Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the –607C allele may increase ischemic stroke risk in the Han Chinese population. In the present study, ...Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the –607C allele may increase ischemic stroke risk in the Han Chinese population. In the present study, we recruited 291 patients with ischemic cerebrovascular disease from the Affiliated Hospital of Qingdao University Medical College, China, and 226 healthy controls. Both patients and controls were from the Han population in northern China. Immunoresonance scattering assays detected increased serum amyloid A protein, C-reactive protein, and interleukin-18 levels in ischemic cerebrovascular disease patients compared with healthy controls. Analysis of the –607C/A （rs1946518） polymorphism in the interleukin-18 gene promoter showed ischemic cerebrovascular disease patients exhibited increased frequencies of the CC genotype and C alleles than healthy controls. Genotype and allele frequencies of the interleukin-18 –137G/C （rs187238） polymorphism and the –13T/C （rs11024595） polymorphism in the 5＇-flanking region of serum amyloid A, showed no significant difference between the two groups. Multivariate logistic regression analysis on the interleukin-18 promoter A/C genetic locus, for correction of age, gender, history of smoking, hypertension, diabetes mellitus, hypercholesteremia, and an ischemic stroke family history, showed ischemic cerebrovascular disease risk in individuals without the A allele （C homozygotes） was 2.2-fold greater than in A allele carriers. Overall, our findings suggest that the –13T/C （rs11024595） polymorphism in the 5′-flanking region of serum amyloid A has no correlation with ischemic cerebrovascular disease, but the C allele of the –607C/A （rs1946518） polymorphism in the interleukin-18 promoter is a high-risk factor for ischemic cerebrovascular disease in the Han population of northern China. In addition, the A allele is likely a protective gene for ischemic cerebrovascular disease.展开更多
Background： MicroRNAs （miRNAs） are key regulators during tumor initiation and progression. MicroRNA-375 （MiR-375） has been proven to play a tumor-suppressive role in various types of human malignancies; however, ...Background： MicroRNAs （miRNAs） are key regulators during tumor initiation and progression. MicroRNA-375 （MiR-375） has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma （ccRCC） remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression. Methods： Quantitative polymerase chain reaction （qPCR） was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro. Results： Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues （cancer vs. normal, 0.804 ±0.079 vs. 1.784 ± 0.200, t = 5.531 P 〈 0.0001 ） and cell lines, and loss ofmiR-375 expression significantly associated with advanced Fuhrman nuclear grades （Grade Ⅲ and Ⅳ vs. Grade Ⅰ and Ⅱ, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003）. Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion （all P 〈 0.05 in both 786-0 and A498 cell lines）. Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target ofmiR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect ofmi R-375. Conclusions： The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile ofmiR-375, and supports its role as a potential therapeutic target in ccRCC treatment.展开更多
Previous studies showed encouraging efficacy of alternating FOLFOX/FOLFIRI for metastatic colorectal cancer(mCRC).This phase 2 trial(NCT04324476)aimed to evaluate efficacy and safety of alternating modified CAPOX(cape...Previous studies showed encouraging efficacy of alternating FOLFOX/FOLFIRI for metastatic colorectal cancer(mCRC).This phase 2 trial(NCT04324476)aimed to evaluate efficacy and safety of alternating modified CAPOX(capecitabine and oxaliplatin)/modified CAPIRI(capecitabine and irinotecan)plus bevacizumab(anti-VEGF-A antibody)in untreated unresectable mCRC.Induction treatment included capecitabine 1000 mg/m^(2) bid D2-8 and D16-22,oxaliplatin 85 mg/m^(2) D1,irinotecan 150 mg/m^(2) D15,and bevacizumab 5 mg/kg D1 and 15 for 28-day cycles(up to six cycles).Capecitabine 1000 mg/m^(2) bid D2-15 and bevacizumab 7.5 mg/kg D1 for 21-day cycles were used as maintenance treatment.52 patients were included.Median follow-up was 25.0 months.Median progression-free survival(PFS;the primary endpoint)was 11.0 months(95%CI 9.0-12.4).Subgroup analyses showed patients with neutrophil-to-lymphocyte ratio<5 or RAS wild-type disease had longer PFS(both P<0.05).Objective response and disease control were obtained in 38(73%;95%CI 59%-84%)and 49(94%;95%CI 84%-99%),respectively.Mean depth of response,conversion and no evidence of disease rates were 46.0%±26.3%,23%and 19%,respectively.Median overall survival was 28.1 months(18.4-34.0).Grade 3-4 treatment-related adverse events(TRAE)occurred in 17(33%)patients.No treatment-related death was reported.The most common grade 3-4 TRAE were hypertension(13[25%]),neutrophil count decreased(three[6%]),and hand-foot syndrome(two[4%]).In addition,grade 3-4 TRAE of diarrhea reported in one[2%]patient and no grade 3-4 peripheral neuropathy occurred.Thus,alternating modified CAPOX/CAPIRI plus bevacizumab had promising efficacy and acceptable safety.The regimen may be a novel option for untreated unresectable mCRC.展开更多
文摘Interleukin-18 gene promoter polymorphisms are potential risk factors for ischemic cerebrovascular disease, and the –607C allele may increase ischemic stroke risk in the Han Chinese population. In the present study, we recruited 291 patients with ischemic cerebrovascular disease from the Affiliated Hospital of Qingdao University Medical College, China, and 226 healthy controls. Both patients and controls were from the Han population in northern China. Immunoresonance scattering assays detected increased serum amyloid A protein, C-reactive protein, and interleukin-18 levels in ischemic cerebrovascular disease patients compared with healthy controls. Analysis of the –607C/A （rs1946518） polymorphism in the interleukin-18 gene promoter showed ischemic cerebrovascular disease patients exhibited increased frequencies of the CC genotype and C alleles than healthy controls. Genotype and allele frequencies of the interleukin-18 –137G/C （rs187238） polymorphism and the –13T/C （rs11024595） polymorphism in the 5＇-flanking region of serum amyloid A, showed no significant difference between the two groups. Multivariate logistic regression analysis on the interleukin-18 promoter A/C genetic locus, for correction of age, gender, history of smoking, hypertension, diabetes mellitus, hypercholesteremia, and an ischemic stroke family history, showed ischemic cerebrovascular disease risk in individuals without the A allele （C homozygotes） was 2.2-fold greater than in A allele carriers. Overall, our findings suggest that the –13T/C （rs11024595） polymorphism in the 5′-flanking region of serum amyloid A has no correlation with ischemic cerebrovascular disease, but the C allele of the –607C/A （rs1946518） polymorphism in the interleukin-18 promoter is a high-risk factor for ischemic cerebrovascular disease in the Han population of northern China. In addition, the A allele is likely a protective gene for ischemic cerebrovascular disease.
基金This work was supported by the grants from the National Natural Science Foundation of China （No. 81702521） and Provincial Natural Science Foundation of Shandong （No. ZR2017PH019 and No. ZR2018BH018）.
文摘Background： MicroRNAs （miRNAs） are key regulators during tumor initiation and progression. MicroRNA-375 （MiR-375） has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma （ccRCC） remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression. Methods： Quantitative polymerase chain reaction （qPCR） was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro. Results： Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues （cancer vs. normal, 0.804 ±0.079 vs. 1.784 ± 0.200, t = 5.531 P 〈 0.0001 ） and cell lines, and loss ofmiR-375 expression significantly associated with advanced Fuhrman nuclear grades （Grade Ⅲ and Ⅳ vs. Grade Ⅰ and Ⅱ, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003）. Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion （all P 〈 0.05 in both 786-0 and A498 cell lines）. Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target ofmiR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect ofmi R-375. Conclusions： The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile ofmiR-375, and supports its role as a potential therapeutic target in ccRCC treatment.
基金supported by Beijing Science and Technology Innovation Medical Development Foundation(grant no.KC2021-JX-0186-106).
文摘Previous studies showed encouraging efficacy of alternating FOLFOX/FOLFIRI for metastatic colorectal cancer(mCRC).This phase 2 trial(NCT04324476)aimed to evaluate efficacy and safety of alternating modified CAPOX(capecitabine and oxaliplatin)/modified CAPIRI(capecitabine and irinotecan)plus bevacizumab(anti-VEGF-A antibody)in untreated unresectable mCRC.Induction treatment included capecitabine 1000 mg/m^(2) bid D2-8 and D16-22,oxaliplatin 85 mg/m^(2) D1,irinotecan 150 mg/m^(2) D15,and bevacizumab 5 mg/kg D1 and 15 for 28-day cycles(up to six cycles).Capecitabine 1000 mg/m^(2) bid D2-15 and bevacizumab 7.5 mg/kg D1 for 21-day cycles were used as maintenance treatment.52 patients were included.Median follow-up was 25.0 months.Median progression-free survival(PFS;the primary endpoint)was 11.0 months(95%CI 9.0-12.4).Subgroup analyses showed patients with neutrophil-to-lymphocyte ratio<5 or RAS wild-type disease had longer PFS(both P<0.05).Objective response and disease control were obtained in 38(73%;95%CI 59%-84%)and 49(94%;95%CI 84%-99%),respectively.Mean depth of response,conversion and no evidence of disease rates were 46.0%±26.3%,23%and 19%,respectively.Median overall survival was 28.1 months(18.4-34.0).Grade 3-4 treatment-related adverse events(TRAE)occurred in 17(33%)patients.No treatment-related death was reported.The most common grade 3-4 TRAE were hypertension(13[25%]),neutrophil count decreased(three[6%]),and hand-foot syndrome(two[4%]).In addition,grade 3-4 TRAE of diarrhea reported in one[2%]patient and no grade 3-4 peripheral neuropathy occurred.Thus,alternating modified CAPOX/CAPIRI plus bevacizumab had promising efficacy and acceptable safety.The regimen may be a novel option for untreated unresectable mCRC.
