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22302274 | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the /"hereditary sensory neuropathies"/) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, /"NTRK1"/ (/"TRKA"/) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, /"NTRK1"/ and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | [
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22302274 | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the /"hereditary sensory neuropathies"/) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of /"SPTLC1"/, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (/"SPTLC1"/, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in /"SPTLC1"/ is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | [
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22302274 | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | Frequency of mutations in the genes associated with /"hereditary sensory and autonomic neuropathy"/ in a UK cohort. | The /"hereditary sensory and autonomic neuropathies"/ (/"HSAN"/, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing /"HSAN"/. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of /"HSAN"/ for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, /"NTRK1"/ (/"TRKA"/) and NGFB. We identified 25 index patients with mutations in six genes associated with /"HSAN"/ (SPTLC1, RAB7, WNK1/HSN2, FAM134B, /"NTRK1"/ and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for /"HSAN"/ are rare suggesting that further /"HSAN"/ genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of /"HSAN"/ in the UK population and should be screened first in all patients with sporadic or autosomal dominant /"HSAN"/. | [
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22302274 | Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. | The hereditary sensory and autonomic neuropathies (HSAN, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing HSAN. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of HSAN for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with HSAN (SPTLC1, RAB7, WNK1/HSN2, FAM134B, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for HSAN are rare suggesting that further HSAN genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of HSAN in the UK population and should be screened first in all patients with sporadic or autosomal dominant HSAN. | Frequency of mutations in the genes associated with /"hereditary sensory and autonomic neuropathy"/ in a UK cohort. | The /"hereditary sensory and autonomic neuropathies"/ (/"HSAN"/, also known as the hereditary sensory neuropathies) are a clinically and genetically heterogeneous group of disorders, characterised by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. To date, mutations in twelve genes have been identified as causing /"HSAN"/. To study the frequency of mutations in these genes and the associated phenotypes, we screened 140 index patients in our inherited neuropathy cohort with a clinical diagnosis of /"HSAN"/ for mutations in the coding regions of SPTLC1, RAB7, WNK1/HSN2, /"FAM134B"/, NTRK1 (TRKA) and NGFB. We identified 25 index patients with mutations in six genes associated with /"HSAN"/ (SPTLC1, RAB7, WNK1/HSN2, /"FAM134B"/, NTRK1 and NGFB); 20 of which appear to be pathogenic giving an overall mutation frequency of 14.3%. Mutations in the known genes for /"HSAN"/ are rare suggesting that further /"HSAN"/ genes are yet to be identified. The p.Cys133Trp mutation in SPTLC1 is the most common cause of /"HSAN"/ in the UK population and should be screened first in all patients with sporadic or autosomal dominant /"HSAN"/. | [
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22322133 | Identification of a novel F11 missense mutation (Ile463Ser) in a family with congenital factor XI deficiency. | We investigated an asymptomatic 19-year-old patient with factor XI deficiency diagnosed in the context of presurgical laboratory screening. The F11 gene was analyzed and a novel missense mutation I463S in exon 12 was identified in heterozygosity in the proband. His mother, also diagnosed with asymptomatic factor XI deficiency, was found to be heterozygous for the same mutation. This novel amino acid substitution in the serine protease catalytic domain appears to be responsible for the low factor XI levels in both individuals. | Identification of a novel /"F11"/ missense mutation (Ile463Ser) in a family with /"congenital factor XI deficiency"/. | We investigated an asymptomatic 19-year-old patient with /"factor XI deficiency"/ diagnosed in the context of presurgical laboratory screening. The /"F11"/ gene was analyzed and a novel missense mutation I463S in exon 12 was identified in heterozygosity in the proband. His mother, also diagnosed with asymptomatic /"factor XI deficiency"/, was found to be heterozygous for the same mutation. This novel amino acid substitution in the serine protease catalytic domain appears to be responsible for the low factor XI levels in both individuals. | [
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} | Yes |
22388936 | Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. | Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease. | Mutation of the parkinsonism gene /"ATP13A2"/ causes neuronal ceroid-lipofuscinosis. | Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in /"ATP13A2"/ that fully segregates with disease within the family. Mutations in /"ATP13A2"/ are a known cause of /"Kufor-Rakeb syndrome"/ (/"KRS"/), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and /"KRS"/ may share etiological features and implicate the lysosomal pathway in Parkinson's disease. | [
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} | Yes |
22388936 | Mutation of the parkinsonism gene ATP13A2 causes neuronal ceroid-lipofuscinosis. | Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and premature death. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in ATP13A2 that fully segregates with disease within the family. Mutations in ATP13A2 are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease. | Mutation of the parkinsonism gene /"ATP13A2"/ causes neuronal ceroid-lipofuscinosis. | Neuronal ceroid lipofuscinoses (NCLs) comprise a heterogeneous group of metabolic storage diseases that present with the accumulation of autofluorescent lipopigment, neurodegeneration and /"premature death"/. Nine genes have been thus far identified as the cause of different types of NCL, with ages at onset ranging from around birth to adult, although the underlying etiology of the disease still remains elusive. We present a family with typical NCL pathology in which we performed exome sequencing and identified a single homozygous mutation in /"ATP13A2"/ that fully segregates with disease within the family. Mutations in /"ATP13A2"/ are a known cause of Kufor-Rakeb syndrome (KRS), a rare parkinsonian phenotype with juvenile onset. These data show that NCL and KRS may share etiological features and implicate the lysosomal pathway in Parkinson's disease. | [
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} | {
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"entity_id": "D003643",
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"text_name": "premature death"
} | No |
22570617 | Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. | Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR=0.69 [95%CI 0.63-0.75], p=1.86 10 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR=1.32 [95%CI 1.21-1.43], p=3.87 10 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR=0.58 [95% CI 0.50-0.67], p=1.17 10 ) and a probable regulatory region on 8q22 (rs284489 [G], OR=0.62 [95% CI 0.53-0.72], p=8.88 10 ). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR=0.59 [95% CI 0.41-0.87], p=0.004 and rs284489 [G], OR=0.76 [95% CI 0.54-1.06], p=0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p=0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. | Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in /"glaucoma"/. | Optic nerve degeneration caused by /"glaucoma"/ is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of /"glaucoma"/ are more likely to harbor risk alleles for /"glaucoma"/-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure /"glaucoma"/ (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of /"glaucoma"/, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the /"CDKN2BAS"/ region on 9p21 (rs2157719 [G], OR=0.69 [95%CI 0.63-0.75], p=1.86 10 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR=1.32 [95%CI 1.21-1.43], p=3.87 10 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the /"CDKN2BAS"/ gene (rs2157719 [G], OR=0.58 [95% CI 0.50-0.67], p=1.17 10 ) and a probable regulatory region on 8q22 (rs284489 [G], OR=0.62 [95% CI 0.53-0.72], p=8.88 10 ). Both NPG loci were also nominally associated with a second type of /"glaucoma"/, exfoliation syndrome glaucoma (rs2157719 [G], OR=0.59 [95% CI 0.41-0.87], p=0.004 and rs284489 [G], OR=0.76 [95% CI 0.54-1.06], p=0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in /"glaucoma"/. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p=0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of /"glaucoma"/. | [
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22570617 | Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. | Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR=0.69 [95%CI 0.63-0.75], p=1.86 10 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR=1.32 [95%CI 1.21-1.43], p=3.87 10 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR=0.58 [95% CI 0.50-0.67], p=1.17 10 ) and a probable regulatory region on 8q22 (rs284489 [G], OR=0.62 [95% CI 0.53-0.72], p=8.88 10 ). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR=0.59 [95% CI 0.41-0.87], p=0.004 and rs284489 [G], OR=0.76 [95% CI 0.54-1.06], p=0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p=0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma. | Common variants at 9p21 and 8q22 are associated with increased susceptibility to /"optic nerve degeneration"/ in glaucoma. | /"Optic nerve degeneration"/ caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR=0.69 [95%CI 0.63-0.75], p=1.86 10 ), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR=1.32 [95%CI 1.21-1.43], p=3.87 10 ). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR=0.58 [95% CI 0.50-0.67], p=1.17 10 ) and a probable regulatory region on 8q22 (rs284489 [G], OR=0.62 [95% CI 0.53-0.72], p=8.88 10 ). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR=0.59 [95% CI 0.41-0.87], p=0.004 and rs284489 [G], OR=0.76 [95% CI 0.54-1.06], p=0.021), suggesting that these loci might contribute more generally to /"optic nerve degeneration"/ in glaucoma. Because both loci influence /"transforming growth factor beta"/ (/"TGF-beta"/) signaling, we performed a genomic pathway analysis that showed an association between the /"TGF-beta"/ pathway and NPG (permuted p=0.009). These results suggest that neuro-protective therapies targeting /"TGF-beta"/ signaling could be effective for multiple forms of glaucoma. | [
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22743652 | Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. | Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK+ and 215 ALK- lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK+ and 49 ALK-) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment. | Histologic and cytomorphologic features of /"ALK-rearranged lung adenocarcinomas"/. | Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (/"ALK"/) define a /"category of lung adenocarcinomas"/ that may be amenable to targeted therapy with the /"ALK"/ inhibitor crizotinib. Defining distinctive features of /"ALK"/-rearranged (/"ALK"/+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of /"ALK"/+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 /"ALK"/+ and 215 /"ALK- lung adenocarcinomas"/ from primary and metastatic sites. All cases were evaluated for /"ALK"/ rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary /"ALK"/+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of /"ALK"/+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting /"ALK"/ rearrangements in lung adenocarcinomas. The scoring system predicted /"ALK"/ rearrangements in a new cohort of 78 lung adenocarcinomas (29 /"ALK"/+ and 49 /"ALK"/-) with a sensitivity of 88% and a specificity of 45%. In conclusion, /"ALK"/+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with /"ALK"/ rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of /"ALK"/+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment. | [
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22743652 | Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. | Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (ALK) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the ALK inhibitor crizotinib. Defining distinctive features of ALK-rearranged (ALK+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of ALK+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary lung tumors. It is unclear whether the findings from prior studies are applicable to metastatic lung tumors or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 ALK+ and 215 ALK- lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for ALK rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary ALK+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic lung tumors and small biopsy/cytology specimens, the only distinguishing morphologic feature of ALK+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting ALK rearrangements in lung adenocarcinomas. The scoring system predicted ALK rearrangements in a new cohort of 78 lung adenocarcinomas (29 ALK+ and 49 ALK-) with a sensitivity of 88% and a specificity of 45%. In conclusion, ALK+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with ALK rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of ALK+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment. | Histologic and cytomorphologic features of ALK-rearranged lung adenocarcinomas. | Chromosomal rearrangements leading to constitutive activation of anaplastic lymphoma receptor tyrosine kinase (/"ALK"/) define a category of lung adenocarcinomas that may be amenable to targeted therapy with the /"ALK"/ inhibitor crizotinib. Defining distinctive features of /"ALK"/-rearranged (/"ALK"/+) lung adenocarcinomas may help identify cases that merit molecular testing. However, data describing the morphologic features of /"ALK"/+ lung adenocarcinomas are conflicting and are primarily based on analysis of resected primary /"lung tumors"/. It is unclear whether the findings from prior studies are applicable to metastatic /"lung tumors"/ or to small biopsy/cytology specimens. To address these issues, we examined resection, excision, small biopsy, and cytology cell block specimens from 104 /"ALK"/+ and 215 ALK- lung adenocarcinomas from primary and metastatic sites. All cases were evaluated for /"ALK"/ rearrangements by fluorescence in situ hybridization. The predominant histologic subtypes and distinctive cytomorphologic features were assessed in each case. Primary /"ALK"/+ lung adenocarcinomas showed a significant association with solid, micropapillary, and papillary-predominant histologic patterns and tumor cells with a signet ring or hepatoid cytomorphology. Among metastatic /"lung tumors"/ and small biopsy/cytology specimens, the only distinguishing morphologic feature of /"ALK"/+ tumors was the presence of signet ring cells. Based on these results, we developed a morphology-based scoring system for predicting /"ALK"/ rearrangements in lung adenocarcinomas. The scoring system predicted /"ALK"/ rearrangements in a new cohort of 78 lung adenocarcinomas (29 /"ALK"/+ and 49 /"ALK"/-) with a sensitivity of 88% and a specificity of 45%. In conclusion, /"ALK"/+ lung adenocarcinomas have distinctive morphologic features, with signet ring cells showing a significant association with /"ALK"/ rearrangements irrespective of tumor site (primary vs metastatic) or specimen type. However, morphologic screening alone will not detect a minority of /"ALK"/+ lung adenocarcinomas, and the routine use of ancillary studies may be warranted to identify all patients who may benefit from crizotinib treatment. | [
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22772592 | CYP4V2 in Bietti's crystalline dystrophy: ocular localization, metabolism of -3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant. | Bietti's crystalline corneoretinal dystrophy (BCD) is a recessive degenerative eye disease caused by germline mutations in the CYP4V2 gene. More than 80% of mutant alleles consist of three mutations, that is, two splice-site alterations and one missense mutation, c.992C>A, which translates to p.H331P. In the present study, we analyzed the expression of CYP4 family members in human tissues and conducted functional studies with the wild-type and p.H331P enzymes, to elucidate the link between CYP4V2 activity and BCD. Expression analysis of 17 CYP1 to CYP4 genes showed CYP4V2 to be a major cytochrome P450 in ARPE-19 cells (a human cell line spontaneously generated from normal human retinal pigmented epithelium) and the only detectable CYP4 transcript. Immunohistochemical analyses demonstrated that CYP4V2 protein was present in epithelial cells of the retina and cornea and the enzyme was localized to endoplasmic reticulum. Recombinant reconstituted CYP4V2 protein metabolized eicosapentaenoic acid and docosahexaenoic acid (an important constituent of the retina) to their respective -hydroxylated products at rates similar to those observed with purified CYP4F2, which is an established hepatic polyunsaturated fatty acid (PUFA) hydroxylase. The disease-associated p.H331P variant was undetectable in Western blot analyses of HepG2 cells stably transduced with lentiviral expression vectors. Finally, overexpression of functional CYP4V2 in HepG2 cells altered lipid homeostasis. We demonstrated that CYP4V2 protein is expressed at high levels in ocular target tissues of BCD, that the enzyme is metabolically active toward PUFAs, and that the functional deficit among patients with BCD who carry the H331P variant is most likely a consequence of the instability of the mutant protein. | /"CYP4V2"/ in /"Bietti's crystalline dystrophy"/: ocular localization, metabolism of -3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant. | /"Bietti's crystalline corneoretinal dystrophy"/ (/"BCD"/) is a recessive degenerative eye disease caused by germline mutations in the /"CYP4V2"/ gene. More than 80% of mutant alleles consist of three mutations, that is, two splice-site alterations and one missense mutation, c.992C>A, which translates to p.H331P. In the present study, we analyzed the expression of CYP4 family members in human tissues and conducted functional studies with the wild-type and p.H331P enzymes, to elucidate the link between /"CYP4V2"/ activity and /"BCD"/. Expression analysis of 17 CYP1 to CYP4 genes showed /"CYP4V2"/ to be a major cytochrome P450 in ARPE-19 cells (a human cell line spontaneously generated from normal human retinal pigmented epithelium) and the only detectable CYP4 transcript. Immunohistochemical analyses demonstrated that /"CYP4V2"/ protein was present in epithelial cells of the retina and cornea and the enzyme was localized to endoplasmic reticulum. Recombinant reconstituted /"CYP4V2"/ protein metabolized eicosapentaenoic acid and docosahexaenoic acid (an important constituent of the retina) to their respective -hydroxylated products at rates similar to those observed with purified CYP4F2, which is an established hepatic polyunsaturated fatty acid (PUFA) hydroxylase. The disease-associated p.H331P variant was undetectable in Western blot analyses of HepG2 cells stably transduced with lentiviral expression vectors. Finally, overexpression of functional /"CYP4V2"/ in HepG2 cells altered lipid homeostasis. We demonstrated that /"CYP4V2"/ protein is expressed at high levels in ocular target tissues of /"BCD"/, that the enzyme is metabolically active toward PUFAs, and that the functional deficit among patients with /"BCD"/ who carry the H331P variant is most likely a consequence of the instability of the mutant protein. | [
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22772592 | CYP4V2 in Bietti's crystalline dystrophy: ocular localization, metabolism of -3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant. | Bietti's crystalline corneoretinal dystrophy (BCD) is a recessive degenerative eye disease caused by germline mutations in the CYP4V2 gene. More than 80% of mutant alleles consist of three mutations, that is, two splice-site alterations and one missense mutation, c.992C>A, which translates to p.H331P. In the present study, we analyzed the expression of CYP4 family members in human tissues and conducted functional studies with the wild-type and p.H331P enzymes, to elucidate the link between CYP4V2 activity and BCD. Expression analysis of 17 CYP1 to CYP4 genes showed CYP4V2 to be a major cytochrome P450 in ARPE-19 cells (a human cell line spontaneously generated from normal human retinal pigmented epithelium) and the only detectable CYP4 transcript. Immunohistochemical analyses demonstrated that CYP4V2 protein was present in epithelial cells of the retina and cornea and the enzyme was localized to endoplasmic reticulum. Recombinant reconstituted CYP4V2 protein metabolized eicosapentaenoic acid and docosahexaenoic acid (an important constituent of the retina) to their respective -hydroxylated products at rates similar to those observed with purified CYP4F2, which is an established hepatic polyunsaturated fatty acid (PUFA) hydroxylase. The disease-associated p.H331P variant was undetectable in Western blot analyses of HepG2 cells stably transduced with lentiviral expression vectors. Finally, overexpression of functional CYP4V2 in HepG2 cells altered lipid homeostasis. We demonstrated that CYP4V2 protein is expressed at high levels in ocular target tissues of BCD, that the enzyme is metabolically active toward PUFAs, and that the functional deficit among patients with BCD who carry the H331P variant is most likely a consequence of the instability of the mutant protein. | CYP4V2 in /"Bietti's crystalline dystrophy"/: ocular localization, metabolism of -3-polyunsaturated fatty acids, and functional deficit of the p.H331P variant. | /"Bietti's crystalline corneoretinal dystrophy"/ (/"BCD"/) is a recessive degenerative eye disease caused by germline mutations in the CYP4V2 gene. More than 80% of mutant alleles consist of three mutations, that is, two splice-site alterations and one missense mutation, c.992C>A, which translates to p.H331P. In the present study, we analyzed the expression of CYP4 family members in human tissues and conducted functional studies with the wild-type and p.H331P enzymes, to elucidate the link between CYP4V2 activity and /"BCD"/. Expression analysis of 17 CYP1 to CYP4 genes showed CYP4V2 to be a major cytochrome P450 in ARPE-19 cells (a human cell line spontaneously generated from normal human retinal pigmented epithelium) and the only detectable CYP4 transcript. Immunohistochemical analyses demonstrated that CYP4V2 protein was present in epithelial cells of the retina and cornea and the enzyme was localized to endoplasmic reticulum. Recombinant reconstituted CYP4V2 protein metabolized eicosapentaenoic acid and docosahexaenoic acid (an important constituent of the retina) to their respective -hydroxylated products at rates similar to those observed with purified /"CYP4F2"/, which is an established hepatic polyunsaturated fatty acid (PUFA) hydroxylase. The disease-associated p.H331P variant was undetectable in Western blot analyses of HepG2 cells stably transduced with lentiviral expression vectors. Finally, overexpression of functional CYP4V2 in HepG2 cells altered lipid homeostasis. We demonstrated that CYP4V2 protein is expressed at high levels in ocular target tissues of /"BCD"/, that the enzyme is metabolically active toward PUFAs, and that the functional deficit among patients with /"BCD"/ who carry the H331P variant is most likely a consequence of the instability of the mutant protein. | [
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} | No |
22802922 | Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. | Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson's disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b(-/-) mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b(-/-) livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr1(-/-) knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD. | Urinary copper elevation in a mouse model of /"Wilson's disease"/ is a regulated process to specifically decrease the hepatic copper load. | Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In /"Wilson's disease"/ (/"WD"/), this function is disrupted due to inactivation of the copper transporter /"ATP7B"/ resulting in hepatic copper overload. High urinary copper is a diagnostic feature of /"WD linked to liver malfunction"/; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live /"Atp7b"/(-/-) mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of /"Atp7b"/(-/-) livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr1(-/-) knockouts, which have normal /"ATP7B"/ function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of /"WD"/. | [
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22802922 | Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. | Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson's disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b(-/-) mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b(-/-) livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter Ctr1 in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific Ctr1(-/-) knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by Ctr1. Thus, hepatic down-regulation of Ctr1 allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of urinary copper excretion may contribute to an improved diagnosis and monitoring of WD. | Urinary copper elevation in a mouse model of Wilson's disease is a regulated process to specifically decrease the hepatic copper load. | Body copper homeostasis is regulated by the liver, which removes excess copper via bile. In Wilson's disease (WD), this function is disrupted due to inactivation of the copper transporter ATP7B resulting in hepatic copper overload. High urinary copper is a diagnostic feature of WD linked to liver malfunction; the mechanism behind urinary copper elevation is not fully understood. Using Positron Emission Tomography-Computed Tomography (PET-CT) imaging of live Atp7b(-/-) mice at different stages of disease, a longitudinal metal analysis, and characterization of copper-binding molecules, we show that urinary copper elevation is a specific regulatory process mediated by distinct molecules. PET-CT and atomic absorption spectroscopy directly demonstrate an age-dependent decrease in the capacity of Atp7b(-/-) livers to accumulate copper, concomitant with an increase in urinary copper. This reciprocal relationship is specific for copper, indicating that cell necrosis is not the primary cause for the initial phase of metal elevation in the urine. Instead, the urinary copper increase is associated with the down-regulation of the copper-transporter /"Ctr1"/ in the liver and appearance of a 2 kDa Small Copper Carrier, SCC, in the urine. SCC is also elevated in the urine of the liver-specific /"Ctr1"/(-/-) knockouts, which have normal ATP7B function, suggesting that SCC is a normal metabolite carrying copper in the serum. In agreement with this hypothesis, partially purified SCC-Cu competes with free copper for uptake by /"Ctr1"/. Thus, hepatic down-regulation of /"Ctr1"/ allows switching to an SCC-mediated removal of copper via kidney when liver function is impaired. These results demonstrate that the body regulates copper export through more than one mechanism; better understanding of /"urinary copper excretion"/ may contribute to an improved diagnosis and monitoring of WD. | [
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23007406 | Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia. | With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111). | Genome-wide association study identifies germline polymorphisms associated with relapse of childhood /"acute lymphoblastic leukemia"/. | With the use of risk-directed therapy for childhood /"acute lymphoblastic leukemia"/ (/"ALL"/), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed /"ALL"/ after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with /"ALL"/ relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the /"PYGL"/ gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of /"childhood ALL"/, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111). | [
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23007406 | Genome-wide association study identifies germline polymorphisms associated with relapse of childhood acute lymphoblastic leukemia. | With the use of risk-directed therapy for childhood acute lymphoblastic leukemia (ALL), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed ALL after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with ALL relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 10(-9)). Fourteen of the 134 relapse SNPs, including variants in PDE4B and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of childhood ALL, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111). | Genome-wide association study identifies germline polymorphisms associated with relapse of childhood /"acute lymphoblastic leukemia"/. | With the use of risk-directed therapy for childhood /"acute lymphoblastic leukemia"/ (/"ALL"/), outcome has improved dramatically in the past 40 years. However, a substantial portion of patients, many of whom have no known risk factors, experience relapse. Taking a genome-wide approach, in the present study, we evaluated the relationships between genotypes at 444 044 single nucleotide polymorphisms (SNPs) with the risk of relapse in 2535 children with newly diagnosed /"ALL"/ after adjusting for genetic ancestry and treatment regimen. We identified 134 SNPs that were reproducibly associated with /"ALL"/ relapse. Of 134 relapse SNPs, 133 remained prognostic after adjusting for all known relapse risk factors, including minimal residual disease, and 111 were significant even among patients who were negative for minimal residual disease after remission induction therapy. The C allele at rs7142143 in the PYGL gene was associated with 3.6-fold higher risk of relapse than the T allele (P = 6.7 10(-9)). Fourteen of the 134 relapse SNPs, including variants in /"PDE4B"/ and ABCB1, were also associated with antileukemic drug pharmacokinetics and/or pharmacodynamics. In the present study, we systematically identified host genetic variations related to treatment outcome of /"childhood ALL"/, most of which were prognostic independent of known risk factors for relapse, and some of which also influenced outcome by affecting host dis-position of antileukemic drugs. All trials are registered at www.clinicaltrials.gov or www.cancer.gov (COG P9904: NCT00005585; COG P9905: NCT00005596; COG P9906: NCT00005603; St Jude Total XIIIB: NCI-T93-0101D; and St Jude Total XV: NCT00137111). | [
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23055271 | Risk for myasthenia gravis maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | Risk for /"myasthenia gravis"/ maps to a (151) Pro > Ala change in /"TNIP1"/ and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset /"myasthenia gravis"/ (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the /"TNFAIP3-interacting protein 1"/, /"TNIP1"/, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at /"TNIP1"/ in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | [
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} | Yes |
23055271 | Risk for myasthenia gravis maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | Risk for /"myasthenia gravis"/ maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset /"myasthenia gravis"/ (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with /"PTPN22"/ (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than /"PTPN22"/ (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | [
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} | Yes |
23055271 | Risk for myasthenia gravis maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | Risk for /"myasthenia gravis"/ maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset /"myasthenia gravis"/ (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, /"HLA-B"/*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the /"HLA-B"/*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | [
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} | No |
23055271 | Risk for myasthenia gravis maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset myasthenia gravis (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that CD8(+) T cells may play a key role in disease initiation or pathogenesis. | Risk for /"myasthenia gravis"/ maps to a (151) Pro > Ala change in TNIP1 and to human leukocyte antigen-B*08. | OBJECTIVE: The objective of this study is to comprehensively define the genetic basis of early onset /"myasthenia gravis"/ (EOMG). METHODS: We have carried out a 2-stage genome-wide association study on a total of 649 North European EOMG patients. Cases were matched 1:4 with controls of European ancestry. We performed imputation and conditional analyses across the major histocompatibility complex, as well as in the top regions of association outside the human leukocyte antigen (HLA) region. RESULTS: We observed the strongest association in the HLA class I region at rs7750641 (p = 1.2 10(-92) ; odds ratio [OR], 6.25). By imputation and conditional analyses, HLA-B*08 proves to be the major associated allele (p = 2.87 10(-113) ; OR, 6.41). In addition to the expected association with PTPN22 (rs2476601; OR, 1.71; p = 8.2 10(-10) ), an imputed coding variant (rs2233290) at position 151 (Pro > Ala) in the TNFAIP3-interacting protein 1, TNIP1, confers even stronger risk than PTPN22 (OR, 1.91; p = 3.2 10(-10) ). INTERPRETATION: The association at TNIP1 in EOMG implies disease mechanisms involving ubiquitin-dependent dysregulation of NF-kB signaling. The localization of the major HLA signal to the HLA-B*08 allele suggests that /"CD8"/(+) T cells may play a key role in disease initiation or pathogenesis. | [
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"entity_id": "D009157",
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} | No |
23142968 | Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene. | OBJECTIVE: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49 10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus. | Whole-genome-wide association study in the Bulgarian population reveals /"HHAT"/ as /"schizophrenia"/ susceptibility gene. | OBJECTIVE: /"Schizophrenia"/, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with /"schizophrenia"/ in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between /"schizophrenia"/ and the intronic SNP rs7527939 in the /"HHAT"/ gene (P-value of 6.49 10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to /"schizophrenia"/ in the Bulgarian population within the /"HHAT"/ locus. | [
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} | Yes |
23142968 | Whole-genome-wide association study in the Bulgarian population reveals HHAT as schizophrenia susceptibility gene. | OBJECTIVE: Schizophrenia, the most common major psychiatric disorder (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the HHAT gene (P-value of 6.49 10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the HHAT locus. | Whole-genome-wide association study in the Bulgarian population reveals /"HHAT"/ as schizophrenia susceptibility gene. | OBJECTIVE: Schizophrenia, the most common major /"psychiatric disorder"/ (or group of disorders), entails severe decline of higher functions, principally with alterations in cognitive functioning and reality perception. Both genetic and environmental factors are involved in its pathogenesis; however, its genetic background still needs to be clarified. The objective of the study was to reveal genetic markers associated with schizophrenia in the Bulgarian population. METHODS: We have conducted a genome-wide association study using 554 496 single nucleotide polymorphisms (SNPs) in 188 affected and 376 unaffected Bulgarian individuals. Subsequently, the 100 candidate SNPs that revealed the smallest P-values were further evaluated in an additional set of 99 case and 328 control samples. RESULTS: We found a significant association between schizophrenia and the intronic SNP rs7527939 in the /"HHAT"/ gene (P-value of 6.49 10 with an odds ratio of 2.63, 95% confidence interval of 1.89-3.66). We also genotyped additional SNPs within a 58-kb linkage disequilibrium block surrounding the landmark SNP. CONCLUSION: We suggest rs7527939 to be the strongest indicator of susceptibility to schizophrenia in the Bulgarian population within the /"HHAT"/ locus. | [
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23264560 | NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | /"NODAL"/ and SHH dose-dependent double inhibition promotes an /"HPE"/-like phenotype in chick embryos. | /"Holoprosencephaly"/ (/"HPE"/) is a common congenital defect that results from failed or incomplete forebrain cleavage. /"HPE"/ is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that /"HPE"/ involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of /"HPE"/. This could explain the various clinical phenotypes. Screening for /"HPE"/-associated genes in humans suggests the involvement of /"NODAL"/ or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main /"HPE"/ signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the /"NODAL"/ pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused /"HPE"/-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of /"NODAL"/ and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the /"NODAL"/ and SHH pathways, even at low concentration, acted synergistically to promote an /"HPE"/-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of /"HPE"/ and may contribute to the phenotypic variability. | [
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23264560 | NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | NODAL and /"SHH"/ dose-dependent double inhibition promotes an /"HPE"/-like phenotype in chick embryos. | /"Holoprosencephaly"/ (/"HPE"/) is a common congenital defect that results from failed or incomplete forebrain cleavage. /"HPE"/ is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that /"HPE"/ involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of /"HPE"/. This could explain the various clinical phenotypes. Screening for /"HPE"/-associated genes in humans suggests the involvement of NODAL or /"SHH"/ signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main /"HPE"/ signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the /"SHH"/ pathway. We report that both inhibitors caused /"HPE"/-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and /"SHH"/ pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and /"SHH"/ pathways, even at low concentration, acted synergistically to promote an /"HPE"/-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of /"HPE"/ and may contribute to the phenotypic variability. | [
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23264560 | NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | /"NODAL"/ and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common /"congenital defect"/ that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of /"NODAL"/ or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the /"NODAL"/ pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of /"NODAL"/ and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the /"NODAL"/ and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | [
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23264560 | NODAL and SHH dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common congenital defect that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or SHH signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the SHH pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and SHH pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and SHH pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | NODAL and /"SHH"/ dose-dependent double inhibition promotes an HPE-like phenotype in chick embryos. | Holoprosencephaly (HPE) is a common /"congenital defect"/ that results from failed or incomplete forebrain cleavage. HPE is characterized by a wide clinical spectrum, with inter- and intrafamilial variability. This heterogeneity is not well understood and it has been suggested that HPE involves a combination of multiple gene mutations. In this model, several mutated alleles or modifying factors are presumed to act in synergy to cause and determine the severity of HPE. This could explain the various clinical phenotypes. Screening for HPE-associated genes in humans suggests the involvement of NODAL or /"SHH"/ signaling, or both. To test this multigenic hypothesis, we investigated the effects of chemical inhibition of these two main HPE signaling pathways in a chick embryo model. SB-505124, a selective inhibitor of transforming growth factor-B type I receptors was used to inhibit the NODAL pathway. Cyclopamine was used to inhibit the /"SHH"/ pathway. We report that both inhibitors caused HPE-like defects that were dependent on the drug concentration and on the developmental stage at the time of treatment. We also investigated double inhibition of NODAL and /"SHH"/ pathways from the onset of gastrulation by using subthreshold inhibitor concentrations. The inhibitors of the NODAL and /"SHH"/ pathways, even at low concentration, acted synergistically to promote an HPE-like phenotype. These findings support the view that genetic heterogeneity is important in the etiology of HPE and may contribute to the phenotypic variability. | [
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23313952 | Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | Identification of recurrent /"NAB2"/-STAT6 gene fusions in /"solitary fibrous tumor"/ by integrative sequencing. | A 44-year old woman with recurrent /"solitary fibrous tumor"/ (/"SFT"/)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor /"NAB2"/ with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a /"NAB2"/-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of /"NAB2"/-STAT6 fusion proteins was confirmed in /"SFT"/, and the predicted fusion products harbor the early growth response (EGR)-binding domain of /"NAB2"/ fused to the activation domain of STAT6. Overexpression of the /"NAB2"/-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish /"NAB2"/-STAT6 as the defining driver mutation of /"SFT"/ and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | [
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23313952 | Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | Identification of recurrent NAB2-/"STAT6"/ gene fusions in /"solitary fibrous tumor"/ by integrative sequencing. | A 44-year old woman with recurrent /"solitary fibrous tumor"/ (/"SFT"/)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator /"STAT6"/ was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-/"STAT6"/ gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-/"STAT6"/ fusion proteins was confirmed in /"SFT"/, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of /"STAT6"/. Overexpression of the NAB2-/"STAT6"/ gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-/"STAT6"/ as the defining driver mutation of /"SFT"/ and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | [
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23313952 | Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | Identification of recurrent NAB2-/"STAT6"/ gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator /"STAT6"/ was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-/"STAT6"/ gene fusion in all /"tumors"/. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-/"STAT6"/ fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of /"STAT6"/. Overexpression of the NAB2-/"STAT6"/ gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-/"STAT6"/ as the defining driver mutation of SFT and provide an example of how /"neoplasia"/ can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | [
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23313952 | Identification of recurrent NAB2-STAT6 gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator STAT6 was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-STAT6 gene fusion in all tumors. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-STAT6 fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of STAT6. Overexpression of the NAB2-STAT6 gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-STAT6 as the defining driver mutation of SFT and provide an example of how neoplasia can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | Identification of recurrent NAB2-/"STAT6"/ gene fusions in solitary fibrous tumor by integrative sequencing. | A 44-year old woman with recurrent solitary fibrous tumor (SFT)/hemangiopericytoma was enrolled in a clinical sequencing program including whole-exome and transcriptome sequencing. A gene fusion of the transcriptional repressor NAB2 with the transcriptional activator /"STAT6"/ was detected. Transcriptome sequencing of 27 additional SFTs identified the presence of a NAB2-/"STAT6"/ gene fusion in all /"tumors"/. Using RT-PCR and sequencing, we detected this fusion in all 51 SFTs, indicating high levels of recurrence. Expression of NAB2-/"STAT6"/ fusion proteins was confirmed in SFT, and the predicted fusion products harbor the early growth response (EGR)-binding domain of NAB2 fused to the activation domain of /"STAT6"/. Overexpression of the NAB2-/"STAT6"/ gene fusion induced proliferation in cultured cells and activated the expression of EGR-responsive genes. These studies establish NAB2-/"STAT6"/ as the defining driver mutation of SFT and provide an example of how /"neoplasia"/ can be initiated by converting a transcriptional repressor of mitogenic pathways into a transcriptional activator. | [
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23423710 | 5-Aza-2'-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. | Airway smooth muscle (ASM) cell phenotypic switching played an important role in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza-CdR) on PDGF-induced rat ASM cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced DNA methyltransferase 1 (DNMT1) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of DNMT1 protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing DNMT1-mediated DNA methylation was implicated in asthmatic ASM remodeling. We proposed for the first time that DNMT1 played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening ASM remodeling in asthma. Although study of abnormal DNA methylation in PDGF-stimulated ASM cells is in its infancy, this work contributes to providing new insights into the mechanism of ASM remodeling and may be helpful for developing effective treatments for airway remodeling in asthma. | 5-Aza-2'-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. | Airway smooth muscle (ASM) cell phenotypic switching played an important role in airway remodeling in /"asthma"/. In vitro platelet-derived growth factor (PDGF) induced ASM cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza-CdR) on PDGF-induced rat ASM cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced /"DNA methyltransferase 1"/ (/"DNMT1"/) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of /"DNMT1"/ protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing /"DNMT1"/-mediated DNA methylation was implicated in asthmatic ASM remodeling. We proposed for the first time that /"DNMT1"/ played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening ASM remodeling in /"asthma"/. Although study of abnormal DNA methylation in PDGF-stimulated ASM cells is in its infancy, this work contributes to providing new insights into the mechanism of ASM remodeling and may be helpful for developing effective treatments for airway remodeling in /"asthma"/. | [
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23423710 | 5-Aza-2'-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. | Airway smooth muscle (ASM) cell phenotypic switching played an important role in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced ASM cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza-CdR) on PDGF-induced rat ASM cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced DNA methyltransferase 1 (DNMT1) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of DNMT1 protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing DNMT1-mediated DNA methylation was implicated in asthmatic ASM remodeling. We proposed for the first time that DNMT1 played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening ASM remodeling in asthma. Although study of abnormal DNA methylation in PDGF-stimulated ASM cells is in its infancy, this work contributes to providing new insights into the mechanism of ASM remodeling and may be helpful for developing effective treatments for airway remodeling in asthma. | 5-Aza-2'-deoxycytidine inhibited PDGF-induced rat airway smooth muscle cell phenotypic switching. | /"Airway smooth muscle"/ (/"ASM"/) cell phenotypic switching played an important role in airway remodeling in asthma. In vitro platelet-derived growth factor (PDGF) induced /"ASM"/ cell phenotypic switching from a mature to pro-remodeling phenotype, but the mechanism remained incompletely understood. This study was to explore the effect of DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (Aza-CdR) on PDGF-induced rat /"ASM"/ cell phenotypic switching and biological behaviors. Rat airway smooth muscle (RASM) cells were obtained by primary explant techniques. Western blot, 3-dimensional gel contraction, transwell and wound healing assay, and MTT were applied to detect cell phenotypic switching, contractility, migration and proliferation, respectively. Cytoskeleton rearrangement was observed by immunofluorescence. Results showed Aza-CdR inhibited PDGF-induced down-regulation of contractile markers in RASM cells and increased cell contractility. Aza-CdR inhibited PDGF-induced RASM cell migration by abrogating cell morphology change and cytoskeletal reorganization and attenuated the effect of PDGF on proliferating cell nuclear antigen expression and cell cycle progression, ultimately cell proliferation. PDGF-induced /"DNA methyltransferase 1"/ (/"DNMT1"/) expression was mediated by activation of PI3K/Akt and ERK signaling in RASM cells. Selective depletion of /"DNMT1"/ protein by Aza-CdR inhibited PDGF-induced RASM cell phenotypic switching, revealing /"DNMT1"/-mediated DNA methylation was implicated in /"asthmatic ASM"/ remodeling. We proposed for the first time that /"DNMT1"/ played a key role in PDGF-induced RASM cell phenotypic switching and Aza-CdR is promising in intervening /"ASM"/ remodeling in asthma. Although study of abnormal DNA methylation in PDGF-stimulated /"ASM"/ cells is in its infancy, this work contributes to providing new insights into the mechanism of /"ASM"/ remodeling and may be helpful for developing effective treatments for airway remodeling in asthma. | [
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23440206 | PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. | Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. | /"PML"/ mediates /"glioblastoma"/ resistance to mammalian target of rapamycin (mTOR)-targeted therapies. | Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, /"glioblastomas"/ (/"GBMs"/) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (/"PML"/) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear /"PML"/ expression in /"GBMs"/, and genetic overexpression and knockdown approaches demonstrate that /"PML"/ prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the /"PML"/ inhibitor, arsenic trioxide, abrogate /"PML"/ expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for /"PML"/ in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. | [
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23440206 | PML mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. | Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the promyelocytic leukemia (PML) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear PML expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that PML prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the PML inhibitor, arsenic trioxide, abrogate PML expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for PML in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. | /"PML"/ML"/ mediates glioblastoma resistance to mammalian target of rapamycin (mTOR)-targeted therapies. | Despite their nearly universal activation of mammalian target of rapamycin (mTOR) signaling, glioblastomas (GBMs) are strikingly resistant to mTOR-targeted therapy. We analyzed GBM cell lines, patient-derived tumor cell cultures, and clinical samples from patients in phase 1 clinical trials, and find that the /"promyelocytic leukemia"/ (/"PML"/ML"/) gene mediates resistance to mTOR-targeted therapies. Direct mTOR inhibitors and EGF receptor (EGFR) inhibitors that block downstream mTOR signaling promote nuclear /"PML"/ML"/ expression in GBMs, and genetic overexpression and knockdown approaches demonstrate that /"PML"/ML"/ prevents mTOR and EGFR inhibitor-dependent cell death. Low doses of the /"PML"/ML"/ inhibitor, arsenic trioxide, abrogate /"PML"/ML"/ expression and reverse mTOR kinase inhibitor resistance in vivo, thus markedly inhibiting tumor growth and promoting tumor cell death in mice. These results identify a unique role for /"PML"/ML"/ in mTOR and EGFR inhibitor resistance and provide a strong rationale for a combination therapeutic strategy to overcome it. | [
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23505205 | Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. | Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. | Novel /"FOXF1"/ mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. | Alveolar capillary dysplasia with /"misalignment of pulmonary veins"/ (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of /"FOXF1"/ (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known /"FOXF1"/ mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in /"FOXF1"/ function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to /"FOXF1"/. These results corroborate and extend our previous observations and further establish involvement of /"FOXF1"/ in ACD/MPV and lung organogenesis. | [
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23505205 | Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain. | Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. | Novel /"FOXF1"/ mutations in sporadic and familial cases of alveolar /"capillary dysplasia"/ with misaligned pulmonary veins imply a role for its DNA binding domain. | Alveolar /"capillary dysplasia"/ with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of /"FOXF1"/ (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known /"FOXF1"/ mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in /"FOXF1"/ function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to /"FOXF1"/. These results corroborate and extend our previous observations and further establish involvement of /"FOXF1"/ in ACD/MPV and lung organogenesis. | [
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23566200 | TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. | Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (M s) and dendritic cells. M s differentiated with macrophage colony-stimulating factor and interferon-y (My-M s), which are similar to the human intestinal lamina propria CD14(+) M s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated M and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-a production in My-M s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-kB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal M s from patients with CD expressed TGR5. In isolated intestinal CD14(+) M s, a TGR5 agonist could inhibit tumour necrosis factor-a production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease. | /"TGR5"/ signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in /"Crohn's disease"/. | Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. /"TGR5"/, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the /"TGR5"/ pathway in human mononuclear cell lineages. We examined /"TGR5"/ expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (M s) and dendritic cells. M s differentiated with macrophage colony-stimulating factor and interferon-y (My-M s), which are similar to the human intestinal lamina propria CD14(+) M s that contribute to /"Crohn's disease"/ (/"CD"/) pathogenesis by production of pro-inflammatory cytokines, highly expressed /"TGR5"/ compared with any other type of differentiated M and dendritic cells. We also showed that a /"TGR5"/ agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-a production in My-M s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the /"TGR5"/-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-kB p65 activation. Next, we analysed /"TGR5"/ levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with /"CD"/. Compared with non-inflammatory bowel disease, inflamed /"CD"/ LPMCs contained more /"TGR5"/ transcripts. Among LPMCs, isolated CD14(+) intestinal M s from patients with /"CD"/ expressed /"TGR5"/. In isolated intestinal CD14(+) M s, a /"TGR5"/ agonist could inhibit tumour necrosis factor-a production. These results indicate that /"TGR5"/ signalling may have the potential to modulate immune responses in inflammatory bowel disease. | [
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"text_name": "Crohn's disease"
} | Yes |
23566200 | TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in Crohn's disease. | Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (M s) and dendritic cells. M s differentiated with macrophage colony-stimulating factor and interferon-y (My-M s), which are similar to the human intestinal lamina propria CD14(+) M s that contribute to Crohn's disease (CD) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated M and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-a production in My-M s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-kB p65 activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with CD. Compared with non-inflammatory bowel disease, inflamed CD LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal M s from patients with CD expressed TGR5. In isolated intestinal CD14(+) M s, a TGR5 agonist could inhibit tumour necrosis factor-a production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease. | TGR5 signalling inhibits the production of pro-inflammatory cytokines by in vitro differentiated inflammatory and intestinal macrophages in /"Crohn's disease"/. | Bile acids (BAs) play important roles not only in lipid metabolism, but also in signal transduction. TGR5, a transmembrane receptor of BAs, is an immunomodulative factor, but its detailed mechanism remains unclear. Here, we aimed to delineate how BAs operate in immunological responses via the TGR5 pathway in human mononuclear cell lineages. We examined TGR5 expression in human peripheral blood monocytes, several types of in vitro differentiated macrophages (M s) and dendritic cells. M s differentiated with macrophage colony-stimulating factor and interferon-y (My-M s), which are similar to the human intestinal lamina propria CD14(+) M s that contribute to /"Crohn's disease"/ (/"CD"/) pathogenesis by production of pro-inflammatory cytokines, highly expressed TGR5 compared with any other type of differentiated M and dendritic cells. We also showed that a TGR5 agonist and two types of BAs, deoxycholic acid and lithocholic acid, could inhibit tumour necrosis factor-a production in My-M s stimulated by commensal bacterial antigen or lipopolysaccharide. This inhibitory effect was mediated by the TGR5-cAMP pathway to induce phosphorylation of c-Fos that regulated nuclear factor-kB /"p65"/ activation. Next, we analysed TGR5 levels in lamina propria mononuclear cells (LPMCs) obtained from the intestinal mucosa of patients with /"CD"/. Compared with non-inflammatory bowel disease, inflamed /"CD"/ LPMCs contained more TGR5 transcripts. Among LPMCs, isolated CD14(+) intestinal M s from patients with /"CD"/ expressed TGR5. In isolated intestinal CD14(+) M s, a TGR5 agonist could inhibit tumour necrosis factor-a production. These results indicate that TGR5 signalling may have the potential to modulate immune responses in inflammatory bowel disease. | [
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} | No |
23698071 | Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. | Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers. | Selective inhibition of /"p300 HAT"/ blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in /"melanoma"/ cells. | Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator /"p300"//CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of /"p300"//CBP HAT activity, C646, in order to evaluate the functional contributions of /"p300"//CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human /"melanoma"/ and other tumor cells and promotes cellular senescence. Global assessment of the /"p300 HAT"/ transcriptome in human /"melanoma"/ identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of /"melanoma"/ cells after combination treatment with cisplatin. Together, our data suggest that /"p300 HAT"/ activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for /"melanoma"/ and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers. | [
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} | Yes |
23698071 | Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. | Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in tumor development and progression. The transcriptional coactivator p300/CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of p300/CBP HAT activity, C646, in order to evaluate the functional contributions of p300/CBP HAT to tumor development and progression. Here we report that C646 inhibits the growth of human melanoma and other tumor cells and promotes cellular senescence. Global assessment of the p300 HAT transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that p300 HAT activity mediates critical growth regulatory pathways in tumor cells and may serve as a potential therapeutic target for melanoma and other malignancies by promoting cellular responses to DNA damaging agents that are currently ineffective against specific cancers. | Selective inhibition of /"p300 HAT"/ blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. | Epigenetic events, including covalent post-translational modifications of histones, have been demonstrated to have critical roles in /"tumor"/ development and progression. The transcriptional coactivator /"p300"//CBP possesses both histone acetyltransferase (HAT) activity and scaffolding properties that directly influence the transcriptional activation of targeted genes. We have used a potent and specific inhibitor of /"p300"//CBP HAT activity, C646, in order to evaluate the functional contributions of /"p300"//CBP HAT to /"tumor"/ development and progression. Here we report that C646 inhibits the growth of human melanoma and other /"tumor"/ cells and promotes cellular senescence. Global assessment of the /"p300 HAT"/ transcriptome in human melanoma identified functional roles in promoting cell cycle progression, chromatin assembly, and activation of DNA repair pathways through direct transcriptional regulatory mechanisms. In addition, C646 is shown to promote sensitivity to DNA damaging agents, leading to the enhanced apoptosis of melanoma cells after combination treatment with cisplatin. Together, our data suggest that /"p300 HAT"/ activity mediates critical growth regulatory pathways in /"tumor"/ cells and may serve as a potential therapeutic target for melanoma and other /"malignancies"/ by promoting cellular responses to DNA damaging agents that are currently ineffective against specific /"cancers"/. | [
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} | No |
23768946 | Compound heterozygous mutations of the TNXB gene cause primary myopathy. | Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions. | Compound heterozygous mutations of the /"TNXB"/ gene cause primary myopathy. | Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the /"TNXB"/ gene. This study identifies a /"TNX-deficient"/ patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that /"TNX deficiency"/ leads to muscle softness and to mislocalization of myotendinous junctions. | [
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"text_name": "TNX deficiency"
} | Yes |
23768946 | Compound heterozygous mutations of the TNXB gene cause primary myopathy. | Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions. | Compound heterozygous mutations of the /"TNXB"/ gene cause primary myopathy. | Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy /"bruising"/ and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy /"bruising"/. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the /"TNXB"/ gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions. | [
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24211273 | Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. | The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. | Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid /"CB1"/ receptors and apoptotic cell death. | The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective /"CB1"/ receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the /"CB1"/ receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to /"neuronal damage"/ or deficits in the brain. | [
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24211273 | Cytotoxicity of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. | The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute cytotoxicity of synthetic cannabinoids on mouse brain neuronal cells. Cytotoxicity induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced cytotoxicity in the forebrain cultures in a concentration-dependent manner. The cytotoxicity was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of caspase-3, and preincubation with a caspase-3 inhibitor significantly suppressed the cytotoxicity. These synthetic cannabinoids induced apoptosis through a caspase-3-dependent mechanism in the forebrain cultures. Our results indicate that the cytotoxicity of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. | /"Cytotoxicity"/ of synthetic cannabinoids on primary neuronal cells of the forebrain: the involvement of cannabinoid CB1 receptors and apoptotic cell death. | The abuse of herbal products containing synthetic cannabinoids has become an issue of public concern. The purpose of this paper was to evaluate the acute /"cytotoxicity"/ of synthetic cannabinoids on mouse brain neuronal cells. /"Cytotoxicity"/ induced by synthetic cannabinoid (CP-55,940, CP-47,497, CP-47,497-C8, HU-210, JWH-018, JWH-210, AM-2201, and MAM-2201) was examined using forebrain neuronal cultures. These synthetic cannabinoids induced /"cytotoxicity"/ in the forebrain cultures in a concentration-dependent manner. The /"cytotoxicity"/ was suppressed by preincubation with the selective CB1 receptor antagonist AM251, but not with the selective CB2 receptor antagonist AM630. Furthermore, annexin-V-positive cells were found among the treated forebrain cells. Synthetic cannabinoid treatment induced the activation of /"caspase-3"/, and preincubation with a /"caspase-3"/ inhibitor significantly suppressed the /"cytotoxicity"/. These synthetic cannabinoids induced apoptosis through a /"caspase-3"/-dependent mechanism in the forebrain cultures. Our results indicate that the /"cytotoxicity"/ of synthetic cannabinoids towards primary neuronal cells is mediated by the CB1 receptor, but not by the CB2 receptor, and further suggest that caspase cascades may play an important role in the apoptosis induced by these synthetic cannabinoids. In conclusion, excessive synthetic cannabinoid abuse may present a serious acute health concern due to neuronal damage or deficits in the brain. | [
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24277619 | ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample. | Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 * 10(-8)) and two AD-related phenotypes: flushing response (minimum P = 4.75 * 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 * 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. | /"ALDH2"/ is associated to /"alcohol dependence"/ and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample. | /"Alcohol dependence"/ (/"AD"/) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which /"AD"/ segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the /"ALDH2"/ region for /"AD"/ (minimum P = 4.73 * 10(-8)) and two /"AD"/-related phenotypes: flushing response (minimum P = 4.75 * 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 * 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with /"ALDH2"/. /"ALDH2"/ is strongly associated with flushing response, /"AD"/, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for /"AD"/-for an adequate test of association for either /"AD"/ or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. | [
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24277619 | ALDH2 is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample. | Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the ALDH2 region for AD (minimum P = 4.73 * 10(-8)) and two AD-related phenotypes: flushing response (minimum P = 4.75 * 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 * 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with ALDH2. ALDH2 is strongly associated with flushing response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in flushing response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. | /"ALDH2"/ is associated to alcohol dependence and is the major genetic determinant of "daily maximum drinks" in a GWAS study of an isolated rural Chinese sample. | Alcohol dependence (AD) is a moderately heritable phenotype with a small number of known risk genes mapped via linkage or candidate gene studies. We considered 313 males from among 595 members of documented, extended pedigrees in which AD segregates collected in Northern Hunan Province, China. A joint analysis of both males and females could not be performed as the difference in alcohol consumption variance was too large. Genome-wide association analyses were performed for approximately 300,000 single nucleotide polymorphisms (SNPs). Significant associations found in the /"ALDH2"/ region for AD (minimum P = 4.73 * 10(-8)) and two AD-related phenotypes: /"flushing"/ response (minimum P = 4.75 * 10(-26)) and maximum drinks in a 24-hr period (minimum P = 1.54 * 10(-16)). Association of previous candidate SNP, rs10774610 in CCDC63, was confirmed but resulted from linkage disequilibrium with /"ALDH2"/. /"ALDH2"/ is strongly associated with /"flushing"/ response, AD, and maximum drinks in males, with nonsynonymous SNP rs671 explaining 29.2%, 7.9%, and 22.9% of phenotypic variation, respectively, in this sample. When rs671 was considered as a candidate SNP in females, it explained 23.6% of the variation in /"flushing"/ response, but alcohol consumption rates were too low among females-despite familial enrichment for AD-for an adequate test of association for either AD or maximum drinks. These results support a mediating effect of aldehyde dehydrogenase deficiency on alcohol consumption in males and a secondary, culturally mediated limitation on alcohol consumption by females that should be appropriately modeled in future studies of alcohol consumption in populations where this may be a factor. | [
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24640096 | Matrix metalloproteinases and inflammatory cytokines in the oral fluid of patients with chronic generalized periodontitis various structural materials restoration of teeth and dentition. | Results of comparative immunoenzymatic study of matrix metalloproteinase (MMP) 2, 8 and 9, interleukins (IL) If and 6, tissue MMP inhibitors (TIMP-1and TIMP-2) and TNF-a in oral fluid of patients with different teeth and denture constructive materials show that MMP-9 content in oral fluid can serve as a marker of chronic generalized periodontitis because it is elevated in all patients irrespective of presence or absence of metallic tooth restorations. MMP-8 level is elevated as compared to control only in periodontitis patients with metallic restorations. The character of correlative relationships between the parameters studied in various patients'groups demonstrate relative similarity of MMP, IL and TIMP secretion regulation in patients with intact periodontal. In patients with inflammatory destructive periodontal lesions both with and without metallic restorations the correlation data reveal a cascade of biochemical reactions in response to etiologic factors. More pronounced response is observed in periodontitis patients with metallic orthopedic constructions. The presence of chromium-cobalt or chromium-nickel constructions leads to an increase of MMP-2, IL-lf and IL-6 content in oral fluid. | Matrix metalloproteinases and inflammatory cytokines in the oral fluid of patients with chronic generalized /"periodontitis"/ various structural materials restoration of teeth and dentition. | Results of comparative immunoenzymatic study of matrix metalloproteinase (MMP) 2, 8 and 9, interleukins (IL) If and 6, tissue MMP inhibitors (TIMP-1and TIMP-2) and TNF-a in oral fluid of patients with different teeth and denture constructive materials show that /"MMP-9"/ content in oral fluid can serve as a marker of chronic generalized /"periodontitis"/ because it is elevated in all patients irrespective of presence or absence of metallic tooth restorations. MMP-8 level is elevated as compared to control only in /"periodontitis"/ patients with metallic restorations. The character of correlative relationships between the parameters studied in various patients'groups demonstrate relative similarity of MMP, IL and TIMP secretion regulation in patients with intact periodontal. In patients with inflammatory destructive periodontal lesions both with and without metallic restorations the correlation data reveal a cascade of biochemical reactions in response to etiologic factors. More pronounced response is observed in /"periodontitis"/ patients with metallic orthopedic constructions. The presence of chromium-cobalt or chromium-nickel constructions leads to an increase of MMP-2, IL-lf and IL-6 content in oral fluid. | [
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24640096 | Matrix metalloproteinases and inflammatory cytokines in the oral fluid of patients with chronic generalized periodontitis various structural materials restoration of teeth and dentition. | Results of comparative immunoenzymatic study of matrix metalloproteinase (MMP) 2, 8 and 9, interleukins (IL) If and 6, tissue MMP inhibitors (TIMP-1and TIMP-2) and TNF-a in oral fluid of patients with different teeth and denture constructive materials show that MMP-9 content in oral fluid can serve as a marker of chronic generalized periodontitis because it is elevated in all patients irrespective of presence or absence of metallic tooth restorations. MMP-8 level is elevated as compared to control only in periodontitis patients with metallic restorations. The character of correlative relationships between the parameters studied in various patients'groups demonstrate relative similarity of MMP, IL and TIMP secretion regulation in patients with intact periodontal. In patients with inflammatory destructive periodontal lesions both with and without metallic restorations the correlation data reveal a cascade of biochemical reactions in response to etiologic factors. More pronounced response is observed in periodontitis patients with metallic orthopedic constructions. The presence of chromium-cobalt or chromium-nickel constructions leads to an increase of MMP-2, IL-lf and IL-6 content in oral fluid. | Matrix metalloproteinases and inflammatory cytokines in the oral fluid of patients with chronic generalized /"periodontitis"/ various structural materials restoration of teeth and dentition. | Results of comparative immunoenzymatic study of matrix metalloproteinase (MMP) 2, 8 and 9, interleukins (IL) If and 6, tissue MMP inhibitors (TIMP-1and TIMP-2) and TNF-a in oral fluid of patients with different teeth and denture constructive materials show that MMP-9 content in oral fluid can serve as a marker of chronic generalized /"periodontitis"/ because it is elevated in all patients irrespective of presence or absence of metallic tooth restorations. /"MMP-8"/ level is elevated as compared to control only in /"periodontitis"/ patients with metallic restorations. The character of correlative relationships between the parameters studied in various patients'groups demonstrate relative similarity of MMP, IL and TIMP secretion regulation in patients with intact periodontal. In patients with inflammatory destructive periodontal lesions both with and without metallic restorations the correlation data reveal a cascade of biochemical reactions in response to etiologic factors. More pronounced response is observed in /"periodontitis"/ patients with metallic orthopedic constructions. The presence of chromium-cobalt or chromium-nickel constructions leads to an increase of MMP-2, IL-lf and IL-6 content in oral fluid. | [
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2480601 | Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. | Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred. | /"Pelizaeus-Merzbacher disease"/: tight linkage to /"proteolipid protein"/ gene exon variant. | /"Pelizaeus-Merzbacher disease"/ (/"PMD"/) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for /"proteolipid protein"/ (/"PLP"/). With the jimpy mouse mutation as a precedent, we focused our attention on the human /"PLP"/ gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the /"PLP"/ gene of an affected male from a large Indiana /"PMD"/ kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned /"PMD"/ kindred. Our results show tight linkage (theta = 0) of /"PMD"/ to /"PLP"/ with a lod (logarithm of odds) score of 4.62. In six other unrelated /"PMD"/ kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the /"PMD"/-causing defect may have been delineated in one kindred. | [
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2480601 | Pelizaeus-Merzbacher disease: tight linkage to proteolipid protein gene exon variant. | Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the genetic defect has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for proteolipid protein (PLP). With the jimpy mouse mutation as a precedent, we focused our attention on the human PLP gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the PLP gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to PLP with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred. | Pelizaeus-Merzbacher disease: tight linkage to /"proteolipid protein"/ gene exon variant. | Pelizaeus-Merzbacher disease (PMD) is a human X chromosome-linked dysmyelination disorder of the central nervous system for which the /"genetic defect"/ has not yet been established. The jimpy mutation jp of the mouse is an X chromosome-linked disorder of myelin formation. The mutation is at an intron/exon splice site in the mouse gene for /"proteolipid protein"/ (/"PLP"/). With the jimpy mouse mutation as a precedent, we focused our attention on the human /"PLP"/ gene, which is found at Xq22. The polymerase chain reaction was used to amplify the exons of the /"PLP"/ gene of an affected male from a large Indiana PMD kindred. DNA sequencing showed a C----T transition at nucleotide 40 of the second exon. An affected third cousin also showed this sequence variation, while two unaffected male relatives (sons of an obligate carrier female) had the normal cytidine nucleotide. Allele-specific oligonucleotides were used to generate data for linkage studies on the above mentioned PMD kindred. Our results show tight linkage (theta = 0) of PMD to /"PLP"/ with a lod (logarithm of odds) score of 4.62. In six other unrelated PMD kindreds, only the normal-sequence oligonucleotide hybridized, which indicates genetic heterogeneity. The radical nature of the predicted amino acid change (proline to leucine), suggests that the PMD-causing defect may have been delineated in one kindred. | [
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24868163 | Blood and urine levels of heavy metal pollutants in female and male patients with coronary artery disease. | BACKGROUND: Heavy metal pollutants such as cadmium (Cd), lead (Pb), and mercury (Hg) are rarely the subjects of cardiovascular research although they have been suspected for decades to negatively impact the circulatory system. METHODS: Apart from detailed anamnestic data, urinary levels of Cd and full blood levels of Pb and Hg were measured in 53 female (mean age: 68.04 7.03 years) and 111 male (mean age: 60.68 11.43 years) nonsmoking or never-smoking patients with angiographically verified and precisely quantified coronary artery disease (CAD). RESULTS: Although Cd was quantifiable in 68.3% of subjects, only 34.1% of these patients exceeded the critical 1 g/L Human Biomonitoring (HBM)-I level. Median Pb (20 g/L) and Hg (0.55 g/L) levels were lower than the HBM-I, as well as reference levels of Pb. Wine consumption was the main source for Pb, fish and wine consumption for Hg, and previous nicotine abuse for Cd. There was no correlation between Cd, Pb, or Hg and severity of CAD although severity correlated positively with atherosclerosis parameters (uric acid, creatinine, triglycerides, blood urea nitrogen, C-reactive protein) and negatively with high density lipoprotein cholesterol. CONCLUSION: Cd levels detected in CAD patients were high compared to German and European reference levels but it could not be proven that urine levels of Cd and blood levels of Hg or Pb played a major role in the genesis of CAD, particularly when compared to well-known biomarkers such as blood pressure, glucose, and lipids. | Blood and urine levels of heavy metal pollutants in female and male patients with /"coronary artery disease"/. | BACKGROUND: Heavy metal pollutants such as cadmium (Cd), lead (Pb), and mercury (Hg) are rarely the subjects of cardiovascular research although they have been suspected for decades to negatively impact the circulatory system. METHODS: Apart from detailed anamnestic data, urinary levels of Cd and full blood levels of Pb and Hg were measured in 53 female (mean age: 68.04 7.03 years) and 111 male (mean age: 60.68 11.43 years) nonsmoking or never-smoking patients with angiographically verified and precisely quantified /"coronary artery disease"/ (/"CAD"/). RESULTS: Although Cd was quantifiable in 68.3% of subjects, only 34.1% of these patients exceeded the critical 1 g/L Human Biomonitoring (HBM)-I level. Median Pb (20 g/L) and Hg (0.55 g/L) levels were lower than the HBM-I, as well as reference levels of Pb. Wine consumption was the main source for Pb, fish and wine consumption for Hg, and previous nicotine abuse for Cd. There was no correlation between Cd, Pb, or Hg and severity of /"CAD"/ although severity correlated positively with atherosclerosis parameters (uric acid, creatinine, triglycerides, blood urea nitrogen, /"C-reactive protein"/) and negatively with high density lipoprotein cholesterol. CONCLUSION: Cd levels detected in /"CAD"/ patients were high compared to German and European reference levels but it could not be proven that urine levels of Cd and blood levels of Hg or Pb played a major role in the genesis of /"CAD"/, particularly when compared to well-known biomarkers such as blood pressure, glucose, and lipids. | [
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"text_name": "coronary artery disease"
} | Yes |
24868163 | Blood and urine levels of heavy metal pollutants in female and male patients with coronary artery disease. | BACKGROUND: Heavy metal pollutants such as cadmium (Cd), lead (Pb), and mercury (Hg) are rarely the subjects of cardiovascular research although they have been suspected for decades to negatively impact the circulatory system. METHODS: Apart from detailed anamnestic data, urinary levels of Cd and full blood levels of Pb and Hg were measured in 53 female (mean age: 68.04 7.03 years) and 111 male (mean age: 60.68 11.43 years) nonsmoking or never-smoking patients with angiographically verified and precisely quantified coronary artery disease (CAD). RESULTS: Although Cd was quantifiable in 68.3% of subjects, only 34.1% of these patients exceeded the critical 1 g/L Human Biomonitoring (HBM)-I level. Median Pb (20 g/L) and Hg (0.55 g/L) levels were lower than the HBM-I, as well as reference levels of Pb. Wine consumption was the main source for Pb, fish and wine consumption for Hg, and previous nicotine abuse for Cd. There was no correlation between Cd, Pb, or Hg and severity of CAD although severity correlated positively with atherosclerosis parameters (uric acid, creatinine, triglycerides, blood urea nitrogen, C-reactive protein) and negatively with high density lipoprotein cholesterol. CONCLUSION: Cd levels detected in CAD patients were high compared to German and European reference levels but it could not be proven that urine levels of Cd and blood levels of Hg or Pb played a major role in the genesis of CAD, particularly when compared to well-known biomarkers such as blood pressure, glucose, and lipids. | Blood and urine levels of heavy metal pollutants in female and male patients with coronary artery disease. | BACKGROUND: Heavy metal pollutants such as cadmium (Cd), lead (Pb), and mercury (Hg) are rarely the subjects of cardiovascular research although they have been suspected for decades to negatively impact the circulatory system. METHODS: Apart from detailed anamnestic data, urinary levels of Cd and full blood levels of Pb and Hg were measured in 53 female (mean age: 68.04 7.03 years) and 111 male (mean age: 60.68 11.43 years) nonsmoking or never-smoking patients with angiographically verified and precisely quantified coronary artery disease (CAD). RESULTS: Although Cd was quantifiable in 68.3% of subjects, only 34.1% of these patients exceeded the critical 1 g/L Human Biomonitoring (HBM)-I level. Median Pb (20 g/L) and Hg (0.55 g/L) levels were lower than the HBM-I, as well as reference levels of Pb. Wine consumption was the main source for Pb, fish and wine consumption for Hg, and previous nicotine abuse for Cd. There was no correlation between Cd, Pb, or Hg and severity of CAD although severity correlated positively with /"atherosclerosis"/ parameters (uric acid, creatinine, triglycerides, blood urea nitrogen, /"C-reactive protein"/) and negatively with high density lipoprotein cholesterol. CONCLUSION: Cd levels detected in CAD patients were high compared to German and European reference levels but it could not be proven that urine levels of Cd and blood levels of Hg or Pb played a major role in the genesis of CAD, particularly when compared to well-known biomarkers such as blood pressure, glucose, and lipids. | [
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"entity_id": "D050197",
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"text_name": "atherosclerosis"
} | No |
24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the ErbB pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, /"ERBB2"/, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the ErbB signaling pathway in /"GBC"/ pathogenesis. | [
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"text_name": "gallbladder carcinoma"
} | Yes |
24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the ErbB pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), /"KRAS"/ (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the ErbB signaling pathway in /"GBC"/ pathogenesis. | [
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} | Yes |
24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the /"ErbB"/ pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, /"ErbB"/ signaling (including /"EGFR"/, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with /"ErbB"/ pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the /"ErbB"/ signaling pathway in /"GBC"/ pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the ErbB pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include /"TP53"/ (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the ErbB signaling pathway in /"GBC"/ pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the ErbB pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and /"ERBB3"/ (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, /"ERBB3"/, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the ErbB signaling pathway in /"GBC"/ pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of /"gallbladder carcinoma"/ identifies recurrent mutations in the ErbB pathway. | Individuals with /"gallbladder carcinoma"/ (/"GBC"/), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for /"GBC"/ in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, /"ERBB4"/ and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the /"GBC"/ samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in /"GBC"/ and highlight the key role of the ErbB signaling pathway in /"GBC"/ pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), /"KRAS"/ (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the /"ErbB"/ pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, /"ErbB"/ signaling (including /"EGFR"/, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with /"ErbB"/ pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the /"ErbB"/ signaling pathway in GBC pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, /"ERBB4"/ and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the /"ErbB"/ pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, /"ErbB"/ signaling (including /"EGFR"/, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with /"ErbB"/ pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the /"ErbB"/ signaling pathway in GBC pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include /"TP53"/ (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | [
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24997986 | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 tumor-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, ErbB signaling (including EGFR, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with ErbB pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the ErbB signaling pathway in GBC pathogenesis. | Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the /"ErbB"/ pathway. | Individuals with gallbladder carcinoma (GBC), the most aggressive malignancy of the biliary tract, have a poor prognosis. Here we report the identification of somatic mutations for GBC in 57 /"tumor"/-normal pairs through a combination of exome sequencing and ultra-deep sequencing of cancer-related genes. The mutation pattern is defined by a dominant prevalence of C>T mutations at TCN sites. Genes with a significant frequency (false discovery rate (FDR)<0.05) of non-silent mutations include TP53 (47.1%), KRAS (7.8%) and ERBB3 (11.8%). Moreover, /"ErbB"/ signaling (including /"EGFR"/, ERBB2, ERBB3, ERBB4 and their downstream genes) is the most extensively mutated pathway, affecting 36.8% (21/57) of the GBC samples. Multivariate analyses further show that cases with /"ErbB"/ pathway mutations have a worse outcome (P=0.001). These findings provide insight into the somatic mutational landscape in GBC and highlight the key role of the /"ErbB"/ signaling pathway in GBC pathogenesis. | [
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25015659 | Initial biological qualification of SBDP-145 as a biomarker of compound-induced neurodegeneration in the rat. | Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which neurodegeneration was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP-145 concentration in rats with minimal to slight neurodegenerative lesions, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced neurodegeneration in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause neurodegeneration. | Initial biological qualification of SBDP-145 as a biomarker of compound-induced /"neurodegeneration"/ in the rat. | Detection of compound-related /"neurodegeneration"/ is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of /"neurodegeneration"/ in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid /"alpha-II spectrin"/ is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which /"neurodegeneration"/ was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP-145 concentration in rats with minimal to slight /"neurodegenerative lesions"/, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced /"neurodegeneration"/ in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause /"neurodegeneration"/. | [
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25015659 | Initial biological qualification of SBDP-145 as a biomarker of compound-induced neurodegeneration in the rat. | Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of neurotoxicity for use in non-clinical and clinical safety studies. Non-erythroid alpha-II spectrin is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which neurodegeneration was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP-145 concentration in rats with minimal to slight neurodegenerative lesions, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced neurodegeneration in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause neurodegeneration. | Initial biological qualification of SBDP-145 as a biomarker of compound-induced neurodegeneration in the rat. | Detection of compound-related neurodegeneration is currently limited to brain histopathology in veterinary species and functional measurements such as electroencephalography and observation of clinical signs in patients. The objective of these studies was to investigate whether concentrations of spectrin breakdown product 145 (SBDP-145) in cerebrospinal fluid (CSF) correlate with the severity of neurodegeneration in rats administered neurotoxic agents, as part of a longer term objective of developing in vivo biomarkers of /"neurotoxicity"/ for use in non-clinical and clinical safety studies. Non-erythroid /"alpha-II spectrin"/ is a cytoskeletal protein cleaved by the protease calpain when this enzyme is activated by dysregulation of calcium in injured cells. Calcium dysregulation is also associated with some toxicological responses in animals, and may be sufficient to activate neuronal calpain and produce SBDPs that can be released into CSF. Neurotoxicants (kainic acid, 2-chloropropionic acid, bromethalin, and pentylenetetrazole) known to affect different portions of the brain were administered to rats in dose-response and time-course studies in which neurodegeneration was measured by histopathology and SBDP-145 concentrations in CSF were measured by ELISA. We consistently observed >3-fold increases in SBDP-145 concentration in rats with minimal to slight neurodegenerative lesions, and 20 to 150-fold increases in animals with more severe lesions. In contrast, compounds that caused non-degenerative changes in central nervous system (CNS) did not increase SBDP-145 in CSF. These data support expanded use of SBDP-145 as a biomarker for monitoring compound-induced neurodegeneration in pre-clinical studies, and support the investigation of clinical applications of this biomarker to promote safe dosing of patients with compounds that have potential to cause neurodegeneration. | [
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25256182 | Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. | BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0 10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14 10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91 10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA. | Genome-wide association study of /"intracranial aneurysm"/ identifies a new association on chromosome 7. | BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to /"intracranial aneurysms"/ (/"IA"/) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 /"IA"/ cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (/"CDKN2BAS"/; rs10733376: P<1.0 10(-11)), in a gene previously associated with /"IA"/. A novel region on chromosome 7, near HDAC9, was associated with /"IA"/ (rs10230207; P=4.14 10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91 10(-10)). CONCLUSIONS: We detected a novel region associated with /"IA"/ susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and /"IA"/. | [
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} | Yes |
25256182 | Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. | BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0 10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14 10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91 10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA. | Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7. | BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0 10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near /"HDAC9"/, was associated with IA (rs10230207; P=4.14 10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91 10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with /"ischemic stroke"/ and the large vessel stroke occlusive subtype (including /"HDAC9"/), suggesting a possible genetic link between this stroke subtype and IA. | [
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2533336 | The role of the central serotonergic system in pilocarpine-induced seizures: receptor mechanisms. | Modification of central serotonergic transmission resulted in alterations of pilocarpine convulsive activity in male Wistar rats. Seizure activity was increased after pizotifen injection and the latency period to onset of convulsions was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in seizure protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced seizures. In conclusion, the present study suggests that the inhibition of pilocarpine-induced seizures may be mediated by stimulation of 5-HT1A and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals. | The role of the central serotonergic system in pilocarpine-induced /"seizures"/: receptor mechanisms. | Modification of central serotonergic transmission resulted in alterations of pilocarpine /"convulsive"/ activity in male Wistar rats. /"Seizure"/ activity was increased after pizotifen injection and the latency period to onset of /"convulsions"/ was shortened in animals pretreated with mianserine and quipazine. Stimulation of /"5-HT1A"/ receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in /"seizure"/ protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced /"seizures"/. In conclusion, the present study suggests that the inhibition of pilocarpine-induced /"seizures"/ may be mediated by stimulation of /"5-HT1A"/ and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals. | [
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} | Yes |
2533336 | The role of the central serotonergic system in pilocarpine-induced seizures: receptor mechanisms. | Modification of central serotonergic transmission resulted in alterations of pilocarpine convulsive activity in male Wistar rats. Seizure activity was increased after pizotifen injection and the latency period to onset of convulsions was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of 5-HT1B receptors with cyanopindolol resulted in seizure protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced seizures. In conclusion, the present study suggests that the inhibition of pilocarpine-induced seizures may be mediated by stimulation of 5-HT1A and by blockade of 5-HT1B receptors, located probably on the cholinergic terminals. | The role of the central serotonergic system in pilocarpine-induced /"seizures"/: receptor mechanisms. | Modification of central serotonergic transmission resulted in alterations of pilocarpine /"convulsive"/ activity in male Wistar rats. /"Seizure"/ activity was increased after pizotifen injection and the latency period to onset of /"convulsions"/ was shortened in animals pretreated with mianserine and quipazine. Stimulation of 5-HT1A receptors with 8-hydroxy-di-N,N-propylaminotetralin (8-OH-DPAT) and blockade of /"5-HT1B"/ receptors with cyanopindolol resulted in /"seizure"/ protection. Intracerebroventricular injections of 5,6-dihydroxytryptamine (5,6-DHT) did not change the protective effect of cyanopindolol. Other agents specifically affecting serotonergic receptors, the agonists 1-(3-chlorophenyl)piperazine (mCPP) and 5-methoxytryptamine (5-MT) and the antagonists spiperone, metergoline, methysergide, cyproheptadine and metoclopramide, did not influence pilocarpine-induced /"seizures"/. In conclusion, the present study suggests that the inhibition of pilocarpine-induced /"seizures"/ may be mediated by stimulation of 5-HT1A and by blockade of /"5-HT1B"/ receptors, located probably on the cholinergic terminals. | [
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25356585 | Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma. | BACKGROUND: Cancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in glioblastoma multiforme (GBM), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression. METHODS: Comparisons were performed between the transcriptomics of primary GBM tumors and unmatched non-malignant brain tissue, and between GBM cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells. RESULTS: Of the 311 protease genes identified to be differentially expressed in both GBM tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues transferrin receptor (TFRC) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and cathepsin K (CTSK), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in GBM cell lines. CTSK overexpression was validated using RT-qPCR in GBM tissues as well. Cathepsin K immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of cathepsin K were overexpressed in GBM tissues and cells. CONCLUSIONS: The presence of high levels of inactive proforms of cathepsin K in GBM tissues and cells indicate that in GBM the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role. | Expression analysis of all protease genes reveals /"cathepsin K"/ to be overexpressed in /"glioblastoma"/. | BACKGROUND: Cancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in /"glioblastoma multiforme"/ (/"GBM"/), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression. METHODS: Comparisons were performed between the transcriptomics of primary /"GBM tumors"/ and unmatched non-malignant brain tissue, and between /"GBM"/ cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells. RESULTS: Of the 311 protease genes identified to be differentially expressed in both /"GBM"/ tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues transferrin receptor (TFRC) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and /"cathepsin K"/ (/"CTSK"/), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in /"GBM"/ cell lines. /"CTSK"/ overexpression was validated using RT-qPCR in /"GBM"/ tissues as well. /"Cathepsin K"/ immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of /"cathepsin K"/ were overexpressed in /"GBM"/ tissues and cells. CONCLUSIONS: The presence of high levels of inactive proforms of /"cathepsin K"/ in /"GBM"/ tissues and cells indicate that in /"GBM"/ the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role. | [
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25356585 | Expression analysis of all protease genes reveals cathepsin K to be overexpressed in glioblastoma. | BACKGROUND: Cancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in glioblastoma multiforme (GBM), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression. METHODS: Comparisons were performed between the transcriptomics of primary GBM tumors and unmatched non-malignant brain tissue, and between GBM cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells. RESULTS: Of the 311 protease genes identified to be differentially expressed in both GBM tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues transferrin receptor (TFRC) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and cathepsin K (CTSK), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in GBM cell lines. CTSK overexpression was validated using RT-qPCR in GBM tissues as well. Cathepsin K immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of cathepsin K were overexpressed in GBM tissues and cells. CONCLUSIONS: The presence of high levels of inactive proforms of cathepsin K in GBM tissues and cells indicate that in GBM the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role. | Expression analysis of all protease genes reveals cathepsin K to be overexpressed in /"glioblastoma"/. | BACKGROUND: Cancer genome and transcriptome analyses advanced our understanding of cancer biology. We performed transcriptome analysis of all known genes of peptidases also called proteases and their endogenous inhibitors in /"glioblastoma multiforme"/ (/"GBM"/), which is one of the most aggressive and deadly types of brain cancers, where unbalanced proteolysis is associated with tumor progression. METHODS: Comparisons were performed between the transcriptomics of primary /"GBM tumors"/ and unmatched non-malignant brain tissue, and between /"GBM"/ cell lines (U87-MG and U373) and a control human astrocyte cell line (NHA). Publicly-available data sets and our own datasets were integrated and normalized using bioinformatics tools to reveal protease and protease inhibitor genes with deregulated expression in both malignant versus non-malignant tissues and cells. RESULTS: Of the 311 protease genes identified to be differentially expressed in both /"GBM"/ tissues and cells, 5 genes were highly overexpressed, 2 genes coding for non-peptidase homologues /"transferrin receptor"/ (/"TFRC"/) and G protein-coupled receptor 56 (GPR56), as well as 3 genes coding for the proteases endoplasmic reticulum aminopeptidase 2 (ERAP2), glutamine-fructose-6-phosphate transaminase 2 (GFPT2) and cathepsin K (CTSK), whereas one gene, that of the serine protease carboxypeptidase E (CPE) was strongly reduced in expression. Seventy five protease inhibitor genes were differentially expressed, of which 3 genes were highly overexpressed, the genes coding for stefin B (CSTB), peptidase inhibitor 3 (PI3 also named elafin) and CD74. Seven out of 8 genes (except CSTB) were validated using RT-qPCR in /"GBM"/ cell lines. CTSK overexpression was validated using RT-qPCR in /"GBM"/ tissues as well. Cathepsin K immunohistochemical staining and western blotting showed that only proteolytically inactive proforms of cathepsin K were overexpressed in /"GBM"/ tissues and cells. CONCLUSIONS: The presence of high levels of inactive proforms of cathepsin K in /"GBM"/ tissues and cells indicate that in /"GBM"/ the proteolytic/collagenolytic role is not its primary function but it plays rather a different yet unknown role. | [
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25466283 | Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. | Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS. | Loss-of-Function Mutations in /"WDR73"/ Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: /"Galloway-Mowat Syndrome"/. | /"Galloway-Mowat syndrome"/ is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified /"WDR73"/ as a gene in which mutations cause /"Galloway-Mowat syndrome"/ in two unrelated families. /"WDR73"/ encodes a WD40-repeat-containing protein of unknown function. Here, we show that /"WDR73"/ was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and /"WDR73"/-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that /"WDR73"/ plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, /"WDR73"/ mutations cause /"Galloway-Mowat syndrome"/ in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. /"WDR73"/ is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS. | [
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25466283 | Loss-of-Function Mutations in WDR73 Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. | Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified WDR73 as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. WDR73 encodes a WD40-repeat-containing protein of unknown function. Here, we show that WDR73 was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and WDR73-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that WDR73 plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, WDR73 mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe intellectual disability, and homogenous brain MRI features. WDR73 is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS. | Loss-of-Function Mutations in /"WDR73"/ Are Responsible for Microcephaly and Steroid-Resistant Nephrotic Syndrome: Galloway-Mowat Syndrome. | Galloway-Mowat syndrome is a rare autosomal-recessive condition characterized by nephrotic syndrome associated with microcephaly and neurological impairment. Through a combination of autozygosity mapping and whole-exome sequencing, we identified /"WDR73"/ as a gene in which mutations cause Galloway-Mowat syndrome in two unrelated families. /"WDR73"/ encodes a WD40-repeat-containing protein of unknown function. Here, we show that /"WDR73"/ was present in the brain and kidney and was located diffusely in the cytoplasm during interphase but relocalized to spindle poles and astral microtubules during mitosis. Fibroblasts from one affected child and /"WDR73"/-depleted podocytes displayed abnormal nuclear morphology, low cell viability, and alterations of the microtubule network. These data suggest that /"WDR73"/ plays a crucial role in the maintenance of cell architecture and cell survival. Altogether, /"WDR73"/ mutations cause Galloway-Mowat syndrome in a particular subset of individuals presenting with late-onset nephrotic syndrome, postnatal microcephaly, severe /"intellectual disability"/, and homogenous brain MRI features. /"WDR73"/ is another example of a gene involved in a disease affecting both the kidney glomerulus and the CNS. | [
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26095815 | Trophoblast expression of the minor histocompatibility antigen HA-1 is regulated by oxygen and is increased in placentas from preeclamptic women. | INTRODUCTION: Maternal T-cells reactive towards paternally inherited fetal minor histocompatibility antigens are expanded during pregnancy. Placental trophoblast cells express at least four fetal antigens, including human minor histocompatibility antigen 1 (HA-1). We investigated oxygen as a potential regulator of HA-1 and whether HA-1 expression is altered in preeclamptic placentas. METHODS: Expression and regulation of HA-1 mRNA and protein were examined by qRT-PCR and immunohistochemistry, using first, second, and third trimester placentas, first trimester placental explant cultures, and term purified cytotrophoblast cells. Low oxygen conditions were achieved by varying ambient oxygen, and were mimicked using cobalt chloride. HA-1 mRNA and protein expression levels were evaluated in preeclamptic and control placentas. RESULTS: HA-1 protein expression was higher in the syncytiotrophoblast of first trimester as compared to second trimester and term placentas (P<0.01). HA-1 mRNA was increased in cobalt chloride-treated placental explants and purified cytotrophoblast cells (P = 0.04 and P<0.01, respectively) and in purified cytotrophoblast cells cultured under 2% as compared to 8% and 21% oxygen (P<0.01). HA-1 mRNA expression in preeclamptic vs. control placentas was increased 3.3-fold (P = 0.015). HA-1 protein expression was increased in syncytial nuclear aggregates and the syncytiotrophoblast of preeclamptic vs. control placentas (P = 0.02 and 0.03, respectively). DISCUSSION: Placental HA-1 expression is regulated by oxygen and is increased in the syncytial nuclear aggregates and syncytiotrophoblast of preeclamptic as compared to control placentas. Increased HA-1 expression, combined with increased preeclamptic syncytiotrophoblast deportation, provides a novel potential mechanism for exposure of the maternal immune system to increased fetal antigenic load during preeclampsia. | Trophoblast expression of the /"minor histocompatibility antigen HA-1"/ is regulated by oxygen and is increased in placentas from preeclamptic women. | INTRODUCTION: Maternal T-cells reactive towards paternally inherited fetal minor histocompatibility antigens are expanded during pregnancy. Placental trophoblast cells express at least four fetal antigens, including human minor histocompatibility antigen 1 (/"HA-1"/). We investigated oxygen as a potential regulator of /"HA-1"/ and whether /"HA-1"/ expression is altered in preeclamptic placentas. METHODS: Expression and regulation of /"HA-1"/ mRNA and protein were examined by qRT-PCR and immunohistochemistry, using first, second, and third trimester placentas, first trimester placental explant cultures, and term purified cytotrophoblast cells. Low oxygen conditions were achieved by varying ambient oxygen, and were mimicked using cobalt chloride. /"HA-1"/ mRNA and protein expression levels were evaluated in preeclamptic and control placentas. RESULTS: /"HA-1"/ protein expression was higher in the syncytiotrophoblast of first trimester as compared to second trimester and term placentas (P<0.01). /"HA-1"/ mRNA was increased in cobalt chloride-treated placental explants and purified cytotrophoblast cells (P = 0.04 and P<0.01, respectively) and in purified cytotrophoblast cells cultured under 2% as compared to 8% and 21% oxygen (P<0.01). /"HA-1"/ mRNA expression in preeclamptic vs. control placentas was increased 3.3-fold (P = 0.015). /"HA-1"/ protein expression was increased in syncytial nuclear aggregates and the syncytiotrophoblast of preeclamptic vs. control placentas (P = 0.02 and 0.03, respectively). DISCUSSION: Placental /"HA-1"/ expression is regulated by oxygen and is increased in the syncytial nuclear aggregates and syncytiotrophoblast of preeclamptic as compared to control placentas. Increased /"HA-1"/ expression, combined with increased preeclamptic syncytiotrophoblast deportation, provides a novel potential mechanism for exposure of the maternal immune system to increased fetal antigenic load during /"preeclampsia"/. | [
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26141506 | Citronellol, a natural acyclic monoterpene, attenuates mechanical hyperalgesia response in mice: Evidence of the spinal cord lamina I inhibition. | We evaluated the anti-hyperalgesic effect of citronellol (CT) and investigated the spinal cord lamina I involvement in this effect. Male mice were pre-treated with CT (25, 50 and 100mg/kg, i.p.), indomethacin (10mg/kg, i.p.), dipyrone (60mg/kg, i.p.) or vehicle (saline+Tween 80 0.2%). Thirty minutes after the treatment, 20 L of carrageenan (CG; 300 g/paw), PGE2 (100ng/paw), dopamine (DA; 30 g/paw) or TNF-a (100pg/paw) were injected into the hind paw subplantar region and the mechanical threshold was evaluated with an electronic anesthesiometer. The CT effect on edema formation was evaluated after the right paw subplantar injection of CG (40 L; 1%) through the plethysmometer apparatus. To evaluate the CT action on the spinal cord, the animals were treated with CT (100mg/kg; i.p.) or vehicle (Saline+Tween 80 0.2%; i.p.) and, after 30min, 20 L of CG (300 g/paw; i.pl.) was injected. Ninety minutes after the treatment, the animals were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. CT administration produced a significantly reduction (p<0.05) in the mechanical hyperalgesia induced by CG, TNF-a, PGE2 and DA when compared with control group. The treatment with CT also significantly (p<0.05) decreased the paw edema. The immunofluorescence showed that the CT decrease significantly (p<0.05) the spinal cord lamina I activation. Thus, our results provide that CT attenuates the hyperalgesia, at least in part, through the spinal cord lamina I inhibition. | Citronellol, a natural acyclic monoterpene, attenuates mechanical /"hyperalgesia"/ response in mice: Evidence of the spinal cord lamina I inhibition. | We evaluated the anti-/"hyperalgesic"/ effect of citronellol (CT) and investigated the spinal cord lamina I involvement in this effect. Male mice were pre-treated with CT (25, 50 and 100mg/kg, i.p.), indomethacin (10mg/kg, i.p.), dipyrone (60mg/kg, i.p.) or vehicle (saline+Tween 80 0.2%). Thirty minutes after the treatment, 20 L of carrageenan (CG; 300 g/paw), PGE2 (100ng/paw), dopamine (DA; 30 g/paw) or /"TNF-a"/ (100pg/paw) were injected into the hind paw subplantar region and the mechanical threshold was evaluated with an electronic anesthesiometer. The CT effect on edema formation was evaluated after the right paw subplantar injection of CG (40 L; 1%) through the plethysmometer apparatus. To evaluate the CT action on the spinal cord, the animals were treated with CT (100mg/kg; i.p.) or vehicle (Saline+Tween 80 0.2%; i.p.) and, after 30min, 20 L of CG (300 g/paw; i.pl.) was injected. Ninety minutes after the treatment, the animals were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. CT administration produced a significantly reduction (p<0.05) in the mechanical /"hyperalgesia"/ induced by CG, /"TNF-a"/, PGE2 and DA when compared with control group. The treatment with CT also significantly (p<0.05) decreased the paw edema. The immunofluorescence showed that the CT decrease significantly (p<0.05) the spinal cord lamina I activation. Thus, our results provide that CT attenuates the /"hyperalgesia"/, at least in part, through the spinal cord lamina I inhibition. | [
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26141506 | Citronellol, a natural acyclic monoterpene, attenuates mechanical hyperalgesia response in mice: Evidence of the spinal cord lamina I inhibition. | We evaluated the anti-hyperalgesic effect of citronellol (CT) and investigated the spinal cord lamina I involvement in this effect. Male mice were pre-treated with CT (25, 50 and 100mg/kg, i.p.), indomethacin (10mg/kg, i.p.), dipyrone (60mg/kg, i.p.) or vehicle (saline+Tween 80 0.2%). Thirty minutes after the treatment, 20 L of carrageenan (CG; 300 g/paw), PGE2 (100ng/paw), dopamine (DA; 30 g/paw) or TNF-a (100pg/paw) were injected into the hind paw subplantar region and the mechanical threshold was evaluated with an electronic anesthesiometer. The CT effect on edema formation was evaluated after the right paw subplantar injection of CG (40 L; 1%) through the plethysmometer apparatus. To evaluate the CT action on the spinal cord, the animals were treated with CT (100mg/kg; i.p.) or vehicle (Saline+Tween 80 0.2%; i.p.) and, after 30min, 20 L of CG (300 g/paw; i.pl.) was injected. Ninety minutes after the treatment, the animals were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for Fos protein. CT administration produced a significantly reduction (p<0.05) in the mechanical hyperalgesia induced by CG, TNF-a, PGE2 and DA when compared with control group. The treatment with CT also significantly (p<0.05) decreased the paw edema. The immunofluorescence showed that the CT decrease significantly (p<0.05) the spinal cord lamina I activation. Thus, our results provide that CT attenuates the hyperalgesia, at least in part, through the spinal cord lamina I inhibition. | Citronellol, a natural acyclic monoterpene, attenuates mechanical /"hyperalgesia"/ response in mice: Evidence of the spinal cord lamina I inhibition. | We evaluated the anti-/"hyperalgesic"/ effect of citronellol (CT) and investigated the spinal cord lamina I involvement in this effect. Male mice were pre-treated with CT (25, 50 and 100mg/kg, i.p.), indomethacin (10mg/kg, i.p.), dipyrone (60mg/kg, i.p.) or vehicle (saline+Tween 80 0.2%). Thirty minutes after the treatment, 20 L of carrageenan (CG; 300 g/paw), PGE2 (100ng/paw), dopamine (DA; 30 g/paw) or TNF-a (100pg/paw) were injected into the hind paw subplantar region and the mechanical threshold was evaluated with an electronic anesthesiometer. The CT effect on edema formation was evaluated after the right paw subplantar injection of CG (40 L; 1%) through the plethysmometer apparatus. To evaluate the CT action on the spinal cord, the animals were treated with CT (100mg/kg; i.p.) or vehicle (Saline+Tween 80 0.2%; i.p.) and, after 30min, 20 L of CG (300 g/paw; i.pl.) was injected. Ninety minutes after the treatment, the animals were perfused, the lumbar spinal cord collected, crioprotected, cut and submitted in an immunofluorescence protocol for /"Fos"/ protein. CT administration produced a significantly reduction (p<0.05) in the mechanical /"hyperalgesia"/ induced by CG, TNF-a, PGE2 and DA when compared with control group. The treatment with CT also significantly (p<0.05) decreased the paw edema. The immunofluorescence showed that the CT decrease significantly (p<0.05) the spinal cord lamina I activation. Thus, our results provide that CT attenuates the /"hyperalgesia"/, at least in part, through the spinal cord lamina I inhibition. | [
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26437028 | MMP21 is mutated in human heterotaxy and is required for normal left-right asymmetry in vertebrates. | UNASSIGNED: Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in MMP21 (encoding matrix metallopeptidase 21) in nine index cases with heterotaxy. In addition, Mmp21-mutant mice and mmp21-morphant zebrafish displayed heterotaxy and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates. | /"MMP21"/ is mutated in human /"heterotaxy"/ and is required for normal left-right asymmetry in vertebrates. | UNASSIGNED: Heterotaxy results from a failure to establish normal left-right asymmetry early in embryonic development. By whole-exome sequencing, whole-genome sequencing and high-throughput cohort resequencing, we identified recessive mutations in /"MMP21"/ (encoding /"matrix metallopeptidase 21"/) in nine index cases with /"heterotaxy"/. In addition, /"Mmp21"/-mutant mice and /"mmp21"/-morphant zebrafish displayed /"heterotaxy"/ and abnormal cardiac looping, respectively, suggesting a new role for extracellular matrix remodeling in the establishment of laterality in vertebrates. | [
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} | Yes |
6889048 | Estrogen treatment of tall girls: risk of thrombosis? | In 34 girls who were treated with large doses of ethinylestradiol because of expected excessive tall stature, antithrombin activity in the blood was followed before, during, and after treatment. All girls showed lower levels of antithrombin during treatment than before or after estrogen administration; the mean concentration during treatment was at or below the lower limit of control values (-2 SD). In three girls, the antithrombin levels were so low that the medication was withdrawn. There was no difference between the mean levels of antithrombin activity in the three groups treated with 0.25, 0.50, or 1.0 mg of ethinylestradiol. Deficiency of antithrombin is known to be associated with an increased risk of thrombosis. Therefore, antithrombin concentrations in blood should be determined before and during treatment with large doses of estrogens. | Estrogen treatment of tall girls: risk of /"thrombosis"/? | In 34 girls who were treated with large doses of ethinylestradiol because of expected excessive tall stature, /"antithrombin"/ activity in the blood was followed before, during, and after treatment. All girls showed lower levels of /"antithrombin"/ during treatment than before or after estrogen administration; the mean concentration during treatment was at or below the lower limit of control values (-2 SD). In three girls, the /"antithrombin"/ levels were so low that the medication was withdrawn. There was no difference between the mean levels of /"antithrombin"/ activity in the three groups treated with 0.25, 0.50, or 1.0 mg of ethinylestradiol. Deficiency of /"antithrombin"/ is known to be associated with an increased risk of /"thrombosis"/. Therefore, /"antithrombin"/ concentrations in blood should be determined before and during treatment with large doses of estrogens. | [
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6991409 | Suppression of stimulated plasma renin by clonidine in the dog. | The mechanism by which clonidine suppresses plasma renin activity (PRA) was investigated in dogs anesthetized with pentobarbital. Injection of clonidine (1 micrograms/kg) into the cisterna magna decreased PRA from levels stimulated by prior hemorrhage into a blood reservoir to reduce mean blood pressure by 25% (21.7 ng/ml/hr +/- 6.6 SE leads to 11.1 ng/ml/hr +/- 2.4 SE; p less than 0.05). Clonidine reduced heart rate but mean arterial pressure remained constant due to fluid movement between the reservoir and the arterial circulation of the dog. These effects could not be attributed to leakage of clonidine from the cerebrospinal fluid since intravenous administration of the same dose had no effect on PRA. In animals bilaterally splanchnicotomized at the level of the diaphragm, elevated PRA was not reduced by intracisternal clonidine. When return of reservoir fluid was prevented, animals became hypotensive after central clonidine and renin tended to increase. These results indicate that clonidine reduces stimulated renin by a central mechanism that is dependent upon the integrity of the sympathetic innervation of the kidney. Other stimuli for renin release may override the inhibitory effect of central clonidine. | Suppression of stimulated plasma /"renin"/ by clonidine in the dog. | The mechanism by which clonidine suppresses plasma /"renin"/ activity (PRA) was investigated in dogs anesthetized with pentobarbital. Injection of clonidine (1 micrograms/kg) into the cisterna magna decreased PRA from levels stimulated by prior /"hemorrhage"/ into a blood reservoir to reduce mean blood pressure by 25% (21.7 ng/ml/hr +/- 6.6 SE leads to 11.1 ng/ml/hr +/- 2.4 SE; p less than 0.05). Clonidine reduced heart rate but mean arterial pressure remained constant due to fluid movement between the reservoir and the arterial circulation of the dog. These effects could not be attributed to leakage of clonidine from the cerebrospinal fluid since intravenous administration of the same dose had no effect on PRA. In animals bilaterally splanchnicotomized at the level of the diaphragm, elevated PRA was not reduced by intracisternal clonidine. When return of reservoir fluid was prevented, animals became hypotensive after central clonidine and /"renin"/ tended to increase. These results indicate that clonidine reduces stimulated /"renin"/ by a central mechanism that is dependent upon the integrity of the sympathetic innervation of the kidney. Other stimuli for /"renin"/ release may override the inhibitory effect of central clonidine. | [
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6991409 | Suppression of stimulated plasma renin by clonidine in the dog. | The mechanism by which clonidine suppresses plasma renin activity (PRA) was investigated in dogs anesthetized with pentobarbital. Injection of clonidine (1 micrograms/kg) into the cisterna magna decreased PRA from levels stimulated by prior hemorrhage into a blood reservoir to reduce mean blood pressure by 25% (21.7 ng/ml/hr +/- 6.6 SE leads to 11.1 ng/ml/hr +/- 2.4 SE; p less than 0.05). Clonidine reduced heart rate but mean arterial pressure remained constant due to fluid movement between the reservoir and the arterial circulation of the dog. These effects could not be attributed to leakage of clonidine from the cerebrospinal fluid since intravenous administration of the same dose had no effect on PRA. In animals bilaterally splanchnicotomized at the level of the diaphragm, elevated PRA was not reduced by intracisternal clonidine. When return of reservoir fluid was prevented, animals became hypotensive after central clonidine and renin tended to increase. These results indicate that clonidine reduces stimulated renin by a central mechanism that is dependent upon the integrity of the sympathetic innervation of the kidney. Other stimuli for renin release may override the inhibitory effect of central clonidine. | Suppression of stimulated plasma /"renin"/ by clonidine in the dog. | The mechanism by which clonidine suppresses plasma /"renin"/ activity (PRA) was investigated in dogs anesthetized with pentobarbital. Injection of clonidine (1 micrograms/kg) into the cisterna magna decreased PRA from levels stimulated by prior hemorrhage into a blood reservoir to reduce mean blood pressure by 25% (21.7 ng/ml/hr +/- 6.6 SE leads to 11.1 ng/ml/hr +/- 2.4 SE; p less than 0.05). Clonidine reduced heart rate but mean arterial pressure remained constant due to fluid movement between the reservoir and the arterial circulation of the dog. These effects could not be attributed to leakage of clonidine from the cerebrospinal fluid since intravenous administration of the same dose had no effect on PRA. In animals bilaterally splanchnicotomized at the level of the diaphragm, elevated PRA was not reduced by intracisternal clonidine. When return of reservoir fluid was prevented, animals became /"hypotensive"/ after central clonidine and /"renin"/ tended to increase. These results indicate that clonidine reduces stimulated /"renin"/ by a central mechanism that is dependent upon the integrity of the sympathetic innervation of the kidney. Other stimuli for /"renin"/ release may override the inhibitory effect of central clonidine. | [
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7581378 | Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | /"Crouzon syndrome"/: mutations in two spliceoforms of /"FGFR2"/ and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the /"fibroblast growth factor receptor 2"/ (/"FGFR2"/) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the /"FGFR2"/ gene have been reported to cause both /"Pfeiffer and Crouzon syndrome"/ phenotypes. We now report the finding of a mutation in exon IIIc of the /"FGFR2"/ gene in a kindred affected with /"Crouzon syndrome"/ (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the /"FGFR2"/ protein. This exon is common to both the /"FGFR2"/ and the /"KGFR"/ spliceoforms of the /"FGFR2"/ gene, unlike all previously reported Crouzon mutations, which have been found only in the /"FGFR2"/ spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in /"FGFR2"/ itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | [
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] | {
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} | {
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"entity_id": "D003394",
"entity_type": "Disease",
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} | Yes |
7581378 | Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | Crouzon syndrome: mutations in two spliceoforms of /"FGFR2"/ and a common point mutation shared with /"Jackson-Weiss syndrome"/. | Dominant mutations in the /"fibroblast growth factor receptor 2"/ (/"FGFR2"/) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the /"FGFR2"/ gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the /"FGFR2"/ gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with /"Jackson-Weiss syndrome"/. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the /"FGFR2"/ protein. This exon is common to both the /"FGFR2"/ and the /"KGFR"/ spliceoforms of the /"FGFR2"/ gene, unlike all previously reported Crouzon mutations, which have been found only in the /"FGFR2"/ spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in /"FGFR2"/ itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | [
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7581378 | Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | Crouzon syndrome: mutations in two spliceoforms of /"FGFR2"/ and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the /"fibroblast growth factor receptor 2"/ (/"FGFR2"/) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, /"Pfeiffer, and Apert syndromes"/. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the /"FGFR2"/ gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the /"FGFR2"/ gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the /"FGFR2"/ protein. This exon is common to both the /"FGFR2"/ and the /"KGFR"/ spliceoforms of the /"FGFR2"/ gene, unlike all previously reported Crouzon mutations, which have been found only in the /"FGFR2"/ spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in /"FGFR2"/ itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | [
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7581378 | Crouzon syndrome: mutations in two spliceoforms of FGFR2 and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the fibroblast growth factor receptor 2 (FGFR2) gene have been recently identified as causes of four phenotypically distinct craniosynostosis syndromes, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the craniosynostosis syndromes is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the FGFR2 gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the FGFR2 gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the FGFR2 protein. This exon is common to both the FGFR2 and the KGFR spliceoforms of the FGFR2 gene, unlike all previously reported Crouzon mutations, which have been found only in the FGFR2 spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these craniosynostosis syndromes. The data implies that second-site mutations in FGFR2 itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of craniosynostosis syndromes. | Crouzon syndrome: mutations in two spliceoforms of /"FGFR2"/ and a common point mutation shared with Jackson-Weiss syndrome. | Dominant mutations in the /"fibroblast growth factor receptor 2"/ (/"FGFR2"/) gene have been recently identified as causes of four phenotypically distinct /"craniosynostosis syndromes"/, including Crouzon, Jackson-Weiss, Pfeiffer, and Apert syndromes. These data suggest that the genetics of the /"craniosynostosis syndromes"/ is more complex than would be expected from their simple autosomal-dominant inheritance pattern. Identical mutations in the /"FGFR2"/ gene have been reported to cause both Pfeiffer and Crouzon syndrome phenotypes. We now report the finding of a mutation in exon IIIc of the /"FGFR2"/ gene in a kindred affected with Crouzon syndrome (C1043 to G; Ala344Gly) that is identical to the mutation previously associated with Jackson-Weiss syndrome. We also report finding in a Crouzon kindred a mutation in the 3' end of exon IIIu (formerly referred to as exon 5, exon 7, or exon U) (A878 to C; Gln289Pro) which encodes the amino terminal portion of the Ig-like III domain of the /"FGFR2"/ protein. This exon is common to both the /"FGFR2"/ and the /"KGFR"/ spliceoforms of the /"FGFR2"/ gene, unlike all previously reported Crouzon mutations, which have been found only in the /"FGFR2"/ spliceoform. These findings reveal further unexpected complexity in the molecular genetics of these /"craniosynostosis syndromes"/. The data implies that second-site mutations in /"FGFR2"/ itself (outside of exon IIIc) or in other genes may determine specific aspects of the phenotypes of /"craniosynostosis syndromes"/. | [
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7680712 | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with /"HIV-associated lymphoma"/ has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with /"granulocyte-macrophage colony stimulating factor"/ (/"GMCSF"/) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of /"GMCSF"/. Eight patients received standard dose m-BACOD plus /"GMCSF"/ without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with /"HIV-associated lymphoma"/ using standard dose m-BACOD plus /"GMCSF"/, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | [
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7680712 | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated /"non-Hodgkin's lymphoma"/. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with /"granulocyte-macrophage colony stimulating factor"/ (/"GMCSF"/) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of /"GMCSF"/. Eight patients received standard dose m-BACOD plus /"GMCSF"/ without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus /"GMCSF"/, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | [
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7680712 | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe /"toxicity"/, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the /"toxicity"/ of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with /"granulocyte-macrophage colony stimulating factor"/ (/"GMCSF"/) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of /"GMCSF"/. Eight patients received standard dose m-BACOD plus /"GMCSF"/ without experiencing dose-limiting hematologic /"toxicity"/, although significant nonhematologic /"toxicity"/ was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus /"GMCSF"/, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | [
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} | No |
7680712 | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe toxicity, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the toxicity of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with granulocyte-macrophage colony stimulating factor (GMCSF) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of GMCSF. Eight patients received standard dose m-BACOD plus GMCSF without experiencing dose-limiting hematologic toxicity, although significant nonhematologic toxicity was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus GMCSF, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | Phase I trial of m-BACOD and granulocyte macrophage colony stimulating factor in HIV-associated non-Hodgkin's lymphoma. | The use of full-dose intensive regimens of chemotherapy in patients with HIV-associated lymphoma has often resulted in severe /"toxicity"/, treatment delay, and reduced subsequent dosing. We conducted a Phase I trial to evaluate the /"toxicity"/ of the combination of m-BACOD (methotrexate, Bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone) with /"granulocyte-macrophage colony stimulating factor"/ (/"GMCSF"/) in these patients. A total of 17 patients were entered and treated at three dose levels of m-BACOD in combination with a fixed dose of /"GMCSF"/. Eight patients received standard dose m-BACOD plus /"GMCSF"/ without experiencing dose-limiting hematologic /"toxicity"/, although significant nonhematologic /"toxicity"/ was seen. We conclude that it is feasible to treat patients with HIV-associated lymphoma using standard dose m-BACOD plus /"GMCSF"/, but further study is needed to determine whether full-dose regimens improve survival when compared with reduced dose regimens in these individuals. | [
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7706461 | Glanzmann thrombasthenia resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. | To gain insight into region of the platelet GPIIb-IIIa complex involved in receptor biogenesis and function, we examined the biochemical properties of a defective GPIIb-IIIa complex from patient suffering from type II Glanzmann thrombasthenia. Flow cytometric as well as immunoblot analysis of patient platelets showed significantly reduced levels of GPIIb and GPIIIa compared with a normal control. Patient platelets, however, retained the ability to retract a fibrin clot. Sequence analysis of PCR-amplified platelet GPIIb mRNA revealed an Arg327-->His amino acid substitution between the second and third calcium-binding domains of the GPIIb heavy chain, a residue that is highly conserved among integrin alpha-subunits. The recombinant His327 form of GPIIb was found to be fully capable of associating with GPIIIa, therefore the role of the calcium-binding domains in intersubunit association was further examined by constructing amino-terminal segments of GPIIb that ended before the first, second, and third calcium-binding domains. All three fragments were found to associate with GPIIIa, demonstrating that the calcium-binding domains of GPIIb are not necessary for initial complex formation. Regions amino-terminal to the calcium-binding domains of GPIIb may play a heretofore unappreciated role in integrin subunit association. | /"Glanzmann thrombasthenia"/ resulting from a single amino acid substitution between the second and third calcium-binding domains of /"GPIIb"/. Role of the /"GPIIb"/ amino terminus in integrin subunit association. | To gain insight into region of the platelet /"GPIIb"/-IIIa complex involved in receptor biogenesis and function, we examined the biochemical properties of a defective /"GPIIb"/-IIIa complex from patient suffering from /"type II Glanzmann thrombasthenia"/. Flow cytometric as well as immunoblot analysis of patient platelets showed significantly reduced levels of /"GPIIb"/ and GPIIIa compared with a normal control. Patient platelets, however, retained the ability to retract a fibrin clot. Sequence analysis of PCR-amplified platelet /"GPIIb"/ mRNA revealed an Arg327-->His amino acid substitution between the second and third calcium-binding domains of the /"GPIIb"/ heavy chain, a residue that is highly conserved among integrin alpha-subunits. The recombinant His327 form of /"GPIIb"/ was found to be fully capable of associating with GPIIIa, therefore the role of the calcium-binding domains in intersubunit association was further examined by constructing amino-terminal segments of /"GPIIb"/ that ended before the first, second, and third calcium-binding domains. All three fragments were found to associate with GPIIIa, demonstrating that the calcium-binding domains of /"GPIIb"/ are not necessary for initial complex formation. Regions amino-terminal to the calcium-binding domains of /"GPIIb"/ may play a heretofore unappreciated role in integrin subunit association. | [
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} | Yes |
7706461 | Glanzmann thrombasthenia resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. | To gain insight into region of the platelet GPIIb-IIIa complex involved in receptor biogenesis and function, we examined the biochemical properties of a defective GPIIb-IIIa complex from patient suffering from type II Glanzmann thrombasthenia. Flow cytometric as well as immunoblot analysis of patient platelets showed significantly reduced levels of GPIIb and GPIIIa compared with a normal control. Patient platelets, however, retained the ability to retract a fibrin clot. Sequence analysis of PCR-amplified platelet GPIIb mRNA revealed an Arg327-->His amino acid substitution between the second and third calcium-binding domains of the GPIIb heavy chain, a residue that is highly conserved among integrin alpha-subunits. The recombinant His327 form of GPIIb was found to be fully capable of associating with GPIIIa, therefore the role of the calcium-binding domains in intersubunit association was further examined by constructing amino-terminal segments of GPIIb that ended before the first, second, and third calcium-binding domains. All three fragments were found to associate with GPIIIa, demonstrating that the calcium-binding domains of GPIIb are not necessary for initial complex formation. Regions amino-terminal to the calcium-binding domains of GPIIb may play a heretofore unappreciated role in integrin subunit association. | /"Glanzmann thrombasthenia"/ resulting from a single amino acid substitution between the second and third calcium-binding domains of GPIIb. Role of the GPIIb amino terminus in integrin subunit association. | To gain insight into region of the platelet GPIIb-IIIa complex involved in receptor biogenesis and function, we examined the biochemical properties of a defective GPIIb-IIIa complex from patient suffering from /"type II Glanzmann thrombasthenia"/. Flow cytometric as well as immunoblot analysis of patient platelets showed significantly reduced levels of GPIIb and /"GPIIIa"/ compared with a normal control. Patient platelets, however, retained the ability to retract a fibrin clot. Sequence analysis of PCR-amplified platelet GPIIb mRNA revealed an Arg327-->His amino acid substitution between the second and third calcium-binding domains of the GPIIb heavy chain, a residue that is highly conserved among integrin alpha-subunits. The recombinant His327 form of GPIIb was found to be fully capable of associating with /"GPIIIa"/, therefore the role of the calcium-binding domains in intersubunit association was further examined by constructing amino-terminal segments of GPIIb that ended before the first, second, and third calcium-binding domains. All three fragments were found to associate with /"GPIIIa"/, demonstrating that the calcium-binding domains of GPIIb are not necessary for initial complex formation. Regions amino-terminal to the calcium-binding domains of GPIIb may play a heretofore unappreciated role in integrin subunit association. | [
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} | No |
7706479 | Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. | DNA analysis was performed on 30 unrelated patients with hereditary nonspherocytic hemolytic anemia (HNSHA) who had been found to be pyruvate kinase (PK) deficient by enzyme assay. 19 different mutations were identified among 58 of the 60 alleles at risk. 13 of these were missense mutations that caused single amino acid changes. Included were the following nucleotide substitutions: 401A, 464C, 993A, 1022C, 1076A, 1178G, 1179A, 1373A, 1378A, 1456T, 1484T, 1493A, 1529A. The remaining six mutations were as follows: two nonsense mutations, 721T and 808T; a nucleotide deletion, 307C; a nucleotide insertion, 1089GG; a three nucleotide in frame deletion, 391-392-393 and a deletion of 1149 bp from the PKLR gene that resulted in the loss of exon 11. All the patients were studied for two polymorphic sites, nucleotide (nt) 1705 A/C and a microsatellite in intron 11, to better understand the origin of the mutations. The 1529A mutation, which is the most common mutation in the European population, was found in 25 alleles. With a single exception this mutation was in linkage disequilibrium with both of the polymorphic markers, i.e., found with 1705C and 14 repeats in the microsatellite. This finding is consistent with a single origin of this common mutation. Other mutations occurring more than once were of much lower frequency than the 1529A mutation. | Molecular study of /"pyruvate kinase deficient"/ patients with hereditary nonspherocytic hemolytic anemia. | DNA analysis was performed on 30 unrelated patients with hereditary nonspherocytic hemolytic anemia (HNSHA) who had been found to be pyruvate kinase (PK) deficient by enzyme assay. 19 different mutations were identified among 58 of the 60 alleles at risk. 13 of these were missense mutations that caused single amino acid changes. Included were the following nucleotide substitutions: 401A, 464C, 993A, 1022C, 1076A, 1178G, 1179A, 1373A, 1378A, 1456T, 1484T, 1493A, 1529A. The remaining six mutations were as follows: two nonsense mutations, 721T and 808T; a nucleotide deletion, 307C; a nucleotide insertion, 1089GG; a three nucleotide in frame deletion, 391-392-393 and a deletion of 1149 bp from the /"PKLR"/ gene that resulted in the loss of exon 11. All the patients were studied for two polymorphic sites, nucleotide (nt) 1705 A/C and a microsatellite in intron 11, to better understand the origin of the mutations. The 1529A mutation, which is the most common mutation in the European population, was found in 25 alleles. With a single exception this mutation was in linkage disequilibrium with both of the polymorphic markers, i.e., found with 1705C and 14 repeats in the microsatellite. This finding is consistent with a single origin of this common mutation. Other mutations occurring more than once were of much lower frequency than the 1529A mutation. | [
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7706479 | Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. | DNA analysis was performed on 30 unrelated patients with hereditary nonspherocytic hemolytic anemia (HNSHA) who had been found to be pyruvate kinase (PK) deficient by enzyme assay. 19 different mutations were identified among 58 of the 60 alleles at risk. 13 of these were missense mutations that caused single amino acid changes. Included were the following nucleotide substitutions: 401A, 464C, 993A, 1022C, 1076A, 1178G, 1179A, 1373A, 1378A, 1456T, 1484T, 1493A, 1529A. The remaining six mutations were as follows: two nonsense mutations, 721T and 808T; a nucleotide deletion, 307C; a nucleotide insertion, 1089GG; a three nucleotide in frame deletion, 391-392-393 and a deletion of 1149 bp from the PKLR gene that resulted in the loss of exon 11. All the patients were studied for two polymorphic sites, nucleotide (nt) 1705 A/C and a microsatellite in intron 11, to better understand the origin of the mutations. The 1529A mutation, which is the most common mutation in the European population, was found in 25 alleles. With a single exception this mutation was in linkage disequilibrium with both of the polymorphic markers, i.e., found with 1705C and 14 repeats in the microsatellite. This finding is consistent with a single origin of this common mutation. Other mutations occurring more than once were of much lower frequency than the 1529A mutation. | Molecular study of pyruvate kinase deficient patients with /"hereditary nonspherocytic hemolytic anemia"/. | DNA analysis was performed on 30 unrelated patients with /"hereditary nonspherocytic hemolytic anemia"/ (/"HNSHA"/) who had been found to be pyruvate kinase (PK) deficient by enzyme assay. 19 different mutations were identified among 58 of the 60 alleles at risk. 13 of these were missense mutations that caused single amino acid changes. Included were the following nucleotide substitutions: 401A, 464C, 993A, 1022C, 1076A, 1178G, 1179A, 1373A, 1378A, 1456T, 1484T, 1493A, 1529A. The remaining six mutations were as follows: two nonsense mutations, 721T and 808T; a nucleotide deletion, 307C; a nucleotide insertion, 1089GG; a three nucleotide in frame deletion, 391-392-393 and a deletion of 1149 bp from the /"PKLR"/ gene that resulted in the loss of exon 11. All the patients were studied for two polymorphic sites, nucleotide (nt) 1705 A/C and a microsatellite in intron 11, to better understand the origin of the mutations. The 1529A mutation, which is the most common mutation in the European population, was found in 25 alleles. With a single exception this mutation was in linkage disequilibrium with both of the polymorphic markers, i.e., found with 1705C and 14 repeats in the microsatellite. This finding is consistent with a single origin of this common mutation. Other mutations occurring more than once were of much lower frequency than the 1529A mutation. | [
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7769500 | Insertion variant in intron 9, but not microsatellite in intron 2, of the insulin receptor gene is associated with essential hypertension. | OBJECTIVE: To determine whether a microsatellite polymorphism of the insulin receptor gene (INSR) is associated with essential hypertension, as has been demonstrated previously for an RsaI restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between obese and non-obese subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an RsaI RFLP of INSR: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between obese and non-obese subgroups. The non-obese hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of INSR as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron. | Insertion variant in intron 9, but not microsatellite in intron 2, of the /"insulin receptor"/ gene is associated with essential /"hypertension"/. | OBJECTIVE: To determine whether a microsatellite polymorphism of the /"insulin receptor"/ gene (/"INSR"/) is associated with essential /"hypertension"/, as has been demonstrated previously for an RsaI restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic /"hypertensive"/ patients whose parents were both /"hypertensive"/, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the /"hypertensive"/ and normotensive groups, or between obese and non-obese subgroups of /"hypertensives"/. This is in contrast to the significantly higher frequency seen for the R1- allele of an RsaI RFLP of /"INSR"/: 0.71 in the /"hypertensive"/ group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of /"hypertensives"/ and did not differ between obese and non-obese subgroups. The non-obese /"hypertensives"/ also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the /"hypertension"/-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the /"hypertension"/-associated variants of /"INSR"/ as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron. | [
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7769500 | Insertion variant in intron 9, but not microsatellite in intron 2, of the insulin receptor gene is associated with essential hypertension. | OBJECTIVE: To determine whether a microsatellite polymorphism of the insulin receptor gene (INSR) is associated with essential hypertension, as has been demonstrated previously for an RsaI restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between obese and non-obese subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an RsaI RFLP of INSR: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between obese and non-obese subgroups. The non-obese hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of INSR as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron. | Insertion variant in intron 9, but not microsatellite in intron 2, of the /"insulin receptor"/ gene is associated with essential hypertension. | OBJECTIVE: To determine whether a microsatellite polymorphism of the /"insulin receptor"/ gene (/"INSR"/) is associated with essential hypertension, as has been demonstrated previously for an RsaI restriction fragment length polymorphism (RFLP), and to examine blood pressure and plasma lipid profiles in relation to genotype. DESIGN AND METHODS: The study involved 75 Caucasian, non-diabetic hypertensive patients whose parents were both hypertensive, and 75 age-matched normotensive subjects whose parents were each normotensive after the age of 50 years. Genotypes for the microsatellite polymorphism were determined for each subject using leucocyte DNA and a polymerase chain reaction method. Other parameters, including pretreatment blood pressure, body mass index and plasma lipids, were also determined. RESULTS: Comparison of microsatellite data for the eight genotypes and four alleles that were detected showed no significant difference by chi 2 analysis, either between the hypertensive and normotensive groups, or between /"obese"/ and /"non-obese"/ subgroups of hypertensives. This is in contrast to the significantly higher frequency seen for the R1- allele of an RsaI RFLP of /"INSR"/: 0.71 in the hypertensive group compared with 0.56 in the normotensive group. R1- allele frequency was elevated in all age groups of hypertensives and did not differ between /"obese"/ and /"non-obese"/ subgroups. The /"non-obese"/ hypertensives also had different plasma lipid profiles according to genotypes of the RFLP, with higher total and low-density lipoprotein-cholesterol in patients having the hypertension-associated R1- allele of the intron 9 polymorphism. Moreover, systolic blood pressure was significantly greater in patients carrying the R1- allele and aged > or = 60 years. CONCLUSIONS: The present study allows definition of the hypertension-associated variants of /"INSR"/ as those which are in linkage disequilibrium with a (CA)-repeat insertion polymorphism in intron 9 of the large, 22 exon, > 120-kb gene, but not those associated with a polymorphism in the second intron. | [
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7783416 | Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group. | In patients with type 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for angiotensin I converting enzyme and the presence of diabetic nephropathy. Our objective was (i) to assess this association in a large cohort of patients with type 1 diabetes and (ii) to examine whether this finding also applies to type 2 diabetes. We examined 247 patients with type 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with type 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between type 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between type 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either type 1 or type 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest. | Association of /"ACE"/ gene polymorphism and /"diabetic nephropathy"/? The /"Diabetic Nephropathy"/ Study Group. | In patients with type 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for /"angiotensin I converting enzyme"/ and the presence of /"diabetic nephropathy"/. Our objective was (i) to assess this association in a large cohort of patients with type 1 diabetes and (ii) to examine whether this finding also applies to type 2 diabetes. We examined 247 patients with type 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with type 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between type 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between type 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either type 1 or type 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest. | [
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7783416 | Association of ACE gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group. | In patients with type 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for angiotensin I converting enzyme and the presence of diabetic nephropathy. Our objective was (i) to assess this association in a large cohort of patients with type 1 diabetes and (ii) to examine whether this finding also applies to type 2 diabetes. We examined 247 patients with type 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with type 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between type 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between type 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either type 1 or type 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest. | Association of /"ACE"/ gene polymorphism and diabetic nephropathy? The Diabetic Nephropathy Study Group. | In patients with /"type"/ 1 diabetes an association has been found between an insertion/deletion (I/D) polymorphism in the gene for /"angiotensin I converting enzyme"/ and the presence of diabetic nephropathy. Our objective was (i) to assess this association in a large cohort of patients with /"type"/ 1 diabetes and (ii) to examine whether this finding also applies to /"type"/ 2 diabetes. We examined 247 patients with /"type"/ 1 diabetes of more than 10 years duration (135 patients > or = 20 years): Nephropathy was present in 114 and absent in 133 patients. Furthermore we separately analyzed 455 patients with /"type"/ 2 diabetes of more than 10 years duration (158 patients > or = 20 years). Nephropathy was present in 247 and absent in 208 patients. Nephropathy was defined by confirmed presence of albuminuria > 30 mg/day (or > 20 micrograms/min). The I/D polymorphism was analyzed with PCR technique and alleles were visualized on 2% agarose gels after ethidium staining. Allele frequencies in the overall diabetic population did not differ significantly from the normal population. Distribution of genotypes was not significantly different between /"type"/ 1 patients with and without nephropathy (P = 0.377). Also, no significant difference in genotype distribution was found between /"type"/ 2 diabetic patients with and without nephropathy (P = 0.948). We conclude that no significant association between I/D polymorphism and nephropathy was demonstrable in either /"type"/ 1 or /"type"/ 2 diabetes, despite considerable statistical power of the patient sample and adequate duration of diabetes for nephropathy to become manifest. | [
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7902317 | An adult-type metachromatic leukodystrophy caused by substitution of serine for glycine-122 in arylsulfatase A. | Metachromatic leukodystrophy (MLD) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme arylsulfatase A (ASA). We have identified a new mutation in the ASA gene of a patient with adult-type MLD. In this mutation, the glycine at position 122, a highly conserved residue in the AS gene family, was replaced by serine. In a transient expression study, COS cells transfected with the mutant cDNA carrying 122Gly-->Ser did not show an increase of ASA activity and produced little material immunoreactive to an anti-ASA antibody, despite normal mRNA levels. | An /"adult-type metachromatic leukodystrophy"/ caused by substitution of serine for glycine-122 in /"arylsulfatase A"/. | /"Metachromatic leukodystrophy"/ (/"MLD"/) is a lysosomal storage disease with autosomal recessive inheritance caused by a deficiency of the enzyme /"arylsulfatase A"/ (ASA). We have identified a new mutation in the ASA gene of a patient with adult-type /"MLD"/. In this mutation, the glycine at position 122, a highly conserved residue in the AS gene family, was replaced by serine. In a transient expression study, COS cells transfected with the mutant cDNA carrying 122Gly-->Ser did not show an increase of ASA activity and produced little material immunoreactive to an anti-ASA antibody, despite normal mRNA levels. | [
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} | Yes |