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20842733 | Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. | Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. | Variants in folate pathway genes as modulators of genetic instability and /"lung cancer"/ risk. | Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and /"lung cancer"/ risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 /"lung cancer"/ cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or /"lung cancer"/ risk. However, in a polygenic disease such as /"lung cancer"/, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and /"SHMT"/ polymorphisms may have a significant impact on genetic instability in /"lung cancer"/ patients. With regard to cytogenetic alterations, our results showed that lymphocytes from /"lung cancer"/ patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and /"SHMT"/ allelic variants. These findings support the notion that significant interactions may potentially modulate the /"lung cancer"/ susceptibility and alter the overall the repair abilities of /"lung cancer"/ patients when exposed to tobacco carcinogens such as NNK. | [
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20842733 | Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. | Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. | Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. | Genetic instability plays a crucial role in /"cancer"/ development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and /"SHMT"/ polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and /"SHMT"/ allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. | [
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20842733 | Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. | Genetic instability plays a crucial role in cancer development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, MTHFR1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of MTHFR 677, MTHFR 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. | Variants in folate pathway genes as modulators of genetic instability and lung cancer risk. | Genetic instability plays a crucial role in /"cancer"/ development. The genetic stability of the cell as well as DNA methylation status could be modulated by folate levels. Several studies suggested associations between polymorphisms in folate genes and alterations in protein expression and variations in serum levels of the folate. The objective of this study was to investigate the effect of folate pathway polymorphisms on modulating genetic instability and lung cancer risk. Genotyping of 5 SNPs in folate pathway genes and cytokinesis-blocked micronucleus cytome assay analysis (to determine the genetic instability at baseline and following NNK treatment) was conducted on 180 lung cancer cases and 180 age-, gender-, and smoking-matched controls. Our results showed that individually, folate pathway SNPs were not associated with cytogenetic damage or lung cancer risk. However, in a polygenic disease such as lung cancer, gene-gene interactions are expected to play an important role in determining the phenotypic variability of the diseases. We observed that interactions between MTHFR677, /"MTHFR"/1298, and SHMT polymorphisms may have a significant impact on genetic instability in lung cancer patients. With regard to cytogenetic alterations, our results showed that lymphocytes from lung cancer patients exposed to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK] had considerably increased frequency of cytogenetic damage in presence of /"MTHFR"/ 677, /"MTHFR"/ 1298, and SHMT allelic variants. These findings support the notion that significant interactions may potentially modulate the lung cancer susceptibility and alter the overall the repair abilities of lung cancer patients when exposed to tobacco carcinogens such as NNK. | [
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20854105 | Impact of EXO1 polymorphism in susceptibility to colorectal cancer. | BACKGROUND AND AIM: One candidate gene for colorectal cancer (CRC) susceptibility is exonuclease 1 (EXO1). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of CRC in Iranian patients. METHODS: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with CRC risk and also clinicopathological characteristics. RESULTS: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of CRC (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with CRC at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284). CONCLUSIONS: Our results provide evidence diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with CRC. In addition, despite other investigations, we could define a significant association between the Leu allele and CRC (p = 0.001). | Impact of /"EXO1"/ polymorphism in susceptibility to /"colorectal cancer"/. | BACKGROUND AND AIM: One candidate gene for /"colorectal cancer"/ (/"CRC"/) susceptibility is /"exonuclease 1"/ (/"EXO1"/). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the /"EXO1"/ gene and the risk of /"CRC"/ in Iranian patients. METHODS: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The /"EXO1"/ polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with /"CRC"/ risk and also clinicopathological characteristics. RESULTS: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of /"CRC"/ (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with /"CRC"/ at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284). CONCLUSIONS: Our results provide evidence diagnosing that the Leu/Leu genotype of /"EXO1"/ showed an inverse association with /"CRC"/. In addition, despite other investigations, we could define a significant association between the Leu allele and /"CRC"/ (p = 0.001). | [
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} | Yes |
20854105 | Impact of EXO1 polymorphism in susceptibility to colorectal cancer. | BACKGROUND AND AIM: One candidate gene for colorectal cancer (CRC) susceptibility is exonuclease 1 (EXO1). It is a member of RAD2 nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of CRC in Iranian patients. METHODS: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with CRC risk and also clinicopathological characteristics. RESULTS: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of CRC (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with CRC at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284). CONCLUSIONS: Our results provide evidence diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with CRC. In addition, despite other investigations, we could define a significant association between the Leu allele and CRC (p = 0.001). | Impact of EXO1 polymorphism in susceptibility to /"colorectal cancer"/. | BACKGROUND AND AIM: One candidate gene for /"colorectal cancer"/ (/"CRC"/) susceptibility is exonuclease 1 (EXO1). It is a member of /"RAD2"/ nuclease family, which plays a major role in mismatch repair, DNA replication, and recombination. Single-nucleotide polymorphisms are shown to be related with cancer incidence. The aim of the present study was to examine the association between the L757P polymorphism at exon 13 of the EXO1 gene and the risk of /"CRC"/ in Iranian patients. METHODS: In this case-control study, 90 cases and 98 healthy control samples were analyzed genetically. The EXO1 polymorphism, P757L, was analyzed by polymerase chain reaction-restriction fragment length polymorphism. The obtained polymorphisms were examined for the relationship with /"CRC"/ risk and also clinicopathological characteristics. RESULTS: Our findings showed that patients with the Leu/Leu genotype have a reduced risk of /"CRC"/ (adjusted odds ratio [OR] = 0.192, 95% confidence interval [CI]: 0.040-0.921) when the Pro/Leu and Pro/Pro genotypes were blended and they were considered as the reference. The Leu/Leu genotype also showed a reduced risk (adjusted OR = 0.168, 95% CI: 0.034-0.816) when the Pro/Pro genotype was a reference; nevertheless, the Pro/Leu genotype did not reveal a significant association with /"CRC"/ at the same status (adjusted OR = 0.686, 95% CI: 0.367-1.284). CONCLUSIONS: Our results provide evidence diagnosing that the Leu/Leu genotype of EXO1 showed an inverse association with /"CRC"/. In addition, despite other investigations, we could define a significant association between the Leu allele and /"CRC"/ (p = 0.001). | [
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} | No |
20857490 | Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. | Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and loss of viability. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells. | Transient arrest in a quiescent state allows /"ovarian cancer"/ cells to survive suboptimal growth conditions and is mediated by both /"Mirk"///"dyrk1b"/ and p130/RB2. | Some /"ovarian cancer"/ cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase /"Mirk"///"dyrk1B"/ was expressed in each of seven /"ovarian cancer"/ cell lines and in 21 of 28 resected human /"ovarian cancers"/, and upregulated in 60% of the cancers. Some /"ovarian cancer"/ cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified /"Mirk"/ gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of /"Mirk"/, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced /"Mirk"/ levels. /"Mirk"/ contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, /"Mirk"/ depletion led to increased apoptosis and loss of viability. Because /"Mirk"/ is expressed at low levels in most normal adult tissues, the elevated /"Mirk"/ protein levels in /"ovarian cancers"/ may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells. | [
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20857490 | Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and p130/RB2. | Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, p130/Rb2, and p130/Rb2 complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of p130/Rb2 reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and loss of viability. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells. | Transient arrest in a quiescent state allows ovarian cancer cells to survive suboptimal growth conditions and is mediated by both Mirk/dyrk1b and /"p130"///"RB2"/. | Some ovarian cancer cells in vivo are in a reversible quiescent state where they can contribute to cancer spread under favorable growth conditions. The serine/threonine kinase Mirk/dyrk1B was expressed in each of seven ovarian cancer cell lines and in 21 of 28 resected human ovarian cancers, and upregulated in 60% of the cancers. Some ovarian cancer cells were found in a G0 quiescent state, with the highest fraction in a line with an amplified Mirk gene. Suboptimal culture conditions increased the G0 fraction in SKOV3 and TOV21G, but not OVCAR4 cultures. Less than half as many OVCAR4 cells survived under suboptimal culture conditions as shown by total cell numbers, dye exclusion viability studies, and assay of cleaved apoptotic marker proteins. G0 arrest in TOV21G and SKOV3 cells led to increased levels of Mirk, the CDK inhibitor p27, /"p130"///"Rb2"/, and /"p130"///"Rb2"/ complexed with E2F4. The G0 arrest was transient, and cells exited G0 when fresh nutrients were supplied. Depletion of /"p130"///"Rb2"/ reduced the G0 fraction, increased cell sensitivity to serum-free culture and to cisplatin, and reduced Mirk levels. Mirk contributed to G0 arrest by destabilization of cyclin D1. In TOV21G cells, but not in normal diploid fibroblasts, Mirk depletion led to increased apoptosis and /"loss of viability"/. Because Mirk is expressed at low levels in most normal adult tissues, the elevated Mirk protein levels in ovarian cancers may present a novel therapeutic target, in particular for quiescent tumor cells which are difficult to eradicate by conventional therapies targeting dividing cells. | [
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20939760 | Epidermal growth factor receptor (EGFR) mutation and p-EGFR expression in resected non-small cell lung cancer. | Lung cancer, specifically non-small cell lung cancer (NSCLC), is a leading cause of mortality worldwide. In China, a dramatic increase in the incidence of NSCLC is expected in the next 20 years (Molina et al. Mayo Clin Proc. 2008;83:584 594). Mutated epidermal growth factor receptor (EGFR) status is a known predictor of response to tyrosine kinase inhibitors (TKIs), and immunohistochemistry may be a less costly way of predicting presence of mutation. In this study, mutation analysis of EGFR in 218 cases of NSCLC was performed. One hundred thirty tissue samples were examined via immunohistochemistry of p-EGFR (Y1045 and Y1068) and correlated with mutation status. Mutations were seen in 29% of patients, and were correlated with female sex, nonsmoking history, and adenocarcinoma histology. Phosphorylation at Y1045 was noted in 52% of cases, but in 71% of cases with EGFR mutation (P = .003). Phosphorylation of Y1068 was seen in 55% of cases but in 73% of cases with EGFR mutation (P = .006). This study correlating EGFR mutation with p-EGFR expression in resected NSCLC is one of the largest to date, although TKI response could not be assessed. The data show that, among Chinese patients, detection of p-1045 and p-1068 expression with immunohistochemistry predicts EGFR mutations. Immunohistochemical analysis of p-EGFR may be useful to predict responses to TKI therapy, although future studies are necessary. | /"Epidermal growth factor receptor"/ (/"EGFR"/) mutation and p-/"EGFR"/ expression in resected non-small cell lung cancer. | /"Lung cancer"/, specifically non-small cell lung cancer (NSCLC), is a leading cause of mortality worldwide. In China, a dramatic increase in the incidence of NSCLC is expected in the next 20 years (Molina et al. Mayo Clin Proc. 2008;83:584 594). Mutated /"epidermal growth factor receptor"/ (/"EGFR"/) status is a known predictor of response to tyrosine kinase inhibitors (TKIs), and immunohistochemistry may be a less costly way of predicting presence of mutation. In this study, mutation analysis of /"EGFR"/ in 218 cases of NSCLC was performed. One hundred thirty tissue samples were examined via immunohistochemistry of p-/"EGFR"/ (Y1045 and Y1068) and correlated with mutation status. Mutations were seen in 29% of patients, and were correlated with female sex, nonsmoking history, and adenocarcinoma histology. Phosphorylation at Y1045 was noted in 52% of cases, but in 71% of cases with /"EGFR"/ mutation (P = .003). Phosphorylation of Y1068 was seen in 55% of cases but in 73% of cases with /"EGFR"/ mutation (P = .006). This study correlating /"EGFR"/ mutation with p-/"EGFR"/ expression in resected NSCLC is one of the largest to date, although TKI response could not be assessed. The data show that, among Chinese patients, detection of p-1045 and p-1068 expression with immunohistochemistry predicts /"EGFR"/ mutations. Immunohistochemical analysis of p-/"EGFR"/ may be useful to predict responses to TKI therapy, although future studies are necessary. | [
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20939760 | Epidermal growth factor receptor (EGFR) mutation and p-EGFR expression in resected non-small cell lung cancer. | Lung cancer, specifically non-small cell lung cancer (NSCLC), is a leading cause of mortality worldwide. In China, a dramatic increase in the incidence of NSCLC is expected in the next 20 years (Molina et al. Mayo Clin Proc. 2008;83:584 594). Mutated epidermal growth factor receptor (EGFR) status is a known predictor of response to tyrosine kinase inhibitors (TKIs), and immunohistochemistry may be a less costly way of predicting presence of mutation. In this study, mutation analysis of EGFR in 218 cases of NSCLC was performed. One hundred thirty tissue samples were examined via immunohistochemistry of p-EGFR (Y1045 and Y1068) and correlated with mutation status. Mutations were seen in 29% of patients, and were correlated with female sex, nonsmoking history, and adenocarcinoma histology. Phosphorylation at Y1045 was noted in 52% of cases, but in 71% of cases with EGFR mutation (P = .003). Phosphorylation of Y1068 was seen in 55% of cases but in 73% of cases with EGFR mutation (P = .006). This study correlating EGFR mutation with p-EGFR expression in resected NSCLC is one of the largest to date, although TKI response could not be assessed. The data show that, among Chinese patients, detection of p-1045 and p-1068 expression with immunohistochemistry predicts EGFR mutations. Immunohistochemical analysis of p-EGFR may be useful to predict responses to TKI therapy, although future studies are necessary. | /"Epidermal growth factor receptor"/ (/"EGFR"/) mutation and p-/"EGFR"/ expression in resected /"non-small cell lung cancer"/. | Lung cancer, specifically /"non-small cell lung cancer"/ (/"NSCLC"/), is a leading cause of mortality worldwide. In China, a dramatic increase in the incidence of /"NSCLC"/ is expected in the next 20 years (Molina et al. Mayo Clin Proc. 2008;83:584 594). Mutated /"epidermal growth factor receptor"/ (/"EGFR"/) status is a known predictor of response to tyrosine kinase inhibitors (TKIs), and immunohistochemistry may be a less costly way of predicting presence of mutation. In this study, mutation analysis of /"EGFR"/ in 218 cases of /"NSCLC"/ was performed. One hundred thirty tissue samples were examined via immunohistochemistry of p-/"EGFR"/ (Y1045 and Y1068) and correlated with mutation status. Mutations were seen in 29% of patients, and were correlated with female sex, nonsmoking history, and adenocarcinoma histology. Phosphorylation at Y1045 was noted in 52% of cases, but in 71% of cases with /"EGFR"/ mutation (P = .003). Phosphorylation of Y1068 was seen in 55% of cases but in 73% of cases with /"EGFR"/ mutation (P = .006). This study correlating /"EGFR"/ mutation with p-/"EGFR"/ expression in resected /"NSCLC"/ is one of the largest to date, although TKI response could not be assessed. The data show that, among Chinese patients, detection of p-1045 and p-1068 expression with immunohistochemistry predicts /"EGFR"/ mutations. Immunohistochemical analysis of p-/"EGFR"/ may be useful to predict responses to TKI therapy, although future studies are necessary. | [
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20959826 | KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. | BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect KRAS hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of KRAS mutations in CRC was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for CRC patients harbouring a KRAS mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, KRAS mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS: HRMA was found to be a valid screening method for KRAS mutation detection. The KRAS mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients. | /"KRAS"/ mutation detection and prognostic potential in sporadic /"colorectal cancer"/ using high-resolution melting analysis. | BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 /"colorectal cancer"/ (/"CRC"/) patients to detect /"KRAS"/ hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of /"KRAS"/ mutations in /"CRC"/ was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% /"CRC"/ samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for /"CRC"/ patients harbouring a /"KRAS"/ mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, /"KRAS"/ mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS: HRMA was found to be a valid screening method for /"KRAS"/ mutation detection. The /"KRAS"/ mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients. | [
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20959826 | KRAS mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. | BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of cancers. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect KRAS hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of KRAS mutations in CRC was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for CRC patients harbouring a KRAS mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, KRAS mutation was a negative predictor for OS in patients with rectal cancer and DFS in those with stage II colon cancer. CONCLUSIONS: HRMA was found to be a valid screening method for KRAS mutation detection. The KRAS mutation came forward as a negative predictive factor for OS in patients with rectal cancer and for DFS in stage II colon cancer patients. | /"KRAS"/ mutation detection and prognostic potential in sporadic colorectal cancer using high-resolution melting analysis. | BACKGROUND: The development of targeted therapies has created a pressing clinical need for molecular characterisation of /"cancers"/. In this retrospective study, high-resolution melting analysis (HRMA) was validated and implemented for screening of 164 colorectal cancer (CRC) patients to detect /"KRAS"/ hot-spot mutations and to evaluate its prognostic value. Direct sequencing was used to confirm and characterise HRMA results. METHODS: After establishing its sensitivity, HRMA was validated on seven cell lines and inter- and intra-variation were analysed. The prognostic value of /"KRAS"/ mutations in CRC was evaluated using survival analysis. RESULTS: HRMA revealed abnormal melting patterns in 34.1% CRC samples. Kaplan-Meier survival curves revealed a significantly shorter overall (OS) and disease-free survival (DFS) for CRC patients harbouring a /"KRAS"/ mutation. In the Cox regression analysis, only when colon and rectal cancer were analysed separately, /"KRAS"/ mutation was a negative predictor for OS in patients with /"rectal cancer"/ and DFS in those with /"stage II colon cancer"/. CONCLUSIONS: HRMA was found to be a valid screening method for /"KRAS"/ mutation detection. The /"KRAS"/ mutation came forward as a negative predictive factor for OS in patients with /"rectal cancer"/ and for /"DFS in stage II colon cancer"/ patients. | [
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20973260 | Association of vascular endothelial growth factor gene polymorphisms with susceptibility to epithelial ovarian cancer. | BACKGROUND: Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with susceptibility to epithelial ovarian cancer (EOC). METHODS: This case-control study included 303 EOC patients and 303 healthy controls. Genotyping of the VEGF gene polymorphisms at j460C/T, j1154G/A, j2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T, and -2578C/A polymorphisms between patients and controls. However, the frequencies of -1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12Y2.39). The haplotype analysis suggested that the -460T/ -1154A/ -2578C haplotype exhibited a decrease in the risk of developing EOC compared with the -460T/ -1154G/ -2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999). CONCLUSIONS: The study suggested a possible association between the VEGF -1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the VEGF -460C/T, +936C/T, and -2578C/A polymorphisms with the risk for EOC. | Association of /"vascular endothelial growth factor"/ gene polymorphisms with susceptibility to /"epithelial ovarian cancer"/. | BACKGROUND: /"Vascular endothelial growth factor"/ (/"VEGF"/) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the /"VEGF"/ gene with susceptibility to /"epithelial ovarian cancer"/ (/"EOC"/). METHODS: This case-control study included 303 /"EOC"/ patients and 303 healthy controls. Genotyping of the /"VEGF"/ gene polymorphisms at j460C/T, j1154G/A, j2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T, and -2578C/A polymorphisms between patients and controls. However, the frequencies of -1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing /"EOC"/ (odds ratio, 1.64; 95% confidence interval, 1.12Y2.39). The haplotype analysis suggested that the -460T/ -1154A/ -2578C haplotype exhibited a decrease in the risk of developing /"EOC"/ compared with the -460T/ -1154G/ -2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999). CONCLUSIONS: The study suggested a possible association between the /"VEGF"/ -1154G/A polymorphism with susceptibility to /"EOC"/, but there is no support for an association of the /"VEGF"/ -460C/T, +936C/T, and -2578C/A polymorphisms with the risk for /"EOC"/. | [
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20973260 | Association of vascular endothelial growth factor gene polymorphisms with susceptibility to epithelial ovarian cancer. | BACKGROUND: Vascular endothelial growth factor (VEGF) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid malignancies. The aim of this study was to investigate the association of polymorphisms in the VEGF gene with susceptibility to epithelial ovarian cancer (EOC). METHODS: This case-control study included 303 EOC patients and 303 healthy controls. Genotyping of the VEGF gene polymorphisms at j460C/T, j1154G/A, j2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T, and -2578C/A polymorphisms between patients and controls. However, the frequencies of -1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12Y2.39). The haplotype analysis suggested that the -460T/ -1154A/ -2578C haplotype exhibited a decrease in the risk of developing EOC compared with the -460T/ -1154G/ -2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999). CONCLUSIONS: The study suggested a possible association between the VEGF -1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the VEGF -460C/T, +936C/T, and -2578C/A polymorphisms with the risk for EOC. | Association of /"vascular endothelial growth factor"/ gene polymorphisms with susceptibility to epithelial ovarian cancer. | BACKGROUND: /"Vascular endothelial growth factor"/ (/"VEGF"/) is a major angiogenic factor involved in a number of pathological processes, including neovascularization, a crucial step in the development of solid /"malignancies"/. The aim of this study was to investigate the association of polymorphisms in the /"VEGF"/ gene with susceptibility to epithelial ovarian cancer (EOC). METHODS: This case-control study included 303 EOC patients and 303 healthy controls. Genotyping of the /"VEGF"/ gene polymorphisms at j460C/T, j1154G/A, j2578C/A, and +936C/T were performed by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: No significant difference was found in allele and genotype distributions of the -460C/T, +936C/T, and -2578C/A polymorphisms between patients and controls. However, the frequencies of -1154G/A genotype and allele were significantly different between the two groups (P = 0.037, P = 0.013). Compared with the G/A + A/A genotype, the G/G genotype could significantly increase the risk of developing EOC (odds ratio, 1.64; 95% confidence interval, 1.12Y2.39). The haplotype analysis suggested that the -460T/ -1154A/ -2578C haplotype exhibited a decrease in the risk of developing EOC compared with the -460T/ -1154G/ -2578C haplotype (odds ratio, 0.644; 95% confidence interval, 0.415-0.999). CONCLUSIONS: The study suggested a possible association between the /"VEGF"/ -1154G/A polymorphism with susceptibility to EOC, but there is no support for an association of the /"VEGF"/ -460C/T, +936C/T, and -2578C/A polymorphisms with the risk for EOC. | [
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20977478 | Analysis of strain-dependent prepulse inhibition points to a role for Shmt1 (SHMT1) in mice and in schizophrenia. | Deficits in prepulse inhibition (PPI) are known in mental illnesses, including schizophrenia. NMDA receptor function affects PPI integrity and D-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both D-serine synthesizing enzyme and enzyme for reversible conversion between glycine and L-serine (Srr and Shmt1, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to schizophrenia. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of D-serine and glycine from the dialysate was higher in B6, compared to C3. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to C3 conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of schizophrenia and genetic associations with the disease. The SHMT1 levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to schizophrenia. | Analysis of strain-dependent prepulse inhibition points to a role for /"Shmt1"/ (/"SHMT1"/) in mice and in /"schizophrenia"/. | Deficits in prepulse inhibition (PPI) are known in mental illnesses, including /"schizophrenia"/. NMDA receptor function affects PPI integrity and D-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both D-serine synthesizing enzyme and enzyme for reversible conversion between glycine and L-serine (Srr and /"Shmt1"/, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to /"schizophrenia"/. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of D-serine and glycine from the dialysate was higher in B6, compared to C3. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in /"Shmt1"/, which elicit lower transcriptional activity in B6 compared to C3 conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of /"schizophrenia"/ and genetic associations with the disease. The /"SHMT1"/ levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between /"SHMT1"/ and /"schizophrenia"/. These results suggest that /"Shmt1"/ (/"SHMT1"/), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to /"schizophrenia"/. | [
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20977478 | Analysis of strain-dependent prepulse inhibition points to a role for Shmt1 (SHMT1) in mice and in schizophrenia. | Deficits in prepulse inhibition (PPI) are known in mental illnesses, including schizophrenia. NMDA receptor function affects PPI integrity and D-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both D-serine synthesizing enzyme and enzyme for reversible conversion between glycine and L-serine (Srr and Shmt1, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to schizophrenia. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of D-serine and glycine from the dialysate was higher in B6, compared to C3. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to C3 conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of schizophrenia and genetic associations with the disease. The SHMT1 levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between SHMT1 and schizophrenia. These results suggest that Shmt1 (SHMT1), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to schizophrenia. | Analysis of strain-dependent prepulse inhibition points to a role for Shmt1 (SHMT1) in mice and in /"schizophrenia"/. | Deficits in prepulse inhibition (PPI) are known in mental illnesses, including /"schizophrenia"/. NMDA receptor function affects PPI integrity and D-serine and glycine are endogenous co-agonists for the receptor. Our previous quantitative trait loci analysis using C57BL/6 (B6) mice with better PPI performance and C3H/He (C3) with lower PPI score, shows that genes for both D-serine synthesizing enzyme and enzyme for reversible conversion between glycine and L-serine (Srr and Shmt1, respectively) are located in the same PPI-quantitative trait loci peak. Therefore, we set out to determine which gene is likely to explain the PPI difference and whether the gene is potentially relevant to /"schizophrenia"/. We first examined brain interstitial fluid levels of the two amino acids using microdialysis. Recovery of D-serine and glycine from the dialysate was higher in B6, compared to /"C3"/. Next, we analyzed expression levels and genetic polymorphisms of the two genes. There were promoter polymorphisms in Shmt1, which elicit lower transcriptional activity in B6 compared to /"C3"/ conforming to the results of brain expression levels, but no functional genetic variants in Srr. Finally, we evaluated expression levels of the two genes in the postmortem brains of /"schizophrenia"/ and genetic associations with the disease. The SHMT1 levels were higher in schizophrenic brains compared to controls, but no changes in SRR levels. We detected a nominal association between SHMT1 and /"schizophrenia"/. These results suggest that Shmt1 (SHMT1), but not Srr, is likely to be one of the genetic components regulating PPI in mice and possibly relevant to /"schizophrenia"/. | [
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20979931 | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | Associations between oxaliplatin-induced /"peripheral neuropathy"/ and polymorphisms of the ERCC1 and /"GSTP1"/ genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and /"glutathione-S-transferases pi 1"/ (/"GSTP1"/) genes. RESULTS: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the /"GSTP1"/ Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and /"GSTP1"/ Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that ERCC1, C118T and /"GSTP1"/ Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | [
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20979931 | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | Associations between oxaliplatin-induced /"peripheral neuropathy"/ and polymorphisms of the /"ERCC1"/ and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the /"excision repair cross-complementation Group 1"/ (/"ERCC1"/) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the /"ERCC1"/ C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). /"ERCC1"/ C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that /"ERCC1"/, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | [
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20979931 | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the /"ERCC1"/ and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic /"neuropathy"/ is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced /"neuropathy"/ and polymorphisms of the /"excision repair cross-complementation Group 1"/ (/"ERCC1"/) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the /"ERCC1"/ C118T polymorphism, Grade 1 chronic /"neuropathy"/ developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic /"neuropathy"/ developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). /"ERCC1"/ C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic /"neuropathy"/. CONCLUSIONS: Our results suggest that /"ERCC1"/, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of /"neuropathy"/ than to the grade of /"neuropathy"/. Most likely these polymorphisms influence patients' sensitivity to /"neuropathy"/. | [
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20979931 | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the ERCC1 and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic neuropathy is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced neuropathy and polymorphisms of the excision repair cross-complementation Group 1 (ERCC1) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the ERCC1 C118T polymorphism, Grade 1 chronic neuropathy developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic neuropathy developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). ERCC1 C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic neuropathy. CONCLUSIONS: Our results suggest that ERCC1, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of neuropathy than to the grade of neuropathy. Most likely these polymorphisms influence patients' sensitivity to neuropathy. | Associations between oxaliplatin-induced peripheral neuropathy and polymorphisms of the /"ERCC1"/ and GSTP1 genes. | OBJECTIVE: Oxaliplatin-induced chronic /"neuropathy"/ is cumulative and dose-limiting; reliable predictors and determination of the mechanism of this toxic effect are needed. METHODS: We retrospectively studied 51 Japanese adults with colorectal cancer who had received oxaliplatin-based chemotherapy to explore the pharmacogenetic association between oxaliplatin-induced /"neuropathy"/ and polymorphisms of the /"excision repair cross-complementation Group 1"/ (/"ERCC1"/) and glutathione-S-transferases pi 1 (GSTP1) genes. RESULTS: For the /"ERCC1"/ C118T polymorphism, Grade 1 chronic /"neuropathy"/ developed earlier in patients with C/T and T/T genotypes (median number of treatment cycles at onset = 6) than in those with the reference C/C genotype (7 cycles; p = 0.0162 by the generalized Wilcoxon test). For the GSTP1 Ile105Val polymorphism, chronic /"neuropathy"/ developed earlier in patients with the reference Ile/Ile genotype (6 cycles) than in those with Ile/Val and Val/Val genotypes (9 cycles; p = 0.0321). /"ERCC1"/ C118T and GSTP1 Ile105Val polymorphisms were not significantly associated with an increased risk of developing Grade 2 or more severe chronic /"neuropathy"/. CONCLUSIONS: Our results suggest that /"ERCC1"/, C118T and GSTP1 Ile105Val polymorphisms are more strongly related to the time until onset of /"neuropathy"/ than to the grade of /"neuropathy"/. Most likely these polymorphisms influence patients' sensitivity to /"neuropathy"/. | [
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21040232 | New mutation c.374C>T and a putative disease-associated haplotype within SCN1B gene in Tunisian families with febrile seizures. | BACKGROUND: Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. METHODS: A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of SCN1B gene in the GEFS+ syndrome in previous studies, SCN1B on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. RESULTS: A sequencing analysis of the SCN1B gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. CONCLUSION: Our results support that SCN1B is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others. | New mutation c.374C>T and a putative disease-associated haplotype within /"SCN1B"/ gene in Tunisian families with febrile seizures. | BACKGROUND: Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. METHODS: A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of /"SCN1B"/ gene in the GEFS+ syndrome in previous studies, /"SCN1B"/ on /"GEFS+"/1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. RESULTS: A sequencing analysis of the /"SCN1B"/ gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. CONCLUSION: Our results support that /"SCN1B"/ is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others. | [
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21040232 | New mutation c.374C>T and a putative disease-associated haplotype within SCN1B gene in Tunisian families with febrile seizures. | BACKGROUND: Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. METHODS: A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of SCN1B gene in the GEFS+ syndrome in previous studies, SCN1B on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. RESULTS: A sequencing analysis of the SCN1B gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. CONCLUSION: Our results support that SCN1B is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others. | New mutation c.374C>T and a putative disease-associated haplotype within /"SCN1B"/ gene in Tunisian families with febrile seizures. | BACKGROUND: Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true /"epileptic disease"/ but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. METHODS: A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of /"SCN1B"/ gene in the GEFS+ syndrome in previous studies, /"SCN1B"/ on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. RESULTS: A sequencing analysis of the /"SCN1B"/ gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. CONCLUSION: Our results support that /"SCN1B"/ is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others. | [
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21044966 | Survival of MUTYH-associated polyposis patients with colorectal cancer and matched control colorectal cancer patients. | BACKGROUND: MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population. METHODS: In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided. RESULTS: Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). CONCLUSIONS: In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer. | Survival of /"MUTYH"/-associated polyposis patients with /"colorectal cancer"/ and matched control /"colorectal cancer"/ patients. | BACKGROUND: /"MUTYH"/-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of /"colorectal cancer"/ that is up to 100%. Because specific histological and molecular genetic features of /"MUTYH"/-associated /"polyposis colorectal cancers"/ might influence tumor behavior and patient survival, we compared survival between patients with /"MUTYH-associated polyposis colorectal cancer"/ and matched control patients with /"colorectal cancer"/ from the general population. METHODS: In this retrospective multicenter cohort study from Europe, 147 patients with /"MUTYH-associated polyposis colorectal cancer"/ were compared with 272 population-based control patients with /"colorectal cancer"/ who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of /"colorectal cancer"/. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with /"MUTYH-associated polyposis colorectal cancer"/ and control patients with /"colorectal cancer"/. All statistical tests were two-sided. RESULTS: Five-year survival for patients with /"MUTYH-associated polyposis colorectal cancer"/ was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for /"MUTYH-associated polyposis colorectal cancer"/ patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). CONCLUSIONS: In a European study cohort, we found statistically significantly better survival for patients with /"MUTYH-associated polyposis colorectal cancer"/ than for matched control patients with /"colorectal cancer"/. | [
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21044966 | Survival of MUTYH-associated polyposis patients with colorectal cancer and matched control colorectal cancer patients. | BACKGROUND: MUTYH-associated polyposis is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of MUTYH-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population. METHODS: In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided. RESULTS: Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). CONCLUSIONS: In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer. | Survival of /"MUTYH"/-associated /"polyposis"/ patients with colorectal cancer and matched control colorectal cancer patients. | BACKGROUND: /"MUTYH"/-associated /"polyposis"/ is a recessively inherited disorder characterized by a lifetime risk of colorectal cancer that is up to 100%. Because specific histological and molecular genetic features of /"MUTYH"/-associated polyposis colorectal cancers might influence tumor behavior and patient survival, we compared survival between patients with MUTYH-associated polyposis colorectal cancer and matched control patients with colorectal cancer from the general population. METHODS: In this retrospective multicenter cohort study from Europe, 147 patients with MUTYH-associated polyposis colorectal cancer were compared with 272 population-based control patients with colorectal cancer who were matched for country, age at diagnosis, year of diagnosis, stage, and subsite of colorectal cancer. Kaplan-Meier survival and Cox regression analyses were used to compare survival between patients with MUTYH-associated polyposis colorectal cancer and control patients with colorectal cancer. All statistical tests were two-sided. RESULTS: Five-year survival for patients with MUTYH-associated polyposis colorectal cancer was 78% (95% confidence interval [CI] = 70% to 84%) and for control patients was 63% (95% CI = 56% to 69%) (log-rank test, P = .002). After adjustment for differences in age, stage, sex, subsite, country, and year of diagnosis, survival remained better for MUTYH-associated polyposis colorectal cancer patients than for control patients (hazard ratio of death = 0.48, 95% CI = 0.32 to 0.72). CONCLUSIONS: In a European study cohort, we found statistically significantly better survival for patients with MUTYH-associated polyposis colorectal cancer than for matched control patients with colorectal cancer. | [
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21074862 | Clinical and immunological differences between early and late-onset myasthenia gravis in Japan. | Immunological characteristics of myasthenia gravis (MG) with late-onset have not been fully elucidated. We examined several autoantibodies and HLA-DRB1 genotyping in 260 Japanese MG patients. Sixty-two MG patients had thymoma. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. HLA-DRB1 genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset MG were different from early-onset in Japan. | Clinical and immunological differences between early and late-onset /"myasthenia gravis"/ in Japan. | Immunological characteristics of /"myasthenia gravis"/ (/"MG"/) with late-onset have not been fully elucidated. We examined several autoantibodies and /"HLA-DRB1"/ genotyping in 260 Japanese /"MG"/ patients. Sixty-two /"MG"/ patients had thymoma. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. /"HLA-DRB1"/ genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset /"MG"/ were different from early-onset in Japan. | [
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21074862 | Clinical and immunological differences between early and late-onset myasthenia gravis in Japan. | Immunological characteristics of myasthenia gravis (MG) with late-onset have not been fully elucidated. We examined several autoantibodies and HLA-DRB1 genotyping in 260 Japanese MG patients. Sixty-two MG patients had thymoma. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. HLA-DRB1 genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset MG were different from early-onset in Japan. | Clinical and immunological differences between early and late-onset myasthenia gravis in Japan. | Immunological characteristics of myasthenia gravis (MG) with late-onset have not been fully elucidated. We examined several autoantibodies and /"HLA-DRB1"/ genotyping in 260 Japanese MG patients. Sixty-two MG patients had /"thymoma"/. The others were divided into early-onset and late-onset groups separated by an age of 50 years. The ocular form was more frequent in late-onset compared to early-onset group. Seropositivity of anti-muscle-specific tyrosine kinase antibody was 2-3% in acetylcholine receptor-seronegative patients. /"HLA-DRB1"/ genotyping failed to detect statistical differences in specific alleles between each group and healthy controls. The immunological profiles in late-onset MG were different from early-onset in Japan. | [
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21094227 | IL-4 mediates dicloxacillin-induced liver injury in mice. | Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 g/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 g/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2). | /"IL-4"/ mediates dicloxacillin-induced /"liver injury"/ in mice. | /"Drug-induced liver injury"/ (/"DILI"/) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict /"DILI"/ in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed /"liver injury"/, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced /"liver injury"/. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma /"interleukin (IL)-4"/ level. Neutralization of /"IL-4"/ suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse /"IL-4"/ administration (0.5 or 2.0 g/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 g/mouse, i.p.) administration on dicloxacillin-induced /"liver injury"/. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced /"liver injury"/ is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2). | [
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21094227 | IL-4 mediates dicloxacillin-induced liver injury in mice. | Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 g/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 g/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2). | IL-4 mediates dicloxacillin-induced /"liver injury"/ in mice. | /"Drug-induced liver injury"/ (/"DILI"/) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict /"DILI"/ in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed /"liver injury"/, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced /"liver injury"/. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 g/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (/"CRTh2"/) is a cognate receptor for prostaglandin (PG) D(2), and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD(2) (DK-PGD(2); 10 g/mouse, i.p.) administration on dicloxacillin-induced /"liver injury"/. DK-PGD(2)/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced /"liver injury"/ is mediated by a Th2-type immune reaction and exacerbated by DK-PGD(2). | [
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21110240 | APOE epsilon status in Hungarian patients with primary progressive multiple sclerosis. | PRINCIPLES: Apolipoprotein E (ApoE), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The APOE gene (APOE) is involved in neurodegenerative diseases, the best-known association being that between the APOE 4 allele and Alzheimer's disease. Multiple sclerosis (MS) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the APOE gene on the susceptibility of primary progressive MS (PPMS) in Hungary. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers. RESULTS: The number of PPMS patients without the 2 allele was found to be remarkably high, whilst the 2 allele was overrepresented in the RRMS group. A markedly high frequency of the 4 allele was found in the PPMS group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the 2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of MS. CONCLUSIONS: Our findings suggest that the presence of the 2 and 4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters. | /"APOE"/ epsilon status in Hungarian patients with primary progressive /"multiple sclerosis"/. | PRINCIPLES: /"Apolipoprotein E"/ (/"ApoE"/), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The /"APOE"/ gene (/"APOE"/) is involved in neurodegenerative diseases, the best-known association being that between the /"APOE 4"/ allele and Alzheimer's disease. /"Multiple sclerosis"/ (/"MS"/) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the /"APOE"/ gene on the susceptibility of primary progressive MS (PPMS) in Hungary. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers. RESULTS: The number of PPMS patients without the 2 allele was found to be remarkably high, whilst the 2 allele was overrepresented in the RRMS group. A markedly high frequency of the 4 allele was found in the PPMS group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the 2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of /"MS"/. CONCLUSIONS: Our findings suggest that the presence of the 2 and 4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters. | [
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21110240 | APOE epsilon status in Hungarian patients with primary progressive multiple sclerosis. | PRINCIPLES: Apolipoprotein E (ApoE), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The APOE gene (APOE) is involved in neurodegenerative diseases, the best-known association being that between the APOE 4 allele and Alzheimer's disease. Multiple sclerosis (MS) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the APOE gene on the susceptibility of primary progressive MS (PPMS) in Hungary. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers. RESULTS: The number of PPMS patients without the 2 allele was found to be remarkably high, whilst the 2 allele was overrepresented in the RRMS group. A markedly high frequency of the 4 allele was found in the PPMS group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and PPMS groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the 2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of MS. CONCLUSIONS: Our findings suggest that the presence of the 2 and 4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters. | /"APOE"/ epsilon status in Hungarian patients with primary progressive multiple sclerosis. | PRINCIPLES: /"Apolipoprotein E"/ (/"ApoE"/), an important glycoprotein in the transport, uptake and redistribution of cholesterol, is necessary in nerve tissue repair. The /"APOE"/ gene (/"APOE"/) is involved in neurodegenerative diseases, the best-known association being that between the /"APOE 4"/ allele and Alzheimer's disease. Multiple sclerosis (MS) is a chronic inflammatory neurological disease. The aim of this study was to assess (multicentre assessment) the possible influence of the /"APOE"/ gene on the susceptibility of /"primary progressive MS"/ (/"PPMS"/) in Hungary. METHODS: Polymerase chain reaction and restriction fragment length polymorphism were carried out on DNA isolated from 135 volunteers. RESULTS: The number of /"PPMS"/ patients without the 2 allele was found to be remarkably high, whilst the 2 allele was overrepresented in the RRMS group. A markedly high frequency of the 4 allele was found in the /"PPMS"/ group and a very low frequency in the HC group. With regards to the clinical parameters, significant differences were observed between the RRMS and /"PPMS"/ groups. Differences were also detected regarding the EDSS and MSSS scores when the patients were grouped by the presence or absence of the 2 allele. All of the observed differences in the clinical parameters disappeared when the patients were further stratified by the type of MS. CONCLUSIONS: Our findings suggest that the presence of the 2 and 4 alleles may play a role in the development of the disease. However, if any type of the disease has already developed the alleles show no association with the clinical parameters. | [
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21131976 | Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. | We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy. | Mutations in genes encoding subunits of RNA polymerases I and III cause /"Treacher Collins syndrome"/. | We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with /"Treacher Collins syndrome"/ (/"TCS"/). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with /"TCS"/. Furthermore, we discovered mutations in both alleles of /"POLR1C"/ in three individuals with /"TCS"/. These findings identify two additional genes involved in /"TCS"/, confirm the genetic heterogeneity of /"TCS"/ and support the hypothesis that /"TCS"/ is a ribosomopathy. | [
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} | Yes |
21131976 | Mutations in genes encoding subunits of RNA polymerases I and III cause Treacher Collins syndrome. | We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, POLR1D, in an individual with Treacher Collins syndrome (TCS). Subsequently, we detected 20 additional heterozygous mutations of POLR1D in 252 individuals with TCS. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with TCS. These findings identify two additional genes involved in TCS, confirm the genetic heterogeneity of TCS and support the hypothesis that TCS is a ribosomopathy. | Mutations in genes encoding subunits of RNA polymerases I and III cause /"Treacher Collins syndrome"/. | We identified a deletion of a gene encoding a subunit of RNA polymerases I and III, /"POLR1D"/, in an individual with /"Treacher Collins syndrome"/ (/"TCS"/). Subsequently, we detected 20 additional heterozygous mutations of /"POLR1D"/ in 252 individuals with /"TCS"/. Furthermore, we discovered mutations in both alleles of POLR1C in three individuals with /"TCS"/. These findings identify two additional genes involved in /"TCS"/, confirm the genetic heterogeneity of /"TCS"/ and support the hypothesis that /"TCS"/ is a ribosomopathy. | [
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21151597 | Polymorphisms of IL23R and Fuchs' syndrome in a Chinese Han population. | PURPOSE: The aim of the study was to investigate the association of polymorphisms of the interleukin-23 receptor (IL23R) gene with Fuchs' syndrome in a Chinese Han population. METHODS: Three single-nucleotide polymorphisms (SNPs), rs7517847, rs11209032 and rs17375018 of IL23R were genotyped in 138 Chinese Han patients with Fuchs' syndrome and 407 healthy controls by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Data were analyzed by (2) analysis. RESULTS: All genotype and allele distributions in patients with Fuchs' syndrome and healthy controls were in Hardy-Weinberg equilibrium. The frequency of the rs11209032 AA genotype was significantly increased in patients with Fuchs' syndrome as compared to controls (corrected p [pc]=0.036, OR 1.86, 95%CI 1.21 to 2.86). There were no statistically significant differences between patients and healthy controls concerning the other two tested SNPs (rs17375018 and rs7517847). The haplotypes of the tested SNPs were not different between patients and controls. Additionally, analysis according to gender did not show any influence of sex on the association of IL23R with Fuchs' syndrome. CONCLUSIONS: Our results suggested that the rs11209032 AA genotype of the IL23R gene may predispose for Fuchs' syndrome in Chinese patients. | Polymorphisms of /"IL23R"/ and /"Fuchs' syndrome"/ in a Chinese Han population. | PURPOSE: The aim of the study was to investigate the association of polymorphisms of the /"interleukin-23 receptor"/ (/"IL23R"/) gene with /"Fuchs' syndrome"/ in a Chinese Han population. METHODS: Three single-nucleotide polymorphisms (SNPs), rs7517847, rs11209032 and rs17375018 of /"IL23R"/ were genotyped in 138 Chinese Han patients with /"Fuchs' syndrome"/ and 407 healthy controls by using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Data were analyzed by (2) analysis. RESULTS: All genotype and allele distributions in patients with /"Fuchs' syndrome"/ and healthy controls were in Hardy-Weinberg equilibrium. The frequency of the rs11209032 AA genotype was significantly increased in patients with /"Fuchs' syndrome"/ as compared to controls (corrected p [pc]=0.036, OR 1.86, 95%CI 1.21 to 2.86). There were no statistically significant differences between patients and healthy controls concerning the other two tested SNPs (rs17375018 and rs7517847). The haplotypes of the tested SNPs were not different between patients and controls. Additionally, analysis according to gender did not show any influence of sex on the association of /"IL23R"/ with /"Fuchs' syndrome"/. CONCLUSIONS: Our results suggested that the rs11209032 AA genotype of the /"IL23R"/ gene may predispose for /"Fuchs' syndrome"/ in Chinese patients. | [
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21153458 | Methylation status and overexpression of COX-2 in Tunisian patients with ductal invasive breast carcinoma. | Inflammation and hormonal signalling induce the cyclooxygenase-2 (COX-2) expression in solid tumours including breast cancer, which in turn affects cell proliferation, apoptosis and metastasis. The aim of this study was to investigate the expression of COX-2 and its association with clinical parameters, patient's survival, hormones receptors (oestrogen, progesterone), ERBB2 and TP53 expression in 83 cases of infiltrating ductal breast carcinomas. Moreover, the methylation status at the CpG islands of the COX-2 gene promoter was also explored in 70 specimens. We showed that tumours exhibiting moderate to intense COX-2 immunostaining were significantly more frequent in patients over 45 years old (p = 0.027). Moreover, a high level of COX-2 expression correlated with a shorter survival time (p log-rank = 0.04) and was an independent prognostic factor (p = 0.022; HR 6.4; 95% CI = 1.3-31.4). On the other hand, hypermethylation of the COX-2 gene promoter was observed in 27% of cases and strongly associated with smaller tumours (<5 cm, p = 0.011). Furthermore, patients with methylated COX-2 pattern have a better 4-year disease-free survival (p = 0.022) as well as a prolonged overall survival (p log-rank test = 0.034). In conclusion, we showed that high COX-2 expression was associated with reduced survival and was an independent prognostic factor. However, hypermethylation of the COX-2 promoter correlated with a better overall survival in Tunisian patients with breast carcinoma. | Methylation status and overexpression of /"COX-2"/ in Tunisian patients with /"ductal invasive breast carcinoma"/. | Inflammation and hormonal signalling induce the /"cyclooxygenase-2"/ (/"COX-2"/) expression in solid tumours including breast cancer, which in turn affects cell proliferation, apoptosis and metastasis. The aim of this study was to investigate the expression of /"COX-2"/ and its association with clinical parameters, patient's survival, hormones receptors (oestrogen, progesterone), ERBB2 and TP53 expression in 83 cases of infiltrating ductal breast carcinomas. Moreover, the methylation status at the CpG islands of the /"COX-2"/ gene promoter was also explored in 70 specimens. We showed that tumours exhibiting moderate to intense /"COX-2"/ immunostaining were significantly more frequent in patients over 45 years old (p = 0.027). Moreover, a high level of /"COX-2"/ expression correlated with a shorter survival time (p log-rank = 0.04) and was an independent prognostic factor (p = 0.022; HR 6.4; 95% CI = 1.3-31.4). On the other hand, hypermethylation of the /"COX-2"/ gene promoter was observed in 27% of cases and strongly associated with smaller tumours (<5 cm, p = 0.011). Furthermore, patients with methylated /"COX-2"/ pattern have a better 4-year disease-free survival (p = 0.022) as well as a prolonged overall survival (p log-rank test = 0.034). In conclusion, we showed that high /"COX-2"/ expression was associated with reduced survival and was an independent prognostic factor. However, hypermethylation of the /"COX-2"/ promoter correlated with a better overall survival in Tunisian patients with breast carcinoma. | [
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} | Yes |
21153458 | Methylation status and overexpression of COX-2 in Tunisian patients with ductal invasive breast carcinoma. | Inflammation and hormonal signalling induce the cyclooxygenase-2 (COX-2) expression in solid tumours including breast cancer, which in turn affects cell proliferation, apoptosis and metastasis. The aim of this study was to investigate the expression of COX-2 and its association with clinical parameters, patient's survival, hormones receptors (oestrogen, progesterone), ERBB2 and TP53 expression in 83 cases of infiltrating ductal breast carcinomas. Moreover, the methylation status at the CpG islands of the COX-2 gene promoter was also explored in 70 specimens. We showed that tumours exhibiting moderate to intense COX-2 immunostaining were significantly more frequent in patients over 45 years old (p = 0.027). Moreover, a high level of COX-2 expression correlated with a shorter survival time (p log-rank = 0.04) and was an independent prognostic factor (p = 0.022; HR 6.4; 95% CI = 1.3-31.4). On the other hand, hypermethylation of the COX-2 gene promoter was observed in 27% of cases and strongly associated with smaller tumours (<5 cm, p = 0.011). Furthermore, patients with methylated COX-2 pattern have a better 4-year disease-free survival (p = 0.022) as well as a prolonged overall survival (p log-rank test = 0.034). In conclusion, we showed that high COX-2 expression was associated with reduced survival and was an independent prognostic factor. However, hypermethylation of the COX-2 promoter correlated with a better overall survival in Tunisian patients with breast carcinoma. | Methylation status and overexpression of /"COX-2"/ in Tunisian patients with ductal invasive breast carcinoma. | Inflammation and hormonal signalling induce the /"cyclooxygenase-2"/ (/"COX-2"/) expression in solid tumours including /"breast cancer"/, which in turn affects cell proliferation, apoptosis and metastasis. The aim of this study was to investigate the expression of /"COX-2"/ and its association with clinical parameters, patient's survival, hormones receptors (oestrogen, progesterone), ERBB2 and TP53 expression in 83 cases of /"infiltrating ductal breast carcinomas"/. Moreover, the methylation status at the CpG islands of the /"COX-2"/ gene promoter was also explored in 70 specimens. We showed that tumours exhibiting moderate to intense /"COX-2"/ immunostaining were significantly more frequent in patients over 45 years old (p = 0.027). Moreover, a high level of /"COX-2"/ expression correlated with a shorter survival time (p log-rank = 0.04) and was an independent prognostic factor (p = 0.022; HR 6.4; 95% CI = 1.3-31.4). On the other hand, hypermethylation of the /"COX-2"/ gene promoter was observed in 27% of cases and strongly associated with smaller tumours (<5 cm, p = 0.011). Furthermore, patients with methylated /"COX-2"/ pattern have a better 4-year disease-free survival (p = 0.022) as well as a prolonged overall survival (p log-rank test = 0.034). In conclusion, we showed that high /"COX-2"/ expression was associated with reduced survival and was an independent prognostic factor. However, hypermethylation of the /"COX-2"/ promoter correlated with a better overall survival in Tunisian patients with /"breast carcinoma"/. | [
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} | No |
21187522 | KRAS genotyping as biomarker in colorectal cancer: a comparison of three commercial kits on histologic material. | BACKGROUND/AIM: The crucial role of KRAS status in new colorectal cancer target therapy raises the issue regarding which testing method to use. This study analysed 112 formalin fixed, paraffin-embedded (FFPE) metastatic tissue samples using three different commercially available kits. PATIENTS AND METHODS: A group of 40 KRAS wild-type (wt), 40 codon 12-mutated and 32 codon-13 mutated samples, previously evaluated by real-time PCR (TheraScreen kit), used as reference method, were analysed by Ampli-set-K-RAS and K-RAS StripAssay kit (herein called kit A and B, respectively) based on two different technologies. RESULTS: The sensitivity of both kits was 92.5% for wt samples, 100% and 95.0% for kit A and B, respectively for samples mutated in codon 12. The specificity was 100% for both kits for all groups of samples. After a minor modification of the kit A method, its specificity reached 100%. CONCLUSION: of low cost and easy to use, kit A may be suitable for use in a routine diagnostic setting. | /"KRAS"/ genotyping as biomarker in /"colorectal cancer"/: a comparison of three commercial kits on histologic material. | BACKGROUND/AIM: The crucial role of /"KRAS"/ status in new /"colorectal cancer"/ target therapy raises the issue regarding which testing method to use. This study analysed 112 formalin fixed, paraffin-embedded (FFPE) metastatic tissue samples using three different commercially available kits. PATIENTS AND METHODS: A group of 40 /"KRAS"/ wild-type (wt), 40 codon 12-mutated and 32 codon-13 mutated samples, previously evaluated by real-time PCR (TheraScreen kit), used as reference method, were analysed by Ampli-set-/"K-RAS"/ and /"K-RAS"/ StripAssay kit (herein called kit A and B, respectively) based on two different technologies. RESULTS: The sensitivity of both kits was 92.5% for wt samples, 100% and 95.0% for kit A and B, respectively for samples mutated in codon 12. The specificity was 100% for both kits for all groups of samples. After a minor modification of the kit A method, its specificity reached 100%. CONCLUSION: of low cost and easy to use, kit A may be suitable for use in a routine diagnostic setting. | [
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} | Yes |
21264219 | DIA1R is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | /"DIA1R"/ is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term /"DIA1R"/ (/"DIA1-Related"/). While DIA1 is autosomal (chromosome 3, position 3q24), /"DIA1R"/ localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and /"DIA1R"/ 433, residues. At the amino acid level, DIA1 and /"DIA1R"/ are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in /"DIA1R"/ are associated with /"X-linked mental retardation"/ (/"XLMR"/) and /"DIA1R"/ deletion is associated with syndromes with ASD-like traits and/or /"XLMR"/. Together, these results support a model where the DIA1 and /"DIA1R"/ gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | [
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} | {
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} | Yes |
21264219 | DIA1R is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | /"DIA1R"/ is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: /"Autism spectrum disorders"/ (/"ASDS"/) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term /"DIA1R"/ (/"DIA1-Related"/). While DIA1 is autosomal (chromosome 3, position 3q24), /"DIA1R"/ localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and /"DIA1R"/ 433, residues. At the amino acid level, DIA1 and /"DIA1R"/ are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in /"DIA1R"/ are associated with X-linked mental retardation (XLMR) and /"DIA1R"/ deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and /"DIA1R"/ gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | [
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21264219 | DIA1R is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | /"DIA1R"/ is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. /"Mental retardation"/ frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term /"DIA1R"/ (/"DIA1-Related"/). While DIA1 is autosomal (chromosome 3, position 3q24), /"DIA1R"/ localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and /"DIA1R"/ 433, residues. At the amino acid level, DIA1 and /"DIA1R"/ are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in /"DIA1R"/ are associated with X-linked mental retardation (XLMR) and /"DIA1R"/ deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and /"DIA1R"/ gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or /"mental retardation"/. | [
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21264219 | DIA1R is an X-linked gene related to Deleted In Autism-1. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation. | DIA1R is an X-linked gene related to /"Deleted In Autism-1"/. | BACKGROUND: Autism spectrum disorders (ASDS) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. /"Mental retardation"/ frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the /"Deleted-In-Autism-1"/ (/"DIA1"/) gene. METHODOLOGY/PRINCIPAL FINDINGS: Using a bioinformatics-based approach, we have identified a human gene closely related to /"DIA1"/, we term DIA1R (DIA1-Related). While /"DIA1"/ is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with /"DIA1"/ encoding 430, and DIA1R 433, residues. At the amino acid level, /"DIA1"/ and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue. CONCLUSIONS/SIGNIFICANCE: Examination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the /"DIA1"/ and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or /"mental retardation"/. | [
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21265945 | Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case. | Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD. | /"Adult-type metachromatic leukodystrophy"/ with compound heterozygous /"ARSA"/ mutations: a case report and phenotypic comparison with a previously reported case. | /"Metachromatic leukodystrophy"/ (/"MLD"/) is an autosomal recessive lysosomal storage disease caused by a /"deficiency of arylsulfatase A"/ A"/. /"MLD"/ is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with /"MLD"/ by genetic analysis, which revealed compound heterozygous /"ARSA"/ missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in /"MLD"/. | [
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21265945 | Adult-type metachromatic leukodystrophy with compound heterozygous ARSA mutations: a case report and phenotypic comparison with a previously reported case. | Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of arylsulfatase A. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous ARSA missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that demonstrated frontal lobe dysfunction. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD. | Adult-type metachromatic leukodystrophy with compound heterozygous /"ARSA"/ mutations: a case report and phenotypic comparison with a previously reported case. | Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal storage disease caused by a deficiency of /"arylsulfatase A"/. MLD is a heterogeneous disease with variable age at onset and variable clinical features. We evaluated a 33-year-old female patient who developed manifestations of disinhibitory behavior. She was diagnosed with MLD by genetic analysis, which revealed compound heterozygous /"ARSA"/ missense mutations (p.G99D and p.T409I). The same combination of mutations was previously reported in a Japanese patient with similar symptoms. We performed additional, detailed neuropsychological tests with functional imaging on the current patient that /"demonstrated frontal lobe dysfunction"/. These results indicate that the mutations have important implications for genotype-phenotype correlation in MLD. | [
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21270338 | Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer. | Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies. | /"Uroporphyrinogen decarboxylase"/ is a radiosensitizing target for /"head and neck cancer"/. | /"Head and neck cancer"/ (/"HNC"/) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in /"HNC"/ treatment. /"Uroporphyrinogen decarboxylase"/ (/"UROD"/), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for /"HNC"/. /"UROD"/ knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in /"HNC"/ cells in vitro and suppressed the in vivo tumor-forming capacity of /"HNC"/ cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, /"UROD"/ was significantly overexpressed in /"HNC"/ patient biopsies. Lower preradiation /"UROD"/ mRNA expression correlated with improved disease-free survival, suggesting that /"UROD"/ could potentially be used to predict radiation response. /"UROD"/ down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed /"UROD"/ as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies. | [
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21270338 | Uroporphyrinogen decarboxylase is a radiosensitizing target for head and neck cancer. | Head and neck cancer (HNC) is the eighth most common malignancy worldwide, comprising a diverse group of cancers affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. Uroporphyrinogen decarboxylase (UROD), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a tumor-selective radiosensitizing target for HNC. UROD knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo tumor-forming capacity of HNC cells, as well as delayed the growth of established tumor xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced tumor oxidative stress. Moreover, UROD was significantly overexpressed in HNC patient biopsies. Lower preradiation UROD mRNA expression correlated with improved disease-free survival, suggesting that UROD could potentially be used to predict radiation response. UROD down-regulation also radiosensitized several different models of human cancer, as well as sensitized tumors to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed UROD as a potent tumor-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human malignancies. | /"Uroporphyrinogen decarboxylase"/ is a radiosensitizing target for head and neck cancer. | Head and neck cancer (HNC) is the eighth most common /"malignancy"/ worldwide, comprising a diverse group of /"cancers"/ affecting the head and neck region. Despite advances in therapeutic options over the last few decades, treatment toxicities and overall clinical outcomes have remained disappointing, thereby underscoring a need to develop novel therapeutic approaches in HNC treatment. /"Uroporphyrinogen decarboxylase"/ (/"UROD"/), a key regulator of heme biosynthesis, was identified from an RNA interference-based high-throughput screen as a /"tumor"/-selective radiosensitizing target for HNC. /"UROD"/ knockdown plus radiation induced caspase-mediated apoptosis and cell cycle arrest in HNC cells in vitro and suppressed the in vivo /"tumor"/-forming capacity of HNC cells, as well as delayed the growth of established /"tumor"/ xenografts in mice. This radiosensitization appeared to be mediated by alterations in iron homeostasis and increased production of reactive oxygen species, resulting in enhanced /"tumor"/ oxidative stress. Moreover, /"UROD"/ was significantly overexpressed in HNC patient biopsies. Lower preradiation /"UROD"/ mRNA expression correlated with improved disease-free survival, suggesting that /"UROD"/ could potentially be used to predict radiation response. /"UROD"/ down-regulation also radiosensitized several different models of human /"cancer"/, as well as sensitized /"tumors"/ to chemotherapeutic agents, including 5-fluorouracil, cisplatin, and paclitaxel. Thus, our study has revealed /"UROD"/ as a potent /"tumor"/-selective sensitizer for both radiation and chemotherapy, with potential relevance to many human /"malignancies"/. | [
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21285140 | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | Copy number variants in /"schizophrenia"/: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with /"schizophrenia"/ and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with /"schizophrenia"/ or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in /"NRXN1"/. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of /"schizophrenia"/ with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic /"NRXN1"/ deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of /"schizophrenia"/. | [
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21285140 | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | Copy number variants in /"schizophrenia"/: confirmation of five previous findings and new evidence for 3q29 microdeletions and /"VIPR2"/ duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with /"schizophrenia"/ and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with /"schizophrenia"/ or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for /"vasoactive intestinal peptide receptor 2"/ (/"VIPR2"/), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of /"schizophrenia"/ with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including /"VIPR2"/, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of /"schizophrenia"/. | [
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21285140 | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and /"VIPR2"/ duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the /"Molecular Genetics of Schizophrenia study"/ (/"MGS"/) and additional available data. METHOD: After quality control, /"MGS"/ data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of /"MGS"/ data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for /"vasoactive intestinal peptide receptor 2"/ (/"VIPR2"/), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including /"VIPR2"/, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | [
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21285140 | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications. | OBJECTIVE: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data. METHOD: After quality control, MGS data for 3,945 subjects with schizophrenia or /"schizoaffective disorder"/ and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction. RESULTS: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in /"NRXN1"/. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications. CONCLUSIONS: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic /"NRXN1"/ deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including /"IL1R2"/, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, /"GNA12"/ and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, /"DAP"/, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, /"PRDM1"/, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, /"IL7R"/, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-/"IL8RB"/, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, /"IL12B"/, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and /"LSP1"/. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, /"IL8RA"/-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, /"IRF5"/, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, /"JAK2"/, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and /"LSP1"/. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (/"P < 5"/ * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed /"inflammatory bowel disease"/ risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional /"ulcerative colitis"/ risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in /"ulcerative colitis"/ have identified 18 susceptibility loci. We conducted a meta-analysis of six /"ulcerative colitis"/ genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (/"P < 5"/ * 10(-8)), increasing the number of /"ulcerative colitis"/-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and /"ulcerative colitis"/. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, /"JAK2"/, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, /"IL8RA"/-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, /"GNA12"/ and LSP1. The total number of confirmed /"inflammatory bowel disease"/ risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, /"PRDM1"/, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, /"IL7R"/, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, /"PRDM1"/, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed /"inflammatory bowel disease"/ risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, /"DAP"/, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between /"Crohn's disease"/ and ulcerative colitis. | [
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21297633 | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, IL12B, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed inflammatory bowel disease risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | Meta-analysis identifies 29 additional ulcerative colitis risk loci, increasing the number of confirmed associations to 47. | Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P < 5 * 10(-8)), increasing the number of ulcerative colitis-associated loci to 47. After annotating associated regions using GRAIL, expression quantitative trait loci data and correlations with non-synonymous SNPs, we identified many candidate genes that provide potentially important insights into disease pathogenesis, including IL1R2, IL8RA-IL8RB, IL7R, /"IL12B"/, DAP, PRDM1, JAK2, IRF5, GNA12 and LSP1. The total number of confirmed /"inflammatory bowel disease"/ risk loci is now 99, including a minimum of 28 shared association signals between Crohn's disease and ulcerative colitis. | [
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21300947 | The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. | CONTEXT: The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD. | The /"brain-derived neurotrophic factor"/ Val66Met polymorphism and prediction of neural risk for /"Alzheimer disease"/. | CONTEXT: The /"brain-derived neurotrophic factor"/ (/"BDNF"/) Val66Met (rs6265) polymorphism may predict the risk of /"Alzheimer disease"/ (/"AD"/). However, genetic association studies of the /"BDNF"/ gene with /"AD"/ have produced equivocal results. Imaging-genetics strategies may clarify the manner in which /"BDNF"/ gene variation predicts the risk of /"AD"/ via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the /"BDNF"/ Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to /"AD"/ by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The /"BDNF"/ Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The /"BDNF"/ Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The /"BDNF"/ gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of /"AD"/. Our novel findings provide convergent evidence in vivo for a /"BDNF"/ genetic mechanism of susceptibility in an intermediate phenotype related to /"AD"/. | [
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21300947 | The brain-derived neurotrophic factor Val66Met polymorphism and prediction of neural risk for Alzheimer disease. | CONTEXT: The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the BDNF gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which BDNF gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the BDNF Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical thickness, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The BDNF Val66Met genotype, apolipoprotein E genotype, cortical thickness, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The BDNF Val66Met polymorphism interacted with age to predict (1) cortical thickness (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The BDNF gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a BDNF genetic mechanism of susceptibility in an intermediate phenotype related to AD. | The /"brain-derived neurotrophic factor"/ Val66Met polymorphism and prediction of neural risk for Alzheimer disease. | CONTEXT: The /"brain-derived neurotrophic factor"/ (/"BDNF"/) Val66Met (rs6265) polymorphism may predict the risk of Alzheimer disease (AD). However, genetic association studies of the /"BDNF"/ gene with AD have produced equivocal results. Imaging-genetics strategies may clarify the manner in which /"BDNF"/ gene variation predicts the risk of AD via characterization of its effects on at-risk structures or neural networks susceptible in this disorder. OBJECTIVE: To determine whether the /"BDNF"/ Val66Met gene variant interacts with age to predict brain and cognitive measures in healthy volunteers across the adult lifespan in an intermediate phenotype pattern related to AD by examining (1) cortical /"thickness"/, (2) fractional anisotropy of white matter tracts (ie, white matter integrity), and (3) episodic memory performance. DESIGN: A cross-sectional study using genetics, high-resolution magnetic resonance imaging, diffusion tensor imaging, and cognitive testing in healthy individuals spanning the adult lifespan. SETTING: University hospital. PARTICIPANTS: A total of 69 healthy volunteers ranging from 19 to 82 years of age. MAIN OUTCOME MEASURES: The /"BDNF"/ Val66Met genotype, apolipoprotein E genotype, cortical /"thickness"/, microstructural integrity of white matter tracts, and episodic memory performance were evaluated. RESULTS: The /"BDNF"/ Val66Met polymorphism interacted with age to predict (1) cortical /"thickness"/ (prominently at the entorhinal cortex and temporal gyri), (2) fractional anisotropy of white matter tracts (prominently at white matter tracts connecting to the medial temporal lobe), and (3) episodic memory performance. For each of these findings, the pattern was similar: valine/valine individuals in late life were susceptible, and in early adult life, methionine allele carriers demonstrated susceptibility. CONCLUSIONS: The /"BDNF"/ gene confers risk in an age-dependent manner on the brain structures and cognitive functions that are consistent with the neural circuitry vulnerable in the earliest stages of AD. Our novel findings provide convergent evidence in vivo for a /"BDNF"/ genetic mechanism of susceptibility in an intermediate phenotype related to AD. | [
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21313874 | Interferon-gamma low producer genotype +5644 over presented in patients with focal brucellosis. | Genetic polymorphisms that affect production levels of certain cytokines may determine the risk, severity or protection in some infectious diseases like brucellosis. IFN-gamma plays a key role in the defense mechanism against brucella infection. This study aimed to determine the influence of the polymorphism within the +5644 position of IFN-gamma gene on the susceptibility to brucellosis. We investigated the allelic and genotypes distribution of A5644G polymorphism in IFN-gamma gene in an Iranian population comprising 259 patients with brucellosis and 238 healthy controls. The single nucleotide polymorphism was determined using the polymerase chain reaction in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3'-end. Allelic and genotype frequencies of G5644A polymorphism of IFN-gamma gene were not significantly differed between patients with brucellosis and controls (p > 0.05). Stratification of patients to focal and non focal diseases revealed a significant increased of 5644A allele in patients with focal brucellosis (79.31% vs. 61.94%, p = 0.0005). Moreover, multivariate logistic regression models showed patients harboring the INF-y G5644A genotype were significantly more likely to develop focal infectious complications (OR = 3.45, p = 0.0004, 95% CI = 1.26-7.94). The present study suggests that the variant genotypes of G6544A of IFN-gamma might be associated with focal form of brucellosis and play as a genetic risk factor in brucellosis. | /"Interferon-gamma"/ low producer genotype +5644 over presented in patients with focal /"brucellosis"/. | Genetic polymorphisms that affect production levels of certain cytokines may determine the risk, severity or protection in some infectious diseases like /"brucellosis"/. /"IFN-gamma"/ plays a key role in the defense mechanism against brucella infection. This study aimed to determine the influence of the polymorphism within the +5644 position of /"IFN-gamma"/ gene on the susceptibility to /"brucellosis"/. We investigated the allelic and genotypes distribution of A5644G polymorphism in /"IFN-gamma"/ gene in an Iranian population comprising 259 patients with /"brucellosis"/ and 238 healthy controls. The single nucleotide polymorphism was determined using the polymerase chain reaction in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3'-end. Allelic and genotype frequencies of G5644A polymorphism of /"IFN-gamma"/ gene were not significantly differed between patients with /"brucellosis"/ and controls (p > 0.05). Stratification of patients to focal and non focal diseases revealed a significant increased of 5644A allele in patients with focal /"brucellosis"/ (79.31% vs. 61.94%, p = 0.0005). Moreover, multivariate logistic regression models showed patients harboring the INF-y G5644A genotype were significantly more likely to develop focal infectious complications (OR = 3.45, p = 0.0004, 95% CI = 1.26-7.94). The present study suggests that the variant genotypes of G6544A of /"IFN-gamma"/ might be associated with focal form of /"brucellosis"/ and play as a genetic risk factor in /"brucellosis"/. | [
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21313874 | Interferon-gamma low producer genotype +5644 over presented in patients with focal brucellosis. | Genetic polymorphisms that affect production levels of certain cytokines may determine the risk, severity or protection in some infectious diseases like brucellosis. IFN-gamma plays a key role in the defense mechanism against brucella infection. This study aimed to determine the influence of the polymorphism within the +5644 position of IFN-gamma gene on the susceptibility to brucellosis. We investigated the allelic and genotypes distribution of A5644G polymorphism in IFN-gamma gene in an Iranian population comprising 259 patients with brucellosis and 238 healthy controls. The single nucleotide polymorphism was determined using the polymerase chain reaction in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3'-end. Allelic and genotype frequencies of G5644A polymorphism of IFN-gamma gene were not significantly differed between patients with brucellosis and controls (p > 0.05). Stratification of patients to focal and non focal diseases revealed a significant increased of 5644A allele in patients with focal brucellosis (79.31% vs. 61.94%, p = 0.0005). Moreover, multivariate logistic regression models showed patients harboring the INF-y G5644A genotype were significantly more likely to develop focal infectious complications (OR = 3.45, p = 0.0004, 95% CI = 1.26-7.94). The present study suggests that the variant genotypes of G6544A of IFN-gamma might be associated with focal form of brucellosis and play as a genetic risk factor in brucellosis. | /"Interferon-gamma"/ low producer genotype +5644 over presented in patients with focal brucellosis. | Genetic polymorphisms that affect production levels of certain cytokines may determine the risk, severity or protection in some /"infectious diseases"/ like brucellosis. /"IFN-gamma"/ plays a key role in the defense mechanism against brucella infection. This study aimed to determine the influence of the polymorphism within the +5644 position of /"IFN-gamma"/ gene on the susceptibility to brucellosis. We investigated the allelic and genotypes distribution of A5644G polymorphism in /"IFN-gamma"/ gene in an Iranian population comprising 259 patients with brucellosis and 238 healthy controls. The single nucleotide polymorphism was determined using the polymerase chain reaction in association with sequence-specific primers (PCR-SSP) incorporating mismatches at the 3'-end. Allelic and genotype frequencies of G5644A polymorphism of /"IFN-gamma"/ gene were not significantly differed between patients with brucellosis and controls (p > 0.05). Stratification of patients to focal and non focal diseases revealed a significant increased of 5644A allele in patients with focal brucellosis (79.31% vs. 61.94%, p = 0.0005). Moreover, multivariate logistic regression models showed patients harboring the INF-y G5644A genotype were significantly more likely to develop focal /"infectious complications"/ (OR = 3.45, p = 0.0004, 95% CI = 1.26-7.94). The present study suggests that the variant genotypes of G6544A of /"IFN-gamma"/ might be associated with focal form of brucellosis and play as a genetic risk factor in brucellosis. | [
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21440839 | Effects of mercury on the structure and activity of BLM642-1290 recombinant helicase. | OBJECTIVE: Bloom's syndrome is an autosomal recessive disorder characterized by genomic instability and a predisposition to many cancers. Mutations of the BLM gene (encoding a BLM helicase) may form a structure of the etiology of this disease. As a global pollutant, mercury poses a major threat to human health. The current study was conducted to elucidate the effects of Hg(2+) on the structure and activity of BLM642-1290 recombinant helicase, and to further explore the molecular mechanisms of mercury toxicity to the DNA helicase. METHODS: The effects of Hg(2+) on biological activity and structure of BLM642-1290 recombinant helicase were determined by fluorescence polarized, ultraviolet spectroscopic, and free-phosphorus assay technologies, respectively. RESULTS: The helicase activity, the DNA-binding activity, and the ATPase activity of BLM642-1290 recombinant helicase were inhibited by Hg(2+) treatment. The LMCT (ligand-to-metal charge transition) peaks of the helicase were enhanced with the increase of the Hg(2+) level. The LMCT peaks of the same concentration of helicase gradually increased over time. CONCLUSION: The biological activity of BLM642-1290 recombinant helicase is inhibited by Hg(2+) treatment. The conformation of the helicase is significantly altered by Hg(2+). There exist two binding sites between Hg(2+) and the helicase, which are located in the amino acid residues 1063-1066 and 940-944 of the helicase, respectively. | Effects of mercury on the structure and activity of BLM642-1290 recombinant helicase. | OBJECTIVE: /"Bloom's syndrome"/ is an autosomal recessive disorder characterized by genomic instability and a predisposition to many cancers. Mutations of the /"BLM"/ gene (encoding a /"BLM"/ helicase) may form a structure of the etiology of this disease. As a global pollutant, mercury poses a major threat to human health. The current study was conducted to elucidate the effects of Hg(2+) on the structure and activity of BLM642-1290 recombinant helicase, and to further explore the molecular mechanisms of mercury toxicity to the DNA helicase. METHODS: The effects of Hg(2+) on biological activity and structure of BLM642-1290 recombinant helicase were determined by fluorescence polarized, ultraviolet spectroscopic, and free-phosphorus assay technologies, respectively. RESULTS: The helicase activity, the DNA-binding activity, and the ATPase activity of BLM642-1290 recombinant helicase were inhibited by Hg(2+) treatment. The LMCT (ligand-to-metal charge transition) peaks of the helicase were enhanced with the increase of the Hg(2+) level. The LMCT peaks of the same concentration of helicase gradually increased over time. CONCLUSION: The biological activity of BLM642-1290 recombinant helicase is inhibited by Hg(2+) treatment. The conformation of the helicase is significantly altered by Hg(2+). There exist two binding sites between Hg(2+) and the helicase, which are located in the amino acid residues 1063-1066 and 940-944 of the helicase, respectively. | [
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21440839 | Effects of mercury on the structure and activity of BLM642-1290 recombinant helicase. | OBJECTIVE: Bloom's syndrome is an autosomal recessive disorder characterized by genomic instability and a predisposition to many cancers. Mutations of the BLM gene (encoding a BLM helicase) may form a structure of the etiology of this disease. As a global pollutant, mercury poses a major threat to human health. The current study was conducted to elucidate the effects of Hg(2+) on the structure and activity of BLM642-1290 recombinant helicase, and to further explore the molecular mechanisms of mercury toxicity to the DNA helicase. METHODS: The effects of Hg(2+) on biological activity and structure of BLM642-1290 recombinant helicase were determined by fluorescence polarized, ultraviolet spectroscopic, and free-phosphorus assay technologies, respectively. RESULTS: The helicase activity, the DNA-binding activity, and the ATPase activity of BLM642-1290 recombinant helicase were inhibited by Hg(2+) treatment. The LMCT (ligand-to-metal charge transition) peaks of the helicase were enhanced with the increase of the Hg(2+) level. The LMCT peaks of the same concentration of helicase gradually increased over time. CONCLUSION: The biological activity of BLM642-1290 recombinant helicase is inhibited by Hg(2+) treatment. The conformation of the helicase is significantly altered by Hg(2+). There exist two binding sites between Hg(2+) and the helicase, which are located in the amino acid residues 1063-1066 and 940-944 of the helicase, respectively. | Effects of mercury on the structure and activity of BLM642-1290 recombinant /"helicase"/. | OBJECTIVE: Bloom's syndrome is an /"autosomal recessive disorder"/ characterized by genomic instability and a predisposition to many cancers. Mutations of the BLM gene (encoding a BLM /"helicase"/) may form a structure of the etiology of this disease. As a global pollutant, mercury poses a major threat to human health. The current study was conducted to elucidate the effects of Hg(2+) on the structure and activity of BLM642-1290 recombinant /"helicase"/, and to further explore the molecular mechanisms of mercury toxicity to the DNA /"helicase"/. METHODS: The effects of Hg(2+) on biological activity and structure of BLM642-1290 recombinant /"helicase"/ were determined by fluorescence polarized, ultraviolet spectroscopic, and free-phosphorus assay technologies, respectively. RESULTS: The /"helicase"/ activity, the DNA-binding activity, and the ATPase activity of BLM642-1290 recombinant /"helicase"/ were inhibited by Hg(2+) treatment. The LMCT (ligand-to-metal charge transition) peaks of the /"helicase"/ were enhanced with the increase of the Hg(2+) level. The LMCT peaks of the same concentration of /"helicase"/ gradually increased over time. CONCLUSION: The biological activity of BLM642-1290 recombinant /"helicase"/ is inhibited by Hg(2+) treatment. The conformation of the /"helicase"/ is significantly altered by Hg(2+). There exist two binding sites between Hg(2+) and the /"helicase"/, which are located in the amino acid residues 1063-1066 and 940-944 of the /"helicase"/, respectively. | [
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21497595 | Erythropoietin regulates apoptosis, inflammation and tissue remodelling via caspase-3 and IL-1b in isolated hemoperfused kidneys. | Ischemia reperfusion injury associated with apoptosis and inflammation plays crucial roles in renal transplantation. Erythropoietin provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm ischemia, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L erythropoietin. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional erythropoietin. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and erythropoietin in normothermic perfusion. Accordingly, caspase-3 activity as well as its active proteins was increased by normothermic perfusion and furthered by erythropoietin. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1b activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by erythropoietin, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by erythropoietin in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of erythropoietin. In addition, erythropoietin induced a dose-dependent increase in caspase-3 precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated caspase-3 cleavage in cisplatin-treated cells. In conclusion, erythropoietin promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to inflammation clearance, renoprotection and tissue remodelling through caspase-3 and IL-1b in isolated haemoperfused kidneys. | /"Erythropoietin"/ regulates apoptosis, /"inflammation"/ and tissue remodelling via caspase-3 and IL-1b in isolated hemoperfused kidneys. | Ischemia reperfusion injury associated with apoptosis and /"inflammation"/ plays crucial roles in renal transplantation. /"Erythropoietin"/ provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm ischemia, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L /"erythropoietin"/. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional /"erythropoietin"/. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and /"erythropoietin"/ in normothermic perfusion. Accordingly, caspase-3 activity as well as its active proteins was increased by normothermic perfusion and furthered by /"erythropoietin"/. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1b activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by /"erythropoietin"/, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by /"erythropoietin"/ in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of /"erythropoietin"/. In addition, /"erythropoietin"/ induced a dose-dependent increase in caspase-3 precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated caspase-3 cleavage in cisplatin-treated cells. In conclusion, /"erythropoietin"/ promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to /"inflammation"/ clearance, renoprotection and tissue remodelling through caspase-3 and IL-1b in isolated haemoperfused kidneys. | [
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21497595 | Erythropoietin regulates apoptosis, inflammation and tissue remodelling via caspase-3 and IL-1b in isolated hemoperfused kidneys. | Ischemia reperfusion injury associated with apoptosis and inflammation plays crucial roles in renal transplantation. Erythropoietin provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm ischemia, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L erythropoietin. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional erythropoietin. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and erythropoietin in normothermic perfusion. Accordingly, caspase-3 activity as well as its active proteins was increased by normothermic perfusion and furthered by erythropoietin. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1b activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by erythropoietin, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by erythropoietin in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of erythropoietin. In addition, erythropoietin induced a dose-dependent increase in caspase-3 precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated caspase-3 cleavage in cisplatin-treated cells. In conclusion, erythropoietin promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to inflammation clearance, renoprotection and tissue remodelling through caspase-3 and IL-1b in isolated haemoperfused kidneys. | Erythropoietin regulates apoptosis, inflammation and tissue remodelling via /"caspase-3"/ and IL-1b in isolated hemoperfused kidneys. | /"Ischemia"/ reperfusion injury associated with apoptosis and inflammation plays crucial roles in renal transplantation. Erythropoietin provides renoprotection, but its effects and mechanisms on kidney preservation are not fully defined. Porcine kidneys, subjected to 10 min warm /"ischemia"/, underwent 16 h cold storage followed by 2 h normothermic hemoperfusion with or without 5000 units/L erythropoietin. Apoptotic cells were increased in tubular lumens and interstitial areas by normothermic perfusion alone, but decreased in tubular areas by additional erythropoietin. Myeloperoxidase+ cells, free cells and cell debris in tubular lumens were gradually increased by cold storage, normothermic perfusion and erythropoietin in normothermic perfusion. Accordingly, /"caspase-3"/ activity as well as its active proteins was increased by normothermic perfusion and furthered by erythropoietin. In contrast, macrophage L1 protein positive cells in tubulointerstitial areas, cytokine interleukin (IL)-1b activation, tubular dilation and vacuolation were raised by normothermic perfusion, but all alleviated by erythropoietin, with higher urine output. The migration of myeloperoxidase+ cells with apoptotic features and apoptotic cells with polymorphous nuclei from tubulointerstitial areas into tubular lumens was widely displayed in the kidneys, especially those preserved by erythropoietin in normothermic perfusion. HSP70 protein was enhanced by normothermic perfusion regardless of erythropoietin. In addition, erythropoietin induced a dose-dependent increase in /"caspase-3"/ precursor in porcine proximal tubular cells (LLC-PK1) and also stimulated /"caspase-3"/ cleavage in cisplatin-treated cells. In conclusion, erythropoietin promotes inflammatory cell apoptosis, drives inflammatory and apoptotic cells into tubular lumens, eventually leads to inflammation clearance, renoprotection and tissue remodelling through /"caspase-3"/ and IL-1b in isolated haemoperfused kidneys. | [
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21565994 | Lactate dehydrogenase C and energy metabolism in mouse sperm. | We demonstrated previously that disruption of the germ cell-specific lactate dehydrogenase C gene (Ldhc) led to male infertility due to defects in sperm function, including a rapid decline in sperm ATP levels, a decrease in progressive motility, and a failure to develop hyperactivated motility. We hypothesized that lack of LDHC disrupts glycolysis by feedback inhibition, either by causing a defect in renewal of the NAD(+) cofactor essential for activity of glyceraldehyde 3-phosphate dehydrogenase, sperm (GAPDHS), or an accumulation of pyruvate. To test these hypotheses, nuclear magnetic resonance analysis was used to follow the utilization of labeled substrates in real time. We found that in sperm lacking LDHC, glucose consumption was disrupted, but the NAD:NADH ratio and pyruvate levels were unchanged, and pyruvate was rapidly metabolized to lactate. Moreover, the metabolic disorder induced by treatment with the lactate dehydrogenase (LDH) inhibitor sodium oxamate was different from that caused by lack of LDHC. This supported our earlier conclusion that LDHA, an LDH isozyme present in the principal piece of the flagellum, is responsible for the residual LDH activity in sperm lacking LDHC, but suggested that LDHC has an additional role in the maintenance of energy metabolism in sperm. By coimmunoprecipitation coupled with mass spectrometry, we identified 27 proteins associated with LDHC. A majority of these proteins are implicated in ATP synthesis, utilization, transport, and/or sequestration. This led us to hypothesize that in addition to its role in glycolysis, LDHC is part of a complex involved in ATP homeostasis that is disrupted in sperm lacking LDHC. | /"Lactate dehydrogenase C"/ and energy metabolism in mouse sperm. | We demonstrated previously that disruption of the germ cell-specific /"lactate dehydrogenase C"/ gene (/"Ldhc"/) led to /"male infertility"/ due to defects in sperm function, including a rapid decline in sperm ATP levels, a decrease in progressive motility, and a failure to develop hyperactivated motility. We hypothesized that lack of /"LDHC"/ disrupts glycolysis by feedback inhibition, either by causing a defect in renewal of the NAD(+) cofactor essential for activity of glyceraldehyde 3-phosphate dehydrogenase, sperm (GAPDHS), or an accumulation of pyruvate. To test these hypotheses, nuclear magnetic resonance analysis was used to follow the utilization of labeled substrates in real time. We found that in sperm lacking /"LDHC"/, glucose consumption was disrupted, but the NAD:NADH ratio and pyruvate levels were unchanged, and pyruvate was rapidly metabolized to lactate. Moreover, the metabolic disorder induced by treatment with the lactate dehydrogenase (LDH) inhibitor sodium oxamate was different from that caused by lack of /"LDHC"/. This supported our earlier conclusion that LDHA, an LDH isozyme present in the principal piece of the flagellum, is responsible for the residual LDH activity in sperm lacking /"LDHC"/, but suggested that /"LDHC"/ has an additional role in the maintenance of energy metabolism in sperm. By coimmunoprecipitation coupled with mass spectrometry, we identified 27 proteins associated with /"LDHC"/. A majority of these proteins are implicated in ATP synthesis, utilization, transport, and/or sequestration. This led us to hypothesize that in addition to its role in glycolysis, /"LDHC"/ is part of a complex involved in ATP homeostasis that is disrupted in sperm lacking /"LDHC"/. | [
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21565994 | Lactate dehydrogenase C and energy metabolism in mouse sperm. | We demonstrated previously that disruption of the germ cell-specific lactate dehydrogenase C gene (Ldhc) led to male infertility due to defects in sperm function, including a rapid decline in sperm ATP levels, a decrease in progressive motility, and a failure to develop hyperactivated motility. We hypothesized that lack of LDHC disrupts glycolysis by feedback inhibition, either by causing a defect in renewal of the NAD(+) cofactor essential for activity of glyceraldehyde 3-phosphate dehydrogenase, sperm (GAPDHS), or an accumulation of pyruvate. To test these hypotheses, nuclear magnetic resonance analysis was used to follow the utilization of labeled substrates in real time. We found that in sperm lacking LDHC, glucose consumption was disrupted, but the NAD:NADH ratio and pyruvate levels were unchanged, and pyruvate was rapidly metabolized to lactate. Moreover, the metabolic disorder induced by treatment with the lactate dehydrogenase (LDH) inhibitor sodium oxamate was different from that caused by lack of LDHC. This supported our earlier conclusion that LDHA, an LDH isozyme present in the principal piece of the flagellum, is responsible for the residual LDH activity in sperm lacking LDHC, but suggested that LDHC has an additional role in the maintenance of energy metabolism in sperm. By coimmunoprecipitation coupled with mass spectrometry, we identified 27 proteins associated with LDHC. A majority of these proteins are implicated in ATP synthesis, utilization, transport, and/or sequestration. This led us to hypothesize that in addition to its role in glycolysis, LDHC is part of a complex involved in ATP homeostasis that is disrupted in sperm lacking LDHC. | /"Lactate dehydrogenase C"/ and energy metabolism in mouse sperm. | We demonstrated previously that disruption of the germ cell-specific /"lactate dehydrogenase C"/ gene (/"Ldhc"/) led to male infertility due to defects in sperm function, including a rapid decline in sperm ATP levels, a decrease in progressive motility, and a failure to develop hyperactivated motility. We hypothesized that lack of /"LDHC"/ disrupts glycolysis by feedback inhibition, either by causing a defect in renewal of the NAD(+) cofactor essential for activity of glyceraldehyde 3-phosphate dehydrogenase, sperm (GAPDHS), or an accumulation of pyruvate. To test these hypotheses, nuclear magnetic resonance analysis was used to follow the utilization of labeled substrates in real time. We found that in sperm lacking /"LDHC"/, glucose consumption was disrupted, but the NAD:NADH ratio and pyruvate levels were unchanged, and pyruvate was rapidly metabolized to lactate. Moreover, the /"metabolic disorder"/ induced by treatment with the lactate dehydrogenase (LDH) inhibitor sodium oxamate was different from that caused by lack of /"LDHC"/. This supported our earlier conclusion that LDHA, an LDH isozyme present in the principal piece of the flagellum, is responsible for the residual LDH activity in sperm lacking /"LDHC"/, but suggested that /"LDHC"/ has an additional role in the maintenance of energy metabolism in sperm. By coimmunoprecipitation coupled with mass spectrometry, we identified 27 proteins associated with /"LDHC"/. A majority of these proteins are implicated in ATP synthesis, utilization, transport, and/or sequestration. This led us to hypothesize that in addition to its role in glycolysis, /"LDHC"/ is part of a complex involved in ATP homeostasis that is disrupted in sperm lacking /"LDHC"/. | [
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21685359 | Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. | BACKGROUND: Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. METHODS: To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 M niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. RESULTS: Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). CONCLUSION: Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential. | Novel effect of antihelminthic Niclosamide on /"S100A4"/-mediated metastatic progression in /"colon cancer"/. | BACKGROUND: Metastasis formation in /"colon cancer"/ severely reduces the survival rate in patients. /"S100A4"/, a calcium-binding protein, is implicated in promoting metastasis formation in /"colon cancer"/. METHODS: To identify a transcription inhibitor of /"S100A4"/, high-throughput screening of 1280 pharmacologically active compounds was performed using a human /"colon cancer"/ cell line expressing a /"S100A4"/ promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. /"Colon cancer"/ cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 M niclosamide to analyze the effect on /"S100A4"/ mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human /"colon cancer"/ (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. RESULTS: Reduced /"S100A4"/ mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated /"colon cancer"/ cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). CONCLUSION: Niclosamide inhibits /"S100A4"/-induced metastasis formation in a mouse model of /"colon cancer"/ and has therapeutic potential. | [
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21685359 | Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. | BACKGROUND: Metastasis formation in colon cancer severely reduces the survival rate in patients. S100A4, a calcium-binding protein, is implicated in promoting metastasis formation in colon cancer. METHODS: To identify a transcription inhibitor of S100A4, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a S100A4 promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 M niclosamide to analyze the effect on S100A4 mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver metastasis was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on metastasis formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. RESULTS: Reduced S100A4 mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver metastasis compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver metastasis formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean metastasis score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). CONCLUSION: Niclosamide inhibits S100A4-induced metastasis formation in a mouse model of colon cancer and has therapeutic potential. | Novel effect of antihelminthic Niclosamide on /"S100A4"/-mediated metastatic progression in colon cancer. | BACKGROUND: /"Metastasis"/ formation in colon cancer severely reduces the survival rate in patients. /"S100A4"/, a calcium-binding protein, is implicated in promoting /"metastasis"/ formation in colon cancer. METHODS: To identify a transcription inhibitor of /"S100A4"/, high-throughput screening of 1280 pharmacologically active compounds was performed using a human colon cancer cell line expressing a /"S100A4"/ promoter-driven luciferase (LUC) reporter gene construct (HCT116-S1004p-LUC). Niclosamide, an antihelminthic agent, was identified as a potential candidate. Colon cancer cell lines (HCT116, SW620, LS174T, SW480, and DLD-1) were treated with 1 M niclosamide to analyze the effect on /"S100A4"/ mRNA and protein expression by quantitative reverse transcription-polymerase chain reaction and immunoblot assays, and effects on cell migration, invasion, proliferation, and colony formation were also assessed in vitro. The effect of niclosamide on liver /"metastasis"/ was assessed in a xenograft mouse model of human colon cancer (n = 8 mice) by in vivo imaging. The long-term effect of niclosamide on /"metastasis"/ formation after discontinued treatment was quantified by scoring, and overall survival (n = 12 mice) was analyzed by Kaplan-Meier method after discontinuation of treatment. All statistical tests were two-sided. RESULTS: Reduced /"S100A4"/ mRNA and protein expression, and inhibited cell migration, invasion, proliferation, and colony formation were observed in niclosamide-treated colon cancer cells in vitro. In vivo imaging of niclosamide-treated mice showed reduced liver /"metastasis"/ compared with solvent-treated control mice (n = 4 mice per group). Compared with the control group, discontinuation of treatment for 26 days showed reduced liver /"metastasis"/ formation in mice (n = 6 mice per group) (control vs discontinuous treatment, mean /"metastasis"/ score = 100% vs 34.9%, mean difference = 65.1%; 95% confidence interval [CI] = 18.4% to 111.9%, P < .01) and increased overall survival (n = 6 mice per group; control vs discontinuous treatment, median survival = 24 vs 46.5 days, ratio = 0.52, 95% CI = 0.19 to 0.84, P = .001). CONCLUSION: Niclosamide inhibits /"S100A4"/-induced /"metastasis"/ formation in a mouse model of colon cancer and has therapeutic potential. | [
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21750109 | European genome-wide association study identifies SLC14A1 as a new urinary bladder cancer susceptibility gene. | Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 * 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. | European genome-wide association study identifies /"SLC14A1"/ as a new /"urinary bladder cancer"/ susceptibility gene. | Three genome-wide association studies in Europe and the USA have reported eight /"urinary bladder cancer"/ (/"UBC"/) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 * 10(-11). /"SLC14A1"/ codes for UTs that define the /"Kidd blood group"/ and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies /"UBC"/ risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of /"UBC"/. | [
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21844576 | Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. | Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism caused by dysfunction of the multienzyme branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Although a few cases of MSUD have been reported in the Korean population, the genetic background of MSUD is not well understood. In this study, we investigated three newborn males who were diagnosed with MSUD using a standard newborn screening test and amino acid analysis. We screened all coding regions of the BCKDHA, BCKDHB and DBT genes for abnormalities using direct sequencing. Changes in these genes are associated with MSUD. For one patient with complex deletion/duplication mutations, we also performed TOPO TA cloning sequencing. Amino acid analysis showed elevated levels of all branched chain amino acids (BCAAs) in all patients. Three patients were either homozygous or compound heterozygous for the BCKDHA mutations. Patient 1 was homozygous for c.1036C>T (p.R346C); patient 2 was heterozygous, with c.632C>T (p.T211M) and c.659C>T (p.A220V); and patient 3 had c.1204_1209dupAAACCC (p.L402_P403dup) and c.1280_1282delTGG (p.L427_A428delinsP). Among these mutations, c.1036C>T, c.632C>T, c.1204_1209dup and c.1280_1282del were novel. These patients had no mutations in either the BCKDHB or the DBT gene. Although this study included only three patients, the five different mutations in these patients may indicate mutational heterogeneity in Korean patients with MSUD. In addition, the BCHDHA gene may present a primary target for clinical genetic analysis. To the best of our knowledge, this is the first report of genetically confirmed MSUD in Korea. | Three Korean patients with /"maple syrup urine disease"/: four novel mutations in the /"BCKDHA"/ gene. | /"Maple syrup urine disease"/ (/"MSUD"/) is a rare, autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism caused by dysfunction of the multienzyme branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Although a few cases of /"MSUD"/ have been reported in the Korean population, the genetic background of /"MSUD"/ is not well understood. In this study, we investigated three newborn males who were diagnosed with /"MSUD"/ using a standard newborn screening test and amino acid analysis. We screened all coding regions of the /"BCKDHA"/, BCKDHB and DBT genes for abnormalities using direct sequencing. Changes in these genes are associated with /"MSUD"/. For one patient with complex deletion/duplication mutations, we also performed TOPO TA cloning sequencing. Amino acid analysis showed elevated levels of all branched chain amino acids (BCAAs) in all patients. Three patients were either homozygous or compound heterozygous for the /"BCKDHA"/ mutations. Patient 1 was homozygous for c.1036C>T (p.R346C); patient 2 was heterozygous, with c.632C>T (p.T211M) and c.659C>T (p.A220V); and patient 3 had c.1204_1209dupAAACCC (p.L402_P403dup) and c.1280_1282delTGG (p.L427_A428delinsP). Among these mutations, c.1036C>T, c.632C>T, c.1204_1209dup and c.1280_1282del were novel. These patients had no mutations in either the BCKDHB or the DBT gene. Although this study included only three patients, the five different mutations in these patients may indicate mutational heterogeneity in Korean patients with /"MSUD"/. In addition, the BCHDHA gene may present a primary target for clinical genetic analysis. To the best of our knowledge, this is the first report of genetically confirmed /"MSUD"/ in Korea. | [
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21844576 | Three Korean patients with maple syrup urine disease: four novel mutations in the BCKDHA gene. | Maple syrup urine disease (MSUD) is a rare, autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism caused by dysfunction of the multienzyme branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Although a few cases of MSUD have been reported in the Korean population, the genetic background of MSUD is not well understood. In this study, we investigated three newborn males who were diagnosed with MSUD using a standard newborn screening test and amino acid analysis. We screened all coding regions of the BCKDHA, BCKDHB and DBT genes for abnormalities using direct sequencing. Changes in these genes are associated with MSUD. For one patient with complex deletion/duplication mutations, we also performed TOPO TA cloning sequencing. Amino acid analysis showed elevated levels of all branched chain amino acids (BCAAs) in all patients. Three patients were either homozygous or compound heterozygous for the BCKDHA mutations. Patient 1 was homozygous for c.1036C>T (p.R346C); patient 2 was heterozygous, with c.632C>T (p.T211M) and c.659C>T (p.A220V); and patient 3 had c.1204_1209dupAAACCC (p.L402_P403dup) and c.1280_1282delTGG (p.L427_A428delinsP). Among these mutations, c.1036C>T, c.632C>T, c.1204_1209dup and c.1280_1282del were novel. These patients had no mutations in either the BCKDHB or the DBT gene. Although this study included only three patients, the five different mutations in these patients may indicate mutational heterogeneity in Korean patients with MSUD. In addition, the BCHDHA gene may present a primary target for clinical genetic analysis. To the best of our knowledge, this is the first report of genetically confirmed MSUD in Korea. | Three Korean patients with /"maple syrup urine disease"/: four novel mutations in the BCKDHA gene. | /"Maple syrup urine disease"/ (/"MSUD"/) is a rare, autosomal recessive disorder of branched-chain amino acid (BCAA) metabolism caused by dysfunction of the multienzyme branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex. Although a few cases of /"MSUD"/ have been reported in the Korean population, the genetic background of /"MSUD"/ is not well understood. In this study, we investigated three newborn males who were diagnosed with /"MSUD"/ using a standard newborn screening test and amino acid analysis. We screened all coding regions of the BCKDHA, /"BCKDHB"/ and DBT genes for abnormalities using direct sequencing. Changes in these genes are associated with /"MSUD"/. For one patient with complex deletion/duplication mutations, we also performed TOPO TA cloning sequencing. Amino acid analysis showed elevated levels of all branched chain amino acids (BCAAs) in all patients. Three patients were either homozygous or compound heterozygous for the BCKDHA mutations. Patient 1 was homozygous for c.1036C>T (p.R346C); patient 2 was heterozygous, with c.632C>T (p.T211M) and c.659C>T (p.A220V); and patient 3 had c.1204_1209dupAAACCC (p.L402_P403dup) and c.1280_1282delTGG (p.L427_A428delinsP). Among these mutations, c.1036C>T, c.632C>T, c.1204_1209dup and c.1280_1282del were novel. These patients had no mutations in either the /"BCKDHB"/ or the DBT gene. Although this study included only three patients, the five different mutations in these patients may indicate mutational heterogeneity in Korean patients with /"MSUD"/. In addition, the BCHDHA gene may present a primary target for clinical genetic analysis. To the best of our knowledge, this is the first report of genetically confirmed /"MSUD"/ in Korea. | [
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21966456 | Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin E receptor 3 (EP3) gene (PTGER3) polymorphisms. We also reported that EP3 is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that EP3 in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of EP3 protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the EP3 protein and evaluated the immunohistological staining of EP3 protein in the conjunctival epithelium of patients with ocular surface diseases. EP3 was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of EP3 in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of EP3 protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | Prostaglandin E receptor subtype /"EP3"/ expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on /"Stevens-Johnson Syndrome"/ (/"SJS"/) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin /"E receptor 3 (EP3)"/ gene (/"PTGER3"/) polymorphisms. We also reported that /"EP3"/ is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that /"EP3"/ in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of /"EP3"/ protein in the conjunctiva of patients with various ocular surface diseases such as /"SJS"//TEN, chemical eye burns, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to /"SJS"//TEN, chemical eye burns, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the /"EP3"/ protein and evaluated the immunohistological staining of /"EP3"/ protein in the conjunctival epithelium of patients with ocular surface diseases. /"EP3"/ was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of /"SJS"//TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of /"EP3"/ in conjunctival epithelium and the pathogenesis and pathology of /"SJS"//TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of /"EP3"/ protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | [
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21966456 | Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin E receptor 3 (EP3) gene (PTGER3) polymorphisms. We also reported that EP3 is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that EP3 in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of EP3 protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the EP3 protein and evaluated the immunohistological staining of EP3 protein in the conjunctival epithelium of patients with ocular surface diseases. EP3 was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of EP3 in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of EP3 protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | Prostaglandin E receptor subtype /"EP3"/ expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin /"E receptor 3 (EP3)"/ gene (/"PTGER3"/) polymorphisms. We also reported that /"EP3"/ is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that /"EP3"/ in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of /"EP3"/ protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren's ulcers, and /"ocular cicatricial pemphigoid"/ (/"OCP"/). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and /"OCP"/, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the /"EP3"/ protein and evaluated the immunohistological staining of /"EP3"/ protein in the conjunctival epithelium of patients with ocular surface diseases. /"EP3"/ was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and /"OCP"/ patients. CONCLUSIONS: We posit an association between the down-regulation of /"EP3"/ in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and /"OCP"/, and suggest a common mechanism(s) in the pathology of these diseases. The examination of /"EP3"/ protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | [
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21966456 | Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin E receptor 3 (EP3) gene (PTGER3) polymorphisms. We also reported that EP3 is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that EP3 in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of EP3 protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the EP3 protein and evaluated the immunohistological staining of EP3 protein in the conjunctival epithelium of patients with ocular surface diseases. EP3 was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of EP3 in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of EP3 protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | Prostaglandin E receptor subtype /"EP3"/ expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin /"E receptor 3 (EP3)"/ gene (/"PTGER3"/) polymorphisms. We also reported that /"EP3"/ is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that /"EP3"/ in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of /"EP3"/ protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, /"Mooren's ulcers"/, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with /"Mooren's ulcers"/ treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the /"EP3"/ protein and evaluated the immunohistological staining of /"EP3"/ protein in the conjunctival epithelium of patients with ocular surface diseases. /"EP3"/ was expressed in the conjunctival epithelium of patients with chemical eye burns and /"Mooren's ulcer"/ and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of /"EP3"/ in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of /"EP3"/ protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | [
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21966456 | Prostaglandin E receptor subtype EP3 expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin E receptor 3 (EP3) gene (PTGER3) polymorphisms. We also reported that EP3 is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that EP3 in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of EP3 protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, chemical eye burns, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, chemical eye burns, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the EP3 protein and evaluated the immunohistological staining of EP3 protein in the conjunctival epithelium of patients with ocular surface diseases. EP3 was expressed in the conjunctival epithelium of patients with chemical eye burns and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of EP3 in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of EP3 protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | Prostaglandin E receptor subtype /"EP3"/ expression in human conjunctival epithelium and its changes in various ocular surface disorders. | BACKGROUND: In our earlier genome-wide association study on Stevens-Johnson Syndrome (SJS) and its severe variant, toxic epidermal necrolysis (TEN), we found that in Japanese patients with these severe ocular surface complications there was an association with prostaglandin /"E receptor 3 (EP3)"/ gene (/"PTGER3"/) polymorphisms. We also reported that /"EP3"/ is dominantly expressed in the ocular surface-, especially the conjunctival epithelium, and suggested that /"EP3"/ in the conjunctival epithelium may down-regulate ocular surface inflammation. In the current study we investigated the expression of /"EP3"/ protein in the conjunctiva of patients with various ocular surface diseases such as SJS/TEN, /"chemical eye burns"/, Mooren's ulcers, and ocular cicatricial pemphigoid (OCP). METHODOLOGY/PRINCIPAL FINDINGS: Conjunctival tissues were obtained from patients undergoing surgical reconstruction of the ocular surface due to SJS/TEN, /"chemical eye burns"/, and OCP, and from patients with Mooren's ulcers treated by resection of the inflammatory conjunctiva. The controls were nearly normal human conjunctival tissues acquired at surgery for conjunctivochalasis. We performed immunohistological analysis of the /"EP3"/ protein and evaluated the immunohistological staining of /"EP3"/ protein in the conjunctival epithelium of patients with ocular surface diseases. /"EP3"/ was expressed in the conjunctival epithelium of patients with /"chemical eye burns"/ and Mooren's ulcer and in normal human conjunctival epithelium. However, it was markedly down-regulated in the conjunctival epithelium of SJS/TEN and OCP patients. CONCLUSIONS: We posit an association between the down-regulation of /"EP3"/ in conjunctival epithelium and the pathogenesis and pathology of SJS/TEN and OCP, and suggest a common mechanism(s) in the pathology of these diseases. The examination of /"EP3"/ protein expression in conjunctival epithelium may aid in the differential diagnosis of various ocular surface diseases. | [
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21966470 | Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. | Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology. | Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from /"Rett syndrome"/ patients as in vitro disease model. | /"Rett syndrome"/ (/"RTT"/) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (/"MECP2"/) gene. Excellent /"RTT"/ mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many /"MeCP2"/ target genes, better understanding of the neurobiological consequences of the loss- or mis-function of /"MeCP2"/, and drug testing in /"RTT"/ mice and clinical trials in human /"RTT"/ patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female /"RTT"/ patients with common and rare /"RTT"/ mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of /"RTT"/ patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic /"RTT"/ pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the /"RTT"/ research community for studying disease pathology, screening for novel drugs, and testing toxicology. | [
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21966470 | Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. | Rett syndrome (RTT) is an autism spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (MECP2) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many MeCP2 target genes, better understanding of the neurobiological consequences of the loss- or mis-function of MeCP2, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology. | Isogenic pairs of wild type and mutant induced pluripotent stem cell (iPSC) lines from Rett syndrome patients as in vitro disease model. | Rett syndrome (RTT) is an /"autism"/ spectrum developmental disorder caused by mutations in the X-linked methyl-CpG binding protein 2 (/"MECP2"/) gene. Excellent RTT mouse models have been created to study the disease mechanisms, leading to many important findings with potential therapeutic implications. These include the identification of many /"MeCP2"/ target genes, better understanding of the neurobiological consequences of the loss- or mis-function of /"MeCP2"/, and drug testing in RTT mice and clinical trials in human RTT patients. However, because of potential differences in the underlying biology between humans and common research animals, there is a need to establish cell culture-based human models for studying disease mechanisms to validate and expand the knowledge acquired in animal models. Taking advantage of the nonrandom pattern of X chromosome inactivation in female induced pluripotent stem cells (iPSC), we have generated isogenic pairs of wild type and mutant iPSC lines from several female RTT patients with common and rare RTT mutations. R294X (arginine 294 to stop codon) is a common mutation carried by 5-6% of RTT patients. iPSCs carrying the R294X mutation has not been studied. We differentiated three R294X iPSC lines and their isogenic wild type control iPSC into neurons with high efficiency and consistency, and observed characteristic RTT pathology in R294X neurons. These isogenic iPSC lines provide unique resources to the RTT research community for studying disease pathology, screening for novel drugs, and testing toxicology. | [
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21983886 | Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia. | Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL. | Association between polymorphisms of EPHX1 and /"XRCC1"/ genes and the risk of childhood /"acute lymphoblastic leukemia"/. | Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood /"acute lymphoblastic leukemia"/ (/"ALL"/) in Turkish population, comprised of 190 healthy controls and 167 /"ALL"/ patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in /"ALL"/ patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of /"childhood ALL"/ (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of /"ALL"/. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of /"ALL"/ 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein /"XRCC1"/ Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of /"childhood ALL"/. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of /"XRCC1"/ in the same individuals significantly increased the risk of /"childhood ALL"/ up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of /"childhood ALL 8"/.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, /"XRCC1"/, this situation ultimately leads to significantly increased susceptibility for /"childhood ALL"/. | [
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21983886 | Association between polymorphisms of EPHX1 and XRCC1 genes and the risk of childhood acute lymphoblastic leukemia. | Microsomal epoxide hydrolase, EPHX1, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between EPHX1 Tyr113His and His139Arg variants, and the risk of incidence of childhood acute lymphoblastic leukemia (ALL) in Turkish population, comprised of 190 healthy controls and 167 ALL patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in ALL patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of childhood ALL (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of ALL. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of ALL 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for EPHX1 Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of childhood ALL. Accordingly, the co-presence of Tyr113His variant of EPHX1 and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of childhood ALL up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of childhood ALL 8.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with EPHX1 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for childhood ALL. | Association between polymorphisms of /"EPHX1"/ and XRCC1 genes and the risk of childhood /"acute lymphoblastic leukemia"/. | /"Microsomal epoxide hydrolase"/, /"EPHX1"/, plays a central role in the detoxification of potentially genotoxic epoxide intermediates. In this study, we firstly aimed to investigate the relationship between /"EPHX1"/ Tyr113His and His139Arg variants, and the risk of incidence of childhood /"acute lymphoblastic leukemia"/ (/"ALL"/) in Turkish population, comprised of 190 healthy controls and 167 /"ALL"/ patients. In exon 3 Tyr113His polymorphism, 113His/His homozygous mutant genotype with slow activity was 18.6% in /"ALL"/ patients and 9% in controls, indicating 113His/His slow activity genotype was significantly associated with an increased risk of /"childhood ALL"/ (OR: 2.3, 95% CI, 1.2-4.4, P = 0.01). No significant association was found between exon 4 His139Arg variant and the risk of /"ALL"/. When both exon 3 Tyr113His and exon 4 His139Arg polymorphisms were considered together, only the exon 3 113His/His, homozygous mutant, slow activity genotype with exon 4 wild-type genotype 139His/His was significantly increased the risk of /"ALL"/ 2.4-fold (OR: 2.4, P = 0.02). We also evaluated whether haplotype analysis for /"EPHX1"/ Tyr113His polymorphism together with DNA protein XRCC1 Arg399Gln variant known for its deficient DNA repair capacity would represent more prominent risk factors for the development of /"childhood ALL"/. Accordingly, the co-presence of Tyr113His variant of /"EPHX1"/ and Arg399Gln variant of XRCC1 in the same individuals significantly increased the risk of /"childhood ALL"/ up to 2.1-fold (OR = 2.1, P = 0.03). Moreover, homozygous mutant genotype for both genes significantly and considerably increased the risk of /"childhood ALL 8"/.5-fold (OR: 8.5, P = 0.03). In conclusion, individuals with /"EPHX1"/ 113His/His slow activity genotype may not detoxify reactive carcinogenic epoxides efficiently, binding of reactive epoxides to DNA cause DNA damage. With the inadequate polymorphic DNA repair protein, XRCC1, this situation ultimately leads to significantly increased susceptibility for /"childhood ALL"/. | [
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21992601 | Implication of CD38 gene in podocyte epithelial-to-mesenchymal transition and glomerular sclerosis. | CD38 is a multifunctional protein involving in a number of signalling pathways. Given that the lack of CD38 is considered as a dedifferentiation marker of lymphocytes and other cells, we hypothesized that CD38 and its signalling pathway may participate in the epithelial-to-mesenchymal transition (EMT) process of podocytes and thereby regulates the integrity of glomerular structure and function. Western blot analysis and RT-PCR demonstrated that renal tissue CD38 expression was lacking in CD38(-/-) mice or substantially reduced in renal CD38 shRNA-transfected WT (CD38-shRNA) mice compared to CD38(+/+) littermates. Confocal fluorescent microscopy demonstrated the reduced expression of epithelial markers (P-Cadherin, ZO-1 and podocin) and increased expression of mesenchymal markers (FSP-1, a-SMA and desmin) in the glomeruli of CD38(-/-) and CD38-shRNA mice compared to CD38(+/+) mice. Morphological examinations showed profound injury in the glomeruli of CD38(-/-) or CD38-shRNA mice compared to CD38(+/+) mice. This enhanced glomerular injury in CD38(-/-) or CD38-shRNA mice was accompanied by increased albuminuria and proteinuria. DOCA/high salt treatment further decreased the expression of epithelial markers and increased the abundance of mesenchymal markers, which were accompanied by more increased glomerular damage index and mean arterial pressure in CD38(-/-) and CD38-shRNA mice than CD38(+/+) mice. In vitro studies showed that inhibition of CD38 enhances the EMT in podocytes. In conclusion, our observations reveal that the normal expression of CD38 importantly contributes to the differentiation and function of podocytes and the defect of this gene expression may be a critical mechanism inducing EMT and consequently resulting in glomerular injury and sclerosis. | Implication of /"CD38"/ gene in podocyte epithelial-to-mesenchymal transition and glomerular sclerosis. | /"CD38"/ is a multifunctional protein involving in a number of signalling pathways. Given that the lack of /"CD38"/ is considered as a dedifferentiation marker of lymphocytes and other cells, we hypothesized that /"CD38"/ and its signalling pathway may participate in the epithelial-to-mesenchymal transition (EMT) process of podocytes and thereby regulates the integrity of glomerular structure and function. Western blot analysis and RT-PCR demonstrated that renal tissue /"CD38"/ expression was lacking in /"CD38"/(-/-) mice or substantially reduced in renal /"CD38"/ shRNA-transfected WT (/"CD38"/-shRNA) mice compared to /"CD38"/(+/+) littermates. Confocal fluorescent microscopy demonstrated the reduced expression of epithelial markers (P-Cadherin, ZO-1 and podocin) and increased expression of mesenchymal markers (FSP-1, a-SMA and desmin) in the glomeruli of /"CD38"/(-/-) and /"CD38"/-shRNA mice compared to /"CD38"/(+/+) mice. Morphological examinations showed profound injury in the glomeruli of /"CD38"/(-/-) or /"CD38"/-shRNA mice compared to /"CD38"/(+/+) mice. This enhanced glomerular injury in /"CD38"/(-/-) or /"CD38"/-shRNA mice was accompanied by increased /"albuminuria"/ and proteinuria. DOCA/high salt treatment further decreased the expression of epithelial markers and increased the abundance of mesenchymal markers, which were accompanied by more increased glomerular damage index and mean arterial pressure in /"CD38"/(-/-) and /"CD38"/-shRNA mice than /"CD38"/(+/+) mice. In vitro studies showed that inhibition of /"CD38"/ enhances the EMT in podocytes. In conclusion, our observations reveal that the normal expression of /"CD38"/ importantly contributes to the differentiation and function of podocytes and the defect of this gene expression may be a critical mechanism inducing EMT and consequently resulting in glomerular injury and sclerosis. | [
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21992601 | Implication of CD38 gene in podocyte epithelial-to-mesenchymal transition and glomerular sclerosis. | CD38 is a multifunctional protein involving in a number of signalling pathways. Given that the lack of CD38 is considered as a dedifferentiation marker of lymphocytes and other cells, we hypothesized that CD38 and its signalling pathway may participate in the epithelial-to-mesenchymal transition (EMT) process of podocytes and thereby regulates the integrity of glomerular structure and function. Western blot analysis and RT-PCR demonstrated that renal tissue CD38 expression was lacking in CD38(-/-) mice or substantially reduced in renal CD38 shRNA-transfected WT (CD38-shRNA) mice compared to CD38(+/+) littermates. Confocal fluorescent microscopy demonstrated the reduced expression of epithelial markers (P-Cadherin, ZO-1 and podocin) and increased expression of mesenchymal markers (FSP-1, a-SMA and desmin) in the glomeruli of CD38(-/-) and CD38-shRNA mice compared to CD38(+/+) mice. Morphological examinations showed profound injury in the glomeruli of CD38(-/-) or CD38-shRNA mice compared to CD38(+/+) mice. This enhanced glomerular injury in CD38(-/-) or CD38-shRNA mice was accompanied by increased albuminuria and proteinuria. DOCA/high salt treatment further decreased the expression of epithelial markers and increased the abundance of mesenchymal markers, which were accompanied by more increased glomerular damage index and mean arterial pressure in CD38(-/-) and CD38-shRNA mice than CD38(+/+) mice. In vitro studies showed that inhibition of CD38 enhances the EMT in podocytes. In conclusion, our observations reveal that the normal expression of CD38 importantly contributes to the differentiation and function of podocytes and the defect of this gene expression may be a critical mechanism inducing EMT and consequently resulting in glomerular injury and sclerosis. | Implication of /"CD38"/ gene in podocyte epithelial-to-mesenchymal transition and /"glomerular sclerosis"/. | /"CD38"/ is a multifunctional protein involving in a number of signalling pathways. Given that the lack of /"CD38"/ is considered as a dedifferentiation marker of lymphocytes and other cells, we hypothesized that /"CD38"/ and its signalling pathway may participate in the epithelial-to-mesenchymal transition (EMT) process of podocytes and thereby regulates the integrity of glomerular structure and function. Western blot analysis and RT-PCR demonstrated that renal tissue /"CD38"/ expression was lacking in /"CD38"/(-/-) mice or substantially reduced in renal /"CD38"/ shRNA-transfected WT (/"CD38"/-shRNA) mice compared to /"CD38"/(+/+) littermates. Confocal fluorescent microscopy demonstrated the reduced expression of epithelial markers (P-Cadherin, ZO-1 and podocin) and increased expression of mesenchymal markers (FSP-1, a-SMA and desmin) in the glomeruli of /"CD38"/(-/-) and /"CD38"/-shRNA mice compared to /"CD38"/(+/+) mice. Morphological examinations showed profound injury in the glomeruli of /"CD38"/(-/-) or /"CD38"/-shRNA mice compared to /"CD38"/(+/+) mice. This enhanced /"glomerular injury"/ in /"CD38"/(-/-) or /"CD38"/-shRNA mice was accompanied by increased albuminuria and proteinuria. DOCA/high salt treatment further decreased the expression of epithelial markers and increased the abundance of mesenchymal markers, which were accompanied by more increased glomerular damage index and mean arterial pressure in /"CD38"/(-/-) and /"CD38"/-shRNA mice than /"CD38"/(+/+) mice. In vitro studies showed that inhibition of /"CD38"/ enhances the EMT in podocytes. In conclusion, our observations reveal that the normal expression of /"CD38"/ importantly contributes to the differentiation and function of podocytes and the defect of this gene expression may be a critical mechanism inducing EMT and consequently resulting in /"glomerular injury"/ and sclerosis. | [
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22119709 | Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. | Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10(-/-) mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10(-/-) mice. After JWH-133 treatment, the percentage of CD4(+) T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-y expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. | Cannabinoid receptor-2 (CB2) agonist ameliorates /"colitis"/ in /"IL-10"/(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. | Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after /"chronic colitis"/ progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after /"chronic colitis"/ in /"IL-10"/(-/-) mice. JWH-133 effectively attenuated the overall clinical score, and reversed /"colitis"/-associated pathogenesis and decrease in body weight in /"IL-10"/(-/-) mice. After JWH-133 treatment, the percentage of CD4(+) T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with /"chronic colitis"/. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced /"colitis"/. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-y expressing cells that were induced during /"colitis"/ progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the /"colitis"/ protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates /"chronic colitis"/ by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. | [
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22119709 | Cannabinoid receptor-2 (CB2) agonist ameliorates colitis in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. | Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after chronic colitis progression has not been investigated. Here, we investigate the effect of cannabinoid receptor-2 (CB2) agonist, JWH-133, after chronic colitis in IL-10(-/-) mice. JWH-133 effectively attenuated the overall clinical score, and reversed colitis-associated pathogenesis and decrease in body weight in IL-10(-/-) mice. After JWH-133 treatment, the percentage of CD4(+) T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with chronic colitis. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced colitis. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-y expressing cells that were induced during colitis progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a CB2 receptor antagonist, reversed the colitis protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through CB2 receptors, and ameliorates chronic colitis by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the CB2 receptor agonists may serve as a therapeutic modality against IBD. | /"Cannabinoid receptor-2"/ (/"CB2"/) agonist ameliorates /"colitis"/ in IL-10(-/-) mice by attenuating the activation of T cells and promoting their apoptosis. | Inflammatory bowel disease (IBD) is a chronic intestinal inflammation caused by hyperactivated effector immune cells that produce pro-inflammatory cytokines. Recent studies have shown that the cannabinoid system may play a critical role in mediating protection against intestinal inflammation. However, the effect of cannabinoid receptor induction after /"chronic colitis"/ progression has not been investigated. Here, we investigate the effect of /"cannabinoid receptor-2"/ (/"CB2"/) agonist, JWH-133, after /"chronic colitis"/ in IL-10(-/-) mice. JWH-133 effectively attenuated the overall clinical score, and reversed /"colitis"/-associated pathogenesis and decrease in body weight in IL-10(-/-) mice. After JWH-133 treatment, the percentage of CD4(+) T cells, neutrophils, mast cells, natural killer (NK1.1) cells, and activated T cells declined in the intestinal lamina propria (LP) and mesenteric lymph nodes (MLN) of mice with /"chronic colitis"/. JWH-133 was also effective in ameliorating dextran sodium sulfate (DSS)-induced /"colitis"/. In this model, JWH-133 reduced the number and percentage of macrophages and IFN-y expressing cells that were induced during /"colitis"/ progression. Treatment with aminoalkylindole 6-iodo-pravadoline (AM630), a /"CB2"/ receptor antagonist, reversed the /"colitis"/ protection provided by JWH-133 treatment. Also, activated T cells were found to undergo apoptosis following JWH-133 treatment both in-vivo and in-vitro. These findings suggest that JWH-133 mediates its effect through /"CB2"/ receptors, and ameliorates /"chronic colitis"/ by inducing apoptosis in activated T cells, reducing the numbers of activated T cells, and suppressing induction of mast cells, NK cells, and neutrophils at sites of inflammation in the LP. These results support the idea that the /"CB2"/ receptor agonists may serve as a therapeutic modality against IBD. | [
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22122352 | Progesterone modulates the expression of interleukin-6 in cultured term human uterine cervical fibroblasts. | PROBLEM: The preventative value of progesterone in preterm labor has been recently recognized, especially when it is administered via vaginal suppository. This study was undertaken to evaluate the effect of progesterone on interleukin-6 (IL-6) production in human uterine cervical fibroblasts (UCFs) treated with lipopolysaccharides (LPS). METHOD OF STUDY: Human uterine cervical tissue was obtained at term, prior to the onset of labor, during the scheduled cesarean section or cesarean hysterectomy. Primary UCF cultures were established and confirmed by immunohistochemistry. IL-6 mRNA and protein expressions were examined by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Lipopolysaccharides stimulation induced a clear time- and dose-dependent increase in IL-6 mRNA and protein levels in UCFs (P < 0.05). Progesterone treatment significantly attenuated LPS-induced increases in IL-6 mRNA and protein expressions in UCFs (P < 0.05). Estrogen exposure had no effect on LPS-induced IL-6 up-regulation and did not modulate the effects of progesterone. CONCLUSION: Our preliminary results suggest that vaginal progesterone might prevent spontaneous preterm labor through a mechanism involving anti-inflammatory effects on UCFs, particularly suppression of IL-6 production. | Progesterone modulates the expression of /"interleukin-6"/ in cultured term human uterine cervical fibroblasts. | PROBLEM: The preventative value of progesterone in /"preterm labor"/ has been recently recognized, especially when it is administered via vaginal suppository. This study was undertaken to evaluate the effect of progesterone on /"interleukin-6"/ (/"IL-6"/) production in human uterine cervical fibroblasts (UCFs) treated with lipopolysaccharides (LPS). METHOD OF STUDY: Human uterine cervical tissue was obtained at term, prior to the onset of labor, during the scheduled cesarean section or cesarean hysterectomy. Primary UCF cultures were established and confirmed by immunohistochemistry. /"IL-6"/ mRNA and protein expressions were examined by reverse-transcription polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. RESULTS: Lipopolysaccharides stimulation induced a clear time- and dose-dependent increase in /"IL-6"/ mRNA and protein levels in UCFs (P < 0.05). Progesterone treatment significantly attenuated LPS-induced increases in /"IL-6"/ mRNA and protein expressions in UCFs (P < 0.05). Estrogen exposure had no effect on LPS-induced /"IL-6"/ up-regulation and did not modulate the effects of progesterone. CONCLUSION: Our preliminary results suggest that vaginal progesterone might prevent spontaneous /"preterm labor"/ through a mechanism involving anti-inflammatory effects on UCFs, particularly suppression of /"IL-6"/ production. | [
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22213154 | Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. | Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. | Update of /"PAX2"/ mutations in renal coloboma syndrome and establishment of a locus-specific database. | Renal coloboma syndrome, also known as /"papillorenal syndrome"/ is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, /"PAX2"/, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the /"PAX2"/ gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl//"PAX2"/. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. | [
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22213154 | Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database. | Renal coloboma syndrome, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and renal malformations. Mutations in the paired-box gene, PAX2, have been identified in approximately half of individuals with classic findings of renal hypoplasia/dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the PAX2 gene and phenotypic variation in individuals with renal coloboma syndrome. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl/PAX2. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. | Update of /"PAX2"/ mutations in /"renal coloboma syndrome"/ and establishment of a locus-specific database. | /"Renal coloboma syndrome"/, also known as papillorenal syndrome is an autosomal-dominant disorder characterized by ocular and /"renal malformations"/. Mutations in the paired-box gene, /"PAX2"/, have been identified in approximately half of individuals with classic findings of /"renal hypoplasia"//dysplasia and abnormalities of the optic nerve. Prior to 2011, there was no actively maintained locus-specific database (LSDB) cataloguing the extent of genetic variation in the /"PAX2"/ gene and phenotypic variation in individuals with /"renal coloboma syndrome"/. Review of published cases and the collective diagnostic experience of three laboratories in the United States, France, and New Zealand identified 55 unique mutations in 173 individuals from 86 families. The three clinical laboratories participating in this collaboration contributed 28 novel variations in 68 individuals in 33 families, which represent a 50% increase in the number of variations, patients, and families published in the medical literature. An LSDB was created using the Leiden Open Variation Database platform: www.lovd.nl//"PAX2"/. The most common findings reported in this series were abnormal renal structure or function (92% of individuals), ophthalmological abnormalities (77% of individuals), and hearing loss (7% of individuals). Additional clinical findings and genetic counseling implications are discussed. | [
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22264700 | Tyrosine hydroxylase deficiency in Taiwanese infants. | We analyzed the clinical manifestations, genetic mutations, treatment responses to L-dopa, and long-term neurologic outcomes in Taiwanese infants with tyrosine hydroxylase deficiency. From 1999 to May 2011, we enrolled six infants who had been diagnosed with tyrosine hydroxylase deficiency by identifying point mutations on the tyrosine hydroxylase gene. Two patients manifested fetal distress during the perinatal period. Four patients exhibited generalized tremor as their first observed neurologic sign at age 3 months. All presented brisk reflexes, hypokinesia, rigidity, distal chorea, and athetosis. We identified a novel missense mutation, I382T, and report on the first patient, to the best of our knowledge, with a homozygous R153X nonsense mutation. Five of six patients responded to L-dopa at a dose of 4.2-34.7 mg/kg/day combined with biperiden or selegiline or both. Long-term neurologic outcomes (median follow-up, 5 years and 10.5 months) revealed two patients demonstrated slightly low intelligence quotients, three demonstrated mild to moderate psychomotor retardation, and one died of respiratory failure. A higher dose of L-dopa, together with alternative therapies, may lead to improvements in motor function. However, several years of observation may be needed to reach definitive conclusions about neurologic outcomes. | /"Tyrosine hydroxylase deficiency"/ in Taiwanese infants. | We analyzed the clinical manifestations, genetic mutations, treatment responses to L-dopa, and long-term neurologic outcomes in /"Taiwanese infants with tyrosine hydroxylase deficiency"/. From 1999 to May 2011, we enrolled six infants who had been diagnosed with /"tyrosine hydroxylase deficiency"/ by identifying point mutations on the /"tyrosine hydroxylase"/ gene. Two patients manifested fetal distress during the perinatal period. Four patients exhibited generalized tremor as their first observed neurologic sign at age 3 months. All presented brisk reflexes, hypokinesia, rigidity, distal chorea, and athetosis. We identified a novel missense mutation, I382T, and report on the first patient, to the best of our knowledge, with a homozygous R153X nonsense mutation. Five of six patients responded to L-dopa at a dose of 4.2-34.7 mg/kg/day combined with biperiden or selegiline or both. Long-term neurologic outcomes (median follow-up, 5 years and 10.5 months) revealed two patients demonstrated slightly low intelligence quotients, three demonstrated mild to moderate psychomotor retardation, and one died of respiratory failure. A higher dose of L-dopa, together with alternative therapies, may lead to improvements in motor function. However, several years of observation may be needed to reach definitive conclusions about neurologic outcomes. | [
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"entity_id": "C537537",
"entity_type": "Disease",
"text_name": "Taiwanese infants with tyrosine hydroxylase deficiency"
} | Yes |