Background：Osteosarcoma is the most common bone malignancy in children and adolescents,and 20%-30%of the patients suffer from poor prognosis because of individual chemoresistance.The ...Hippo/yes-associated protein（YAP） signaling pathway has been shown to play a role in tumor chemoresistance,but no previous report has focused on its involvement in osteosarcoma chemoresistance.This study aimed to investigate the role of the Hippo/YAP signaling pathway in osteosarcoma chemoresistance and to determine potential treatment targets.Methods：Using the Cell Titer-Glo Luminescent cell viability assay and flow cytometry analysis,we determined the proliferation and chemosensitivity of YAP-overexpressing and YAP-knockdown osteosarcoma cells.In addition,using western blotting and the real-time polymerase chain reaction technique,we investigated the alteration of the Hippo/YAP signaling pathway in osteosarcoma cells treated with chemotherapeutic agents.Results：Mammalian sterile 20-like kinase 1（MST1） degradation was increased,and large tumor suppressor kinase1/2（LAT51/2） total protein levels were decreased by methotrexate and doxorubicin,which increased activation and nuclear translocation of YAP.Moreover,YAP increased the proliferation and chemoresistance of MG63 cells.Conclusions：The Hippo/YAP signaling pathway plays a role in osteosarcoma chemoresistance,and YAP is a potential target for reducing chemoresistance.
Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ...ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB
bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.
2 With improvements in medical imaging technology and related basic research, the perception of CSDH as an inflammatory vascular proliferative disease has gradually reached consensus. 3 In addition ...to head trauma, brain atrophy leading to expanded subdural space is the premise and primary reason for the occurrence of CSDH in the older adult population. The study was conducted by the Declaration of Helsinki and was approved by the Institutional Review Board of Capital Medical University. Inclusion criteria were as follows: (1) medical history of head trauma or no clear medical history; (2) symptoms such as headache, vomiting, blurred vision, seizures, memory and mental retardation, or mental disorders; (3) neurologic dysfunction, such as hemiplegia or aphasia; (4) CT showed crescent, half-moon, or fusiform low density appearing mainly below the inner plate cranial bone, possibly accompanied by brain deformation and midline shift; (5) no medication history for CSDH; (6) suspension of anticoagulant drugs such as aspirin for more than 10 days; and (7) non-recurrent CSDH.
Purpose
To compare the clinical, imaging, and arthroscopic characteristics of the torn discoid lateral meniscus (TDLM) in patients greater than 40 years of age with matched controls.
Methods
One ...hundred and ninety-four older patients (211 knees) who underwent arthroscopic surgery for a TDLM were consecutively recruited (Group 1). Another 211 age- and sex-matched controls with a torn semilunar lateral meniscus were included in this study (Group 2). Statistical analyses were used to determine the differences in the clinical, imaging, and arthroscopic characteristics between the two groups.
Results
In our series, more severe medial meniscal extrusion on magnetic resonance imaging was present in Group 1 than in Group 2 and more serious osteoarthritic changes were observed in both the medial and lateral compartments in Group 1. Under the same conditions, chondral lesions in the knee were more serious in Group 1 than in Group 2 when patients were subgrouped according to the presence of a horizontal tear or complex tear.
Conclusions
In the present study, older patients with a torn discoid lateral meniscus exhibited greater and more severe medial meniscal extrusion and more serious osteoarthritis. Therefore, knees with a discoid lateral meniscus displaying medial meniscal extrusion should be monitored carefully with long-term follow-up, because a medial meniscal extrusion may increase the risk of progression to degenerative osteoarthritis of the medial compartment. Regarding the clinical relevance, these findings will be helpful in further revealing that a torn discoid lateral meniscus may affect not only the cartilage in the lateral compartment but also the cartilage in the medial compartment and medial meniscal extrusion.
Level of evidence
III.
The whole outcome for patients with gastric carcinoma (GC) is very poor because most of them remain metastatic disease during survival even at diagnosis or after surgery. Despite many improvements in ...multiple strategies of chemotherapy, immunotherapy, and targeted therapy, exploration of novel alternative therapeutic targets is still warranted. Chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12) have been identified with significantly elevated levels in various malignancies including GC, which correlates with the survival, proliferation, angiogenesis, and metastasis of tumor cells. Increasing experimental evidence suggests an implication of inhibition of CXCL12/CXCR4 axis as a promising targeted therapy, although there are rare trials focused on the therapeutic efficacy of CXCR4 inhibitors in GC until recently. Therefore, it is reasonable to infer that specific antagonists or antibodies targeting CXCL12/CXCR4 axis alone or combined with chemotherapy will be effective and worthy of further translational studies as a potential treatment strategy in advanced GC.
Chemokine receptor 4 (CXCR4) and its chemokine ligand 12 (CXCL12) have been identified with significantly increased levels in various malignancies including gastric carcinoma (GC), which correlates with the survival, proliferation, angiogenesis, and metastasis of tumor cells. Increasing experimental evidence suggest an implication of inhibition of CXCL12/CXCR4 axis as a promising targeted therapy, although there are rare studies focused on the therapeutic efficacy of CXCR4 inhibitors in GC until recently. This review therefore aims to summarize and discuss multiple biological roles of CXCL12/CXCR4 axis and the potential application of CXCR4 inhibitors as a targeted therapy in advanced GC.
Krüppel-like factors (KLFs) are zinc-finger transcriptional factors that regulate target gene expression. Recent studies have shown that KLFs play essential roles in cancer development, whereas the ...function of KLF7 in glioma remains unclear. In this study, we showed that KLF7 was up-regulated in glioma tissues and its expression was inversely correlated with the patients’ survival. Functional experiments demonstrated that KLF7 promoted the proliferation, migration and tumorigenesis of glioma cells. Mechanistically, KLF7 transcriptionally activated argininosuccinate lyase (ASL), which was observed highly expressed in glioma tissues. The biosynthesis of polyamine, a urea cycle metabolite, was enhanced by KLF7 in glioma cells. In addition, ASL contributed to the growth of glioma cells triggered by KLF7. Our findings demonstrate KLF7 as an oncogene and link KLF7 to ASL-mediated polyamine metabolism in glioma.
•KLF7 is over-expressed in glioma and is associated with the patients’ survival.•KLF7 promotes the proliferation, growth, migration and tumorigenesis of glioma cells.•KLF7 transcriptionally activates ASL and enhances the biosynthesis of polyamine.•ASL is highly expressed in glioma and it promotes glioma cell proliferation.
Glioma is the most common primary malignant tumor in the central nervous system. Because of the resistance of glioma to chemoradiotherapy and its aggressive growth, the survival rate of patients with ...glioma has not improved. This study aimed to disclose the effect of retinol dehydrogenase 10 (RDH10) on the migration and invasion of glioma cells, and to explore the potential mechanism.
Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the expression levels of RDH10 in healthy glial cells and glioma cells. Human glioma cell strains, U87 and U251, were infected with negative control or RDH10-interfering lentiviruses. RT-PCR and Western blotting were performed to determine the knockdown efficiency. Scratch and transwell assays were used to assess cell migration and invasion after RDH10 knockdown. Finally, changes in transforming growth factor-β (TGF-β)/SMAD signaling pathway-related expression were examined by Western blotting. Differences between groups were analyzed by one-way analysis of variance.
RDH10 was highly expressed in glioma cells. Compared with the control group, RDH10 knockdown significantly reduced RDH10 messenger RNA and protein expression levels in U87 and U251 glioma cells (U87: 1.00 ± 0.08 vs. 0.22 ± 0.02, t = 16.55, P < 0.001; U251: 1.00 ± 0.17 vs. 0.39 ± 0.01, t = 6.30, P < 0.001). The scratch assay indicated that compared with the control group, RDH10 knockdown significantly inhibited the migration of glioma cells (U87: 1.00% ± 0.04% vs. 2.00% ± 0.25%, t = 6.08, P < 0.01; U251: 1.00% ± 0.11% vs. 2.48% ± 0.31%, t = 5.79, P < 0.01). Furthermore, RDH10 knockdown significantly inhibited the invasive capacity of glioma cells (U87: 97.30 ± 7.01 vs. 13.70 ± 0.58, t = 20.36, P < 0.001; U251: 96.20 ± 7.10 vs. 18.30 ± 2.08, t = 18.51, P < 0.001). Finally, Western blotting demonstrated that compared with the control group, downregulation of RDH10 significantly inhibited TGF-β expression, phosphorylated SMAD2, and phosphorylated SMAD3 (TGF-β: 1.00 ± 0.10 vs. 0.53 ± 0.06, t = 7.05, P < 0.01; phosphorylated SMAD2: 1.00 ± 0.20 vs. 0.42 ± 0.17, t = 4.01, P < 0.01; phosphorylated SMAD3: 1.00 ± 0.18 vs. 0.41 ± 0.12, t = 4.12, P < 0.01).
RDH10 knockdown might inhibit metastasis of glioma cells via the TGF-β/SMAD signaling pathway.
Aims To investigate whether DNA active demethylase TET regulates the expression of tight junction proteins in endothelial cells of the blood-brain barrier (BBB). Methods Correlations between TET2 ...activity (indicated by its catalytic product 5hmC) and the expression of BBB tight junction proteins were examined in Tet2 knockout mice and post-mortem human brain tissues. In cultured endothelial cells, the impact of changes of TET activity on the expression of tight junction protein, ZO-1, was studied. BBB permeability assays were performed in Tet2 knockout mice. Results It was found that the level of 5hmC decreased in brain microvascular endothelial cells of aging mice. In Tet2 knockout mice, the level of 5hmC in endothelial cells was weaker and significantly correlated with the reduced expression of tight junction protein ZO-1. In cultured endothelial cells, H.sub.2O.sub.2 significantly decreased the expression of 5hmC and ZO-1. Tet2 knock-down using siRNA significantly downregulated the expression of ZO-1 in endothelial cells. hMeChip-PCR showed that H.sub.2O.sub.2 decreased the level of 5hmC in the ZO-1 promoter region, which was rescued by N-acetyl cysteine (NAC). Consistently, Tet2 knock-down using siRNA significantly downregulated the level of 5hmC in the ZO-1 promoter region. It was also found that the level of 5hmC decreased in endothelial cells of aging human brains compared with that of adult brains, and the level of ZO-1 was positively correlated with that of 5hmC in microvascular endothelial cells. Conclusions These findings suggest that TET activity is essential in regulating ZO-1 expression of BBB. It might be a potential target for neuroprotection during aging and in diverse neurological conditions. Keywords: The ten-eleven translocation methyl cytosine dioxygenase, 5-hydroxymethylcytosine, Aging, Blood brain barrier, Zonula occludens-1, Vascular endothelial cells
Esophageal squamous cell carcinoma (ESCC) has limited effective treatment strategies. DNA damage response (DDR) genes are of therapeutic interest in multiple cancer types. This study aimed to depict ...the landscape of DDR mutations in ESCC and evaluate the association between DDR mutations and known immunotherapy biomarkers. We recruited 250 Chinese patients with ESCC and performed next-generation sequencing. A total of 107 patients underwent a PD-L1 examination. Among the 250 patients, 73 (29.2%) harbored at least one DDR gene mutation and were defined as DDR-mut. Among the six functional DDR pathways, homologous recombination (HR) accounted for 12.4% (31/250). DDR-mut patients were significantly associated with higher tumor mutational burden than those in the DDR-wt group (p=7.4e-07). Patients with PDL1-H accounted for 21.2% (36/107) of the patients. PDL1-H was more prevalent in DDR-mut than DDR-wt, although the p-value did not reach a significant level (40.5% vs. 30%, p=0.29). Further analysis revealed that BRCA1, one of the most frequently mutated genes in the HR pathway, was significantly associated with PDL1-H (p=0.01). Our data revealed a subset of patients with ESCC harbored DDR gene mutations. Patients with these DDR gene mutations are significantly associated with immune biomarkers, implying the potential feasibility of combining DDR agents with immunotherapy in patients with DDR deficiency.
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