Attenuating glucose metabolism by Fbxw7 promotes Taxol sensitivity of colon cancer cells through downregulating NADPH oxidase 1 (Nox1).

BACKGROUND: Colorectal cancer (CRC), one of the most common malignancies worldwide, is associated with poor survival and has a high mortality rate. Taxol is a chemotherapeutic agent that has been clinically applied as a first-line drug against diverse cancers. Yet, development of drug resistance has become the major challenge for anti-cancer treatments. F-box and WD40 domain protein 7 (Fbxw7) is a known tumor suppressor which is frequently downregulated in cancers. However, the biological roles and mechanisms of Fbxw7 in Taxol resistance are still under investigation. METHODS: We report that Fbxw7 is significantly inactivated in CRC tumors and cell lines compared with normal tissues and colon cells. Expressions of Fbxw7 and Nox1 were detected from human colon tumors and cells by qRT-PCR and Western blot. Glycolysis rate was assessed by glucose uptake and lactate product assay. Interactions between Fbxw7 and Nox1 were determined by co-immunoprecipitation (Co-IP). Chemosensitivity and resistance of colon cancer cells were determined by MTT assay and Annexin V-FITC assay. RESULTS: Overexpression of Fbxw7 sensitized colon cancer cells to Taxol. Moreover, we observed a negative correlation between Fbxw7 and glucose metabolism. From the established Taxol-resistant (TR) cell line from HCT-116, Fbxw7 was found to be markedly downregulated in HCT-116 TR cells. We detected that NADPH oxidase 1 (Nox1), a superoxide-generating NADPH oxidase, is negatively regulated by Fbxw7. The Co-IP assay showed that Fbxw7 interacted with Nox1, which was observed to be significantly upregulated in CRC tissues. Nox1 therefore promotes the Taxol resistance and glucose metabolism of colon cancer cells. Finally, rescue experiments demonstrated that the Fbxw7-promoted Taxol sensitivity was partially through the Nox1-glycolysis axis. Restoration of Nox1 in Fbxw7-overexpressed TR colon cancer cells significantly recovered the Taxol resistance, which could be further overridden by glycolysis inhibition. CONCLUSIONS: Collectively, this study uncovered that targeting the Fbxw7-Nox1-glucose metabolism axis could be an effective strategy against chemoresistant colon cancer.

Effect of combined VEGF165/ SDF-1 gene therapy on vascular remodeling and blood perfusion in cerebral ischemia.

OBJECTIVE Therapeutic neovascularization is a promising strategy for treating patients after an ischemic stroke; however, single-factor therapy has limitations. Stromal cell-derived factor 1 (SDF-1) and vascular endothelial growth factor (VEGF) proteins synergistically promote angiogenesis. In this study, the authors assessed the effect of combined gene therapy with VEGF165 and SDF-1 in a rat model of cerebral infarction. METHODS An adenoviral vector expressing VEGF165 and SDF-1 connected via an internal ribosome entry site was constructed (Ad- VEGF165-SDF-1). A rat model of middle cerebral artery occlusion (MCAO) was established; either Ad- VEGF165-SDF-1 or control adenovirus Ad- LacZ was stereotactically microinjected into the lateral ventricle of 80 rats 24 hours after MCAO. Coexpression and distribution of VEGF165 and SDF-1 were examined by reverse-transcription polymerase chain reaction, Western blotting, and immunofluorescence. The neurological severity score of each rat was measured on Days 3, 7, 14, 21, and 28 after MCAO. Angiogenesis and vascular remodeling were evaluated via bromodeoxyuridine and CD34 immunofluorescence labeling. Relative cerebral infarction volumes were determined by T2-weighted MRI and triphenyltetrazolium chloride staining. Cerebral blood flow, relative cerebral blood volume, and relative mean transmit time were assessed using perfusion-weighted MRI. RESULTS The Ad- VEGF165-SDF-1 vector mediated coexpression of VEGF165 and SDF-1 in multiple sites around the ischemic core, including the cortex, corpus striatum, and hippocampal granular layer. Coexpression of VEGF165 and SDF-1 improved neural function, reduced cerebral infarction volume, increased microvascular density and promoted angiogenesis in the ischemic penumbra, and improved cerebral blood flow and perfusion. CONCLUSIONS Combined VEGF165 and SDF-1 gene therapy represents a potential strategy for improving vascular remodeling and recovery of neural function after cerebral infarction.

Microsurgical treatment for central gyrus region meningioma with epilepsy as primary symptom.

BACKGROUND: The objective of this article was to investigate the operation outcome, complications, and the patient's quality of life after surgical therapy for central gyrus region meningioma with epilepsy as the primary symptom. METHODS: All patients get at least 6 months of follow-up (range, 6-34 mo) after surgery. They underwent preoperative magnetic resonance imaging and video electroencephalography, and their clinical manifestations, imaging characteristics, microsurgical methods, and prognosis were retrospectively analyzed. RESULTS: The meningioma was located in the front and back of the central sulcus vein in 3 and 2 patients, respectively; in the compressed precentral gyrus and central sulcus vein in 3 patients; and in the precentral gyrus and postcentral gyrus each in 1 patient; beside the right sagittal sinus and invaded a thick draining vein on the brain surface in 1 patient and beside the right sagittal sinus and close to the precentral gyrus in 2 patients; invaded the superior sagittal sinus in 8 patients; crossed the cerebral falx and compressed cortex gyrus veins in 1 patient; invaded duramater and irritated skull hyperplasia in 3 patients; invaded duramater and its midline infiltrated into the superior sagittal sinus, was located behind the precentral gyrus, and enveloped the central sulcus vein. They were resected and classified by Simpson standards: 17 of the 26 patients had grade I, 6 patients had in grade II, and 3 patients had in grade III. CONCLUSIONS: Resection of central gyrus region meningioma by microsurgical technique avoids injury to the cerebral cortex, central sulcus vein, and other draining veins. Microsurgery improves the total resection rate, reduces recurrence rate, and lowers disability or death rate.

[Therapeutic effect of infliximab on moderate and severe active rheumatoid arthritis].

OBJECTIVE: To evaluate the clinical efficacy of infliximab in the treatment of moderate and severe active rheumatoid arthritis (RA). METHODS: This randomized double-blind II/III clinical trial involved 30 patients with moderate and severe active RA, who were randomly allocated into 3 groups (groups A, B, and C) at the ratio of 3:1:1. At weeks 0, 2, 6, and 14, the patients in groups A and C received infliximab or placebo, and those in group B had placebo at week 14 with a stable background dose of methotrexate. The indicators for efficacy evaluation included the proportions of ACR20/50/70 of the responders and DAS28. The sharp scores of the hand joints were recorded before and after the treatment. RESULTS: Twenty-nine patients completed the clinical trial (18 in group A, 5 in group B, and 6 in group C). At week 14, the proportions of ACR20/50/70 in the 3 groups reached 83.33%, 60%, and 33.33%, respectively (P<0.05), as compared to 100%, 100%, and 33.33% at week 18 (P<0.05). The other indicators for clinical efficacy evaluation also suggested similar clinical improvement of the patients (P=0.000). The proportions of the patients with DAS28<3.2 and DAS28<2.6 were significantly different. Compared to the baseline, the Sharp scores in group A showed no significant changes at week 18 (P>0.930), while those in group C exhibited significant radiographic progression (P<0.044). CONCLUSION: Infliximab produces good short-term therapeutic effect against moderate and severe active RA and may help arrest the radiographic progression of the diseases, which can be more obvious in patients with moderate severity.