As result, we found modic changes of lumbar endplates are associated with poor absorption of HD after conservative treatment. In addition, patients with modic changes exhibit significantly increased cartilage content and decreased neovascularization and macrophage infiltration in HD tissues, all of which are known to impair spontaneous absorption of herniated tissues. At molecular level, modic changes are associated with decreased expression of matrix metalloproteinase-3 gene, which is a key matrix-degrading enzyme for tissue absorption. Our study established a strong association between modic changes of lumbar endplates and spontaneous absorption of lumbar HD, which provided a potential novel method for prediction of spontaneous absorption.