Glioblastoma cellular MAP4K1 facilitates tumor growth and disrupts T effector cell infiltration.

MAP4K1 has been identified as a cancer immunotherapy target. Whether and how cancer cell-intrinsic MAP4K1 contributes to glioblastoma multiforme (GBM) progression remains unclear. We found that MAP4K1 was highly expressed in the glioma cells of human GBM specimens. High levels of MAP4K1 mRNA were prevalent in IDH-WT and 1p/19q non-codeletion gliomas and correlated with poor prognosis of patients. MAP4K1 silencing inhibited GBM cell proliferation and glioma growth. Transcriptome analysis of GBM cells and patient samples showed that MAP4K1 modulated cytokine‒cytokine receptor interactions and chemokine signaling pathway, including IL-18R and IL-6R Importantly, MAP4K1 loss down-regulated membrane-bound IL-18R/IL-6R by inhibiting the PI3K-AKT pathway, whereas MAP4K1 restoration rescued this phenotype and therefore GBM cell proliferation. MAP4K1 deficiency abolished GBM cell pro-proliferation responses to IL-18, suggesting an oncogenic role of MAP4K1 via the intrinsic IL-18/IL-18R pathway. In addition, GBM cell-derived MAP4K1 impaired T-cell migration and reduced CD8+ T-cell infiltration in mouse glioma models. Together, our findings provide novel insight into the pathological significance of GBM cell-intrinsic MAP4K1 in driving tumor growth and immune evasion by remodeling cytokine-chemokine networks.

Quality evaluation of guidelines for the diagnosis and treatment of radiation enteritis.

OBJECTIVE: To systematically evaluate the guidelines for the diagnosis and treatment of radioactive enteritis, compare their differences and reasons and provide some reference for updating them. METHODS: This study used guidelines related to radiation enteritis by searching a database. Four independent reviewers used the AGREE II evaluation tool to evaluate the quality of the included guidelines, collate their main recommendations, and analyze the highest evidence supporting the main recommendations. RESULTS: Six diagnostic and therapeutic guidelines for radiation enteritis were included in this study, one of which, the American Society for Gastrointestinal Endoscopy guidelines, had an overall score of over 60%, which is worthy of clinical recommendation. In the diagnosis and treatment of radioactive rectal injury, the recommendations for hemorrhagic endoscopic treatment are mature and mainly include (I) argon plasma coagulation; (II) formalin treatment; (III) bipolar electrocoagulation; (IV) heater probe; (V) radiofrequency ablation; and (VI) cryoablation. CONCLUSION: The methodological quality of radioactive enteritis guidelines is unequal; even in the same guidelines, different domains have a large difference. For radioactive rectal damage diagnosis, a type of endoscopic treatment recommendation is more mature, but the overall diagnosis and treatment of radioactive enteritis still lacks high-quality research evidence.

Evaluation of guidelines for diagnosis and treatment of Helicobacter pylori infection.

BACKGROUND: To systematically evaluate the quality of the guidelines for the diagnosis and treatment of Helicobacter pylori infection and to analyze the differences and reasons for the key recommendations in the guidelines. METHODS: Databases and websites were systematically searched to obtain guidelines for the diagnosis and treatment of Helicobacter pylori infection. Four independent reviewers used the Guideline Evaluation Tool (AGREE II) to evaluate the included guidelines. The intraclass correlation coefficient (ICC) and Fleiss' kappa coefficient were used to measure the consistency of evaluation guidelines between guide reviewers. Differences between guidelines and the reasons for the differences were analyzed by comparing the recommendations of different guidelines and the evidence supporting the recommendations. RESULTS: A total of 17 guidelines for Helicobacter pylori infection were included in this study. The AGREE II scores of these guidelines were low overall, with 4 of them had a score of over 60%, which indicates that the guidelines are recommended, and 13 of them having a score ranging from 30 to 60%, which indicates that the guidelines are recommended but need to be revised, while no guideline had a score of 30% or less, which indicates that they were not recommended. The analysis of these guidelines found that there were some differences in the main recommendations. Not all guidelines recommend sequential therapy as the recommended therapy. Whether bismuth quadruple therapy should be used as the recommended first-line therapy is unclear. The antibiotic resistance rate is different in different regions. Combined with the local antibiotic sensitivity test, the eradication rate of Helicobacter pylori can be improved. CONCLUSION: There are significant differences in the quality of Helicobacter pylori infection guidelines and the key recommendations. Improving the deficiencies of existing guidelines is an effective way to develop high-quality guidelines and make reasonable recommendations for the treatment of Helicobacter pylori infection in the future.

MLK3 Is Associated With Poor Prognosis in Patients With Glioblastomas and Actin Cytoskeleton Remodeling in Glioblastoma Cells.

Mixed lineage kinase 3 (MLK3) has been implicated in human melanoma and breast cancers. However, the clinical significance of MLK3 in human gliomas and the underlying cellular and molecular mechanisms remain unclear. We found that MLK3 proteins were highly expressed in high-grade human glioma specimens and especially prevalent in primary and recurrent glioblastoma multiforme (GBM). High levels of MLK3 mRNA were correlated with poor prognosis in patients with isocitrate dehydrogenase (IDH)-wild-type (wt) gliomas. Furthermore, genetic ablation of MLK3 significantly suppressed the migration and invasion abilities of GBM cells and disrupted actin cytoskeleton organization. Importantly, MLK3 directly bound to epidermal growth factor receptor kinase substrate 8 (EPS8) and regulated the cellular location of EPS8, which is essential for actin cytoskeleton rearrangement. Overall, these findings provide evidence that MLK3 upregulation predicts progression and poor prognosis in human IDH-wt gliomas and suggest that MLK3 promotes the migration and invasion of GBM cells by remodeling the actin cytoskeleton via MLK3-EPS8 signaling.

[Initial screening of binding-peptide of the cell surface marker CD133 of cancer stem cells].

OBJECTIVE: To select the binding-peptide of the cell surface marker CD133 of cancer stem cells from phage peptide library, and to find a new tool for research on stem cells, tumor therapy and anti-metastasis of cancer. METHODS: Biotined mouse CD133 extracellular fraction was used as a target to screen phage 7-peptide library by the high affinity of streptavidin and biotin, and the clones were identified by sandwich ELISA and competitive experiment. Single strand DNA was extracted from these positive clones and was analyzed by single-strand dideoxy-sequencing. RESULTS: After three turn solution panning, five peptides with high affinity shared the same amino acid sequence: APSPMIW and three identical peptides with high affinity shared the same amino acid sequence: LQNAPRS. CONCLUSION: The peptides that bind with mouse CD133 extracellular fraction with high affinity and specificity were first screened from the phage peptide library for the first time, which initially indicates that the feasibility of screening from phage peptide library with small molecule polypeptide biotined as a target.

Expression of maspin and kai1 and their clinicopathological significance in carcinogenesis and progression of gastric cancer.

OBJECTIVE: To investigate the roles of maspin and kai1 expression in tumorigenesis and progression of gastric cancer. METHODS: Maspin and kai1 expressions were detected in normal gastric mucosa (n = 182), gastric dysplasia (n = 69), and gastric cancer (n = 113) by immunohisto-chemistry. Their expressions were compared with clinicopathological parameters of tumors. Relationship between maspin and kai1 expression was also concerned in gastric cancer. RESULTS: The positive rates of maspin expression were 79.8% (145/182), 75.4% (52/69), and 50.4% (57/113) in normal gastric mucosa, gastric dysplasia, and gastric cancer, while those of kai1 expression were 81.9% (149/182), 65.2% (49/69), and 58.4% (66/113) in corresponding tissues respectively. Gastric cancer less frequently expressed maspin than the normal gastric mucosa and gastric dysplasia (P < 0.05), while dysplasia and cancer showed less frequent expression of kai1 than normal mucosa (P < 0.05). Maspin expression showed negative association with invasive depth, metastasis, Lauren's and histological classifications (P < 0.05), but not with tumor size, Borrmann's classification, growth pattern or TNM staging (P > 0.05). Kai1 expression was negatively correlated with invasive depth, metastasis, growth pattern, Lauren's and histological classifications (P < 0.05), but not with tumor size, Borrmann's classification or TNM staging (P > 0.05). Maspin and kai1 were collaboratively expressed in gastric cancer (P < 0.05). CONCLUSIONS: Down-regulated expressions of maspin and kai1 play an important role in gastric carcinogenesis. Abnormal expression of maspin and kai1 might have inhibitory effects on invasion and metastasis of gastric cancer and act as an effective and objective marker to indicate the pathobiological behaviors of gastric cancer.

Role of PTEN and MMP-7 expression in growth, invasion, metastasis and angiogenesis of gastric carcinoma.

To investigate the role of PTEN and matrix metalloproteinase-7 (MMP-7) expression in tumorigenesis and progression of gastric carcinoma, their expression in 113 gastric carcinomas was studied by immunohistochemistry. Microvessel density (MVD) was counted using the anti-CD34 antibody. The expressions of PTEN and MMP-7, and MVD were compared with the clinicopathological parameters of tumors, and the relationship between PTEN and MMP-7 expression and MVD was analyzed. It was found that PTEN was expressed less frequently in primary gastric carcinoma cells than in adjacent epithelial cells (P < 0.05), whereas this was reversed for MMP-7 (P < 0.05). PTEN expression was negatively correlated with invasion, metastasis, growth pattern, Lauren's classification and histological classification (P < 0.05). Matrix metalloproteinase-7 expression was positively associated with tumor size, Borrmann's classification, invasive depth, metastasis and TNM staging (P < 0.05), but negative with PTEN expression (P < 0.05). A positive correlation of MVD with tumor size, invasive depth, metastasis and TNM staging was found (P < 0.05). Microvessel density depended on decreased PTEN expression and increased MMP-7 expression (P < 0.05). The results of the present study suggested that down-regulated PTEN expression and up-regulated MMP-7 expression were greatly implicated in tumorigenesis and progression of gastric carcinoma. Close correlation between PTEN on MMP-7 expression provided a novel insight into the regulatory effects of PTEN on MMP-7 expression in gastric carcinoma.

Growth, invasion, metastasis, differentiation, angiogenesis and apoptosis of gastric cancer regulated by expression of PTEN encoding products.

AIM: To investigate expression of PTEN in gastric cancer and to explore its roles in tumorigenesis and progression of gastric cancer. METHODS: Formalin-fixed and paraffin-embedded tissues of adjacent non-tumor mucosa and primary foci from 113 cases of gastric cancers were studied for the expression of PTEN and Caspase-3 and microvessel density (MVD) by streptavidin-peroxidase (S-P) immunohistochemistry with antibodies against PTEN, Caspase-3, and CD34. The relationship between PTEN and Caspase 3 expression and clinicopathological parameters of tumors was compared. RESULTS: Primary gastric cancer cells expressed PTEN less frequently than adjacent epithelial cells of primary foci (54.9 % vs 89.4 %; P=0.000, chi(2)=33.474). PTEN expression was significantly associated with invasive depth (P=0.003, rs=0.274), metastasis (P=0.036, rs=0.197), growth pattern (P=0.008, rs=0.282), Lauren's classification (P=0.000, rs=0.345), and histological classification (P=0.005, rs=0.262) of tumors, but not with tumor size (P=0.639, rs=0.045), Borrmann's classification (P=0.544, rs=0.070) or TNM staging (P=0.172, rs=0.129). PTEN expression was negatively correlated with MDV in primary gastric cancer (P=0.020, F=5.558). Primary gastric cancer cells showed less frequent immunoreactivity to Caspase-3 than adjacent epithelial cells of primary foci (32.7 % vs 50.4 %; P=0.007, chi(2)=7.286). Caspase-3 expression was dependent of PTEN expression in primary gastric cancer cells (P=0.000, chi(2)=15.266). CONCLUSION: Down-regulated expression of PTEN plays an important role in tumorigenesis, progression, growth, differentiation and angiogenesis of gastric cancer. Low expression of PTEN can decrease expression of Caspase-3 to disorder apoptosis of tumor cells, which might explain the molecular mechanisms of PTEN contributions to tumorigenesis and progression of gastric cancer.

Expression of Fas ligand and caspase-3 contributes to formation of immune escape in gastric cancer.

AIM: To study the role of Fas ligand (FasL) and Caspase-3 expression in carcinogenesis and progression of gastric cancer and molecular mechanisms of relevant immune escape. METHODS: FasL and Caspase-3 expression was studied in adjacent epithelial cells, cancer cells and lymphocytes of primary foci, and cancer cells of metastatic foci from 113 cases of gastric cancer by streptavidin-biotin-peroxidase (S-P) immunohistochemistry. Expression of both proteins in cancer cells of primary foci was compared with clinicopathological features of gastric cancer. The relationship between FasL expression in cancer cells and Caspase-3 expression in cancer cells or infiltrating lymphocytes of primary foci was investigated. RESULTS: Cancer cells of primary foci expressed FasL in 53.98 % (61/113) of gastric cancers, more than their adjacent epithelial cells (34.51 %, 39/113) (P=0.003, chi(2)=8.681), while the expression of Caspase-3 in cancer cells of primary foci was detected in 32.74 % (37/113) of gastric cancers, less than in the adjacent epithelial cells (50.44 %, 57/113) (P=0.007, chi(2)=7.286). Infiltrating lymphocytes of the primary foci showed positive immunoreactivity to Caspase-3 in 70.80 % (80/113) of gastric cancers, more than their corresponding adjacent epithelial cells (P=0.001, chi(2)=10.635) or cancer cells of primary foci (P=0.000, chi(2)=32.767). FasL was less expressed in cancer cells of metastases (51.16 %, 22/43) than in those of the corresponding primary foci (81.58 %, 31/38) (P=0.003, chi(2)=9.907). Conversely, Caspase-3 was more expressed in cancer cells of metastases (58.14 %, 25/43) than in those of the corresponding primary foci (34.21 %, 13/38) (P=0.031, chi(2)=4.638). FasL expression was significantly correlated with tumor size (P=0.035,rs=0.276), invasive depth (P=0.039, rs=0.195), metastasis (P=0.039, rs=0.195), differentiation (P=0.015, rs=0.228) and Lauren's classification (P=0.038, rs=0.196), but not with age or gender of patients, growth pattern or TNM staging of gastric cancer (P>0.05). In contrast, Caspase-3 expression showed no correlation with any clinicopathological parameters described above in cancer cells of the primary foci (P>0.05). Interestingly, FasL expression in primary gastric cancer cells paralleled to Caspase-3 expression in infiltrating lymphocytes of the primary foci (P=0.016, chi(2)=5.825). CONCLUSION: Up-regulated expression of FasL and down-regulated expression of Caspase-3 in cancer cells of primary foci play an important role in gastric carcinogenesis. As an effective marker to reveal the biological behaviors, FasL is implicated in differentiation, growth, invasion and metastasis of gastric cancer by inducing apoptosis of infiltrating lymphocytes. Chemical substances derived from the primary foci and metastatic microenvironment can inhibit the growth of metastatic cells by enhancing Caspase-3 expression and diminishing FasL expression.