BackgroundMultidrug resistance (MDR) is one of the major reasons chemotherapy-based treatments fail. Hypoxia is generally associated with tumor chemoresistance. However, the correlation between the heterodimeric hypoxia-inducible factor-1 (HIF-1) and the multidrug resistance (MDR1) gene/transporter P-glycoprotein (P-gp) remains unclear. This study aims to explore the molecular mechanisms of reversing colon cancer MDR by focusing on the target gene HIF-1α.MethodsA chemotherapeutic sensitivity assay was used to observe the efficiency of MDR reversal in LoVo multicellular spheroids (MCS). The apoptotic level induced by different drugs was examined by flow cytometry (FCM). Binding of HIF-1α to the MDR1 gene promoter was evaluated by Chromatin immunoprecipitation (ChIP). The relationship between HIF-1α/P-gp expression and sensitivity to chemotherapy was analyzed.ResultsThe sensitivity of LoVo MCS to all four chemotherapy drugs was decreased to varying degrees under hypoxic conditions. After silencing the HIF-1α gene, the sensitivities of LoVo MCS to all four chemotherapy drugs were restored. The apoptotic levels that all the drugs induced were all decreased to various extents in the hypoxic group. After silencing HIF-1α, the apoptosis level induced by all four chemotherapy drugs increased. The expression of HIF-1α and P-gp was significantly enhanced in LoVo MCS after treatment with hypoxia. Inhibiting HIF-1α significantly decreased the expression of MDR1/P-gp mRNA or protein in both the LoVo monolayers and LoVo MCS. The ChIP assay showed that HIF-1α was bound to the MDR1 gene promoter. Advanced colon carcinoma patients with expression of both HIF-1α and P-gp were more resistant to chemotherapy than that with non expression.ConclusionsHIF-1α inhibition reverses multidrug resistance in colon cancer cells via downregulation of MDR1/P-gp. The expression of HIF-1α and MDR1/P-gp can be used as a predictive marker for chemotherapy resistance in colon cancer.
ObjectiveTo record the MR imaging features of primary central nervous system lymphoma (PCNSL) and compare these features in monofocal and multifocal disease.Materials and MethodsTwenty-one cases of monofocal disease were compared to five cases of multifocal disease. All patients were examined by non-enhanced and contrast-enhanced MRI. Tumor location, tumor size, signal intensity, enhancement characteristics, age distribution, peritumoral edema, cystic changes, and the presence of calcifications were assessed. The MRI features were compared between the monofocal and multifocal disease cases.ResultsThe 26 cases, including both the monofocal and multifocal cases, exhibited 37 lesions. Contrast-enhanced images showed variable enhancement patterns: homogeneous enhancement (33 lesions), ring-like enhancement (2), and 'open-ring-like' enhancement (2). The 'notch sign' was noted in four of 33 homogeneously enhancing lesions. One case of hemorrhage and three cases of cystic formation were observed. Intra-tumoral calcification was not found. The frontal lobe, the corpus callosum and the basal ganglia were commonly affected in both the monofocal and multifocal groups. Tumor size differed significantly between the two groups (t = 3.129, p < 0.01) and mildly or moderately enhanced lesions were more frequently found in the monofocal group (p < 0.05). There was no statistical difference between perifocal edema (p > 0.05) and the signal characteristics (p > 0.05) between the two groups.ConclusionOur data show that PCNSL has a variable enhancement pattern on MR images. We first reported two lesions with an 'open-ring' enhancement as well as four cases with a 'notch sign'. Monofocal PCNSL cases typically have larger sized tumors with mild or moderate enhancement.
Centerpiece mini-plate fixation in unilateral open-door cervical expansive laminoplasty might not increase the complete fracture rate compared with suture suspension and might promote bony fusion of type I complete hinge fractures.
This study aimed to investigate whether single nucleotide polymorphisms (SNPs) in the promoter of the excision repair cross complementation group 5 (ERCC5) gene influences response to oxaliplatin-based chemotherapy. Eighty-three patients with cytologically or histologically confirmed advanced colorectal cancer (CRC), at least one measurable lesion and underwent oxaliplatin-based chemotherapy were studied. To this end, six polymorphisms (-1415C>T, -763A>G, -413C>T, +25A>G, +202C>T, +372C>T) in the ERCC5 promoter were selected for investigation. Genomic DNA was obtained from peripheral blood cells, and polymerase chain reaction-ligation detection reaction was used to analyze these SNPs. The χ 2 test or Fisher's exact test was then used to investigate the association between polymorphisms and chemotherapy response. Our results showed that the response rate among patients with the -763GG genotype (72.7%) was significantly higher than that of other genotypes (22.2% for AA genotype, p = 0.008 and 37.2% for AG genotype, p = 0.046 respectively). In addition, the response rate among patients with the +25AA genotype (75%) was significantly higher than that of other genotypes (24.1% for GG genotype, p = 0.004 and 35.7% for AG genotype, p = 0.022 respectively). Patients with the -763A/+25G haplotype had a higher risk of non-response to oxaliplatin chemotherapy compared to those carrying the -763G/+25A haplotype (OR 2.672, 95% CI 1.353-5.278, p = 0.004). However, no genetic variation was observed at site -413, and no significant association was found between the -1415C>T, +202C>T or +372C>T polymorphisms and chemotherapy response. Therefore, these data suggest that ERCC5 promoter polymorphisms at -763 and +25 may be important predictors of response to oxaliplatin chemotherapy.
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