Colorectal carcinoma(CRC) is a common cause of morbidity and mortality worldwide. Two pathogenic pathways are involved in the development of adenoma to CRC. The first pathway involves APC/β-catenin characterized by c...Colorectal carcinoma(CRC) is a common cause of morbidity and mortality worldwide. Two pathogenic pathways are involved in the development of adenoma to CRC. The first pathway involves APC/β-catenin characterized by chromosomal instability resulting in the accumulation of mutations. The second pathway is characterized by lesions in DNA mismatch repair genes.Aberrant DNA methylation in selected gene promoters has emerged as a new epigenetic pathway in CRC development. CRC screening is the most efficient strategy to reduce death. Specific DNA methylation events occur in multistep carcinogenesis.Epigenetic gene silencing is a causative factor of CRC development. DNA methylations have been extensively examined in stool from CRC and precursor lesions. Many methylated genes have been described in CRC and adenoma, although no definite DNA methylation biomarkers panel has been established. Multiple DNA methylation biomarkers, including secreted frizzled-related protein 2, secreted frizzled-related protein 1, tissue factor pathway inhibitor 2, vimentin, and methylguanine DNA methyltransferase, have been further investigated, and observations have revealed that DNA methylation biomarkers exhibit with high sensitivity and specificity. These markers may also be used to diagnose CRC and adenoma in early stages. Real time polymerase chain reaction(q PCR) is sensitive, scalable, specific, reliable, time saving, and cost effective. Stool exfoliated markers provide advantages, including sensitivity and specificity. A stool q PCR methylation test may also be an enhanced tool for CRC and adenoma screening.展开更多
BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF...BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.展开更多
Genome-wide studies have reported that Parkinson's disease is associated with abnormal expression of various growth factors. In this study, male C57BL/6 mice aged 10 weeks were used to establish Parkinson's di...Genome-wide studies have reported that Parkinson's disease is associated with abnormal expression of various growth factors. In this study, male C57BL/6 mice aged 10 weeks were used to establish Parkinson's disease models using an intraperitoneal injection of 60 mg/kg 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coordination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by l-methyl-4-phenyl-l,2,3s6-tetrahydropyridine, and its mechanism of action is associated with the inhibition of A-type K^+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017 (approval No. KYLL-2017-0012).展开更多
A Mn18Cr2 steel containing TiN precipitates was fabricated by vacuum induction melting.The morphology of TiN precipitates and the interface orientation relationship between TiN and γ-Fe were characterized by means of...A Mn18Cr2 steel containing TiN precipitates was fabricated by vacuum induction melting.The morphology of TiN precipitates and the interface orientation relationship between TiN and γ-Fe were characterized by means of SEM,TEM and SAED,and the formation mechanism of TiN precipitates in Mn18Cr2 steel was clarified.Results show that the TiN precipitates are more likely to exhibit a cubic-shaped morphology and form both within the grain and at the grain boundary of γ-Fe.The interface orientation relationship between TiN and γ-Fe is determined as follows:(100)_(TiN)//■_(γ-Fe),■_(TiN)//■_(γ-Fe).Because of the smallest interfacialmisfit,the secondary close-packed lane {100} of TiN preferentially combines with the close-packed plane {111} of γ-Fe during the precipitation in order to minimize the interface energy.After nucleation,the TiN precipitates exhibit cubic appearance due to the fact that the TiN has a FCC structure with rock salt type structure.This study provides reference for the material design of the austenitic high-manganese steels with excellent yield strength.展开更多
文摘Colorectal carcinoma(CRC) is a common cause of morbidity and mortality worldwide. Two pathogenic pathways are involved in the development of adenoma to CRC. The first pathway involves APC/β-catenin characterized by chromosomal instability resulting in the accumulation of mutations. The second pathway is characterized by lesions in DNA mismatch repair genes.Aberrant DNA methylation in selected gene promoters has emerged as a new epigenetic pathway in CRC development. CRC screening is the most efficient strategy to reduce death. Specific DNA methylation events occur in multistep carcinogenesis.Epigenetic gene silencing is a causative factor of CRC development. DNA methylations have been extensively examined in stool from CRC and precursor lesions. Many methylated genes have been described in CRC and adenoma, although no definite DNA methylation biomarkers panel has been established. Multiple DNA methylation biomarkers, including secreted frizzled-related protein 2, secreted frizzled-related protein 1, tissue factor pathway inhibitor 2, vimentin, and methylguanine DNA methyltransferase, have been further investigated, and observations have revealed that DNA methylation biomarkers exhibit with high sensitivity and specificity. These markers may also be used to diagnose CRC and adenoma in early stages. Real time polymerase chain reaction(q PCR) is sensitive, scalable, specific, reliable, time saving, and cost effective. Stool exfoliated markers provide advantages, including sensitivity and specificity. A stool q PCR methylation test may also be an enhanced tool for CRC and adenoma screening.
基金Supported by the Henan Department of Science and Technology,China,No.162102310317
文摘BACKGROUND The RAS/RAF/MEK/ERK and PI3 K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase(MAPK) signaling pathways, Mutations in any one of the upstream genes(such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer(CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene.AIM To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis METHODS Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF,MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots,and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model.RESULTS Of the 196 patients, 62(32%) carried mutations in codon 12(53/62) or codon 13(9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues,respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis(P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors(P < 0.05), whereas BRAF, MEK,and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence(P <0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression.CONCLUSION KRAS gene mutations do not affect downstream protein expression in CRC.KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.
文摘Genome-wide studies have reported that Parkinson's disease is associated with abnormal expression of various growth factors. In this study, male C57BL/6 mice aged 10 weeks were used to establish Parkinson's disease models using an intraperitoneal injection of 60 mg/kg 1-methyl- 4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coordination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by l-methyl-4-phenyl-l,2,3s6-tetrahydropyridine, and its mechanism of action is associated with the inhibition of A-type K^+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017 (approval No. KYLL-2017-0012).
基金the financial support from the National Natural Science Foundation of China(Grant No.U1604251)the Major Scientific and Technological Project of Luoyang,China(Grant No.2001017A)。
文摘A Mn18Cr2 steel containing TiN precipitates was fabricated by vacuum induction melting.The morphology of TiN precipitates and the interface orientation relationship between TiN and γ-Fe were characterized by means of SEM,TEM and SAED,and the formation mechanism of TiN precipitates in Mn18Cr2 steel was clarified.Results show that the TiN precipitates are more likely to exhibit a cubic-shaped morphology and form both within the grain and at the grain boundary of γ-Fe.The interface orientation relationship between TiN and γ-Fe is determined as follows:(100)_(TiN)//■_(γ-Fe),■_(TiN)//■_(γ-Fe).Because of the smallest interfacialmisfit,the secondary close-packed lane {100} of TiN preferentially combines with the close-packed plane {111} of γ-Fe during the precipitation in order to minimize the interface energy.After nucleation,the TiN precipitates exhibit cubic appearance due to the fact that the TiN has a FCC structure with rock salt type structure.This study provides reference for the material design of the austenitic high-manganese steels with excellent yield strength.
