iqbal ali - Academia.edu (original) (raw)
Papers by iqbal ali
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 2005
Bifid condyle is a rare condition. Most initially reported cases were found in studies conducted ... more Bifid condyle is a rare condition. Most initially reported cases were found in studies conducted on skeletal specimens. While increasing numbers are being reported on living persons, most of them are asymptomatic and have been found on routine dental radiographic examination for other dental complaints. Most of the cases of bifid condyle reported so far have occurred unilaterally and predominantly on the left side. Bifid condyle associated with temporomandibular joint ankylosis is very rare with only 2 cases reported in the English-language literature as far as we know. An additional case of bifid condyle associated with temporomandibular joint ankylosis, involving the right side of mandible, is presented as well as a review of the literature on bifid condyles including those associated with temporomandibular joint ankylosis.
American Journal of Pathology, 2002
The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure... more The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.
Annals of The New York Academy of Sciences, 1978
Management Science, 1986
IQBAL ALI, WADE D. COOK AND MOSHE KRESS Department of General Business, University of Texas, Aust... more IQBAL ALI, WADE D. COOK AND MOSHE KRESS Department of General Business, University of Texas, Austin, Texas 78712 Faculty of Administrative Studies, York University, Toronto, Ontario, Canada M3J 2R6 CEMA, PO Box 2250, Haifa, Israel This paper examines the ...
Management Science, 1986
Cook and Kress (Cook, Wade D., Moshe Kress. 1985. Ordinal ranking with intensity of preference. M... more Cook and Kress (Cook, Wade D., Moshe Kress. 1985. Ordinal ranking with intensity of preference. Management Sci. 31 (1) 26--32.) present a model for representing ordinal preference rankings, where the voter can express intensity or degree of preference. The consensus of a set of m rankings is that ranking whose distance from this set is minimal. The consensus problem is
Journal of Clinical Investigation, 1993
Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its abi... more Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its ability to promote vascular permeability and endothelial cell growth, and its role in tumor development has received considerable attention. In this report, we describe the elevation of VIM-/ VEGF transcript expression in human hepatocellular carcinoma. Surgical samples of 23 patients with hepatocellular carcinoma were studied using reverse transcription-PCR analysis. The oligonucleotide primers were designed to amplify all four known splicing variants that could be ex pressed in the samples studied. Sixteen cases showed VPF/VEGF tran script expression in the tumor (16/23, 69.6%), whereas only 9 of the 23 patients showed it in the corresponding nontumoral part. There was no difference between the pattern of expression of VPF/VEGF isoforms in tumoral and nontumoral tissues. VPF/VEGF mRNA expression in the liver tumors was associated with fibrous capsule formation and septal formation (/' < 0.05 respectively, Fisher's exact /' test). In situ hybridiza tion confirmed the presence of VPF/VEGF mRNA expression in tumor cells and less intensely in hepatocytes of nontumoral liver. We also found that VPF/VEGF expression in the tumor cell was increased in the area adjacent to necrotic regions (presumably hypoxic regions). As a regulator of vascular permeability and endothelial cell growth factor, VPF/VEGF may play an important role in the development of hepatocellular carci noma.
has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating ... more has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins. The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinositol 3,4,5-triphosphate. The PTEN/MMAC1 gene is mutated in the germline of patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 gene in tumors from various tissues, especially endometrium, brain, prostate, and ovary, in which the gene is inactivated very frequently.
Journal of Neurosurgery, 1992
Glioblastoma multiforme, the most common and most lethal primary central nervous system neoplasm,... more Glioblastoma multiforme, the most common and most lethal primary central nervous system neoplasm, is noted for its phenotypic and biological heterogeneity. This heterogeneity may result from genetic alterations accumulated by a single transformed astrocyte as it evolves into a monoclonal tumor. Alternatively, it may be attributed to the presence of multiple biologically and genetically distinct astrocytic populations within a polyclonal tumor. To address the issue of clonal composition of glioblastoma multiforme the authors used two independent approaches: analysis of X-chromosome inactivation and analysis of chromosomes 10 and 17 for tumor-specific somatic deletions. The analysis included 10 tumors from nine female patients with glioblastoma multiforme (eight primary and two recurrent tumors), who were heterozygous at either of two X-chromosome genes (hypoxanthine phosphoribosyl-transferase or phosphoglycerate kinase). Nine glioblastomas multiforme demonstrated a monoclonal pattern on X-chromosome analysis; contamination with normal tissue obscured the analysis in one tumor. Somatic deletions on chromosomes 10 and/or 17 occurred in nine tumors, supporting a monoclonal composition for these tumors. These data suggest that glioblastoma multiforme is a monoclonal neoplasm, derived from the clonal expansion of a single transformed astrocyte that has, as a fundamental step in tumorigenesis, sustained a critical genetic alteration on chromosome 10 and/or 17.
Reduced DNA repair capacity is believed to increase susceptibility to smoking-related cancers. Po... more Reduced DNA repair capacity is believed to increase susceptibility to smoking-related cancers. Polymorphisms in several DNA repair genes have been reported but the role of these variants in generating DNA damage phenotypes in human populations has been less well studied. The aim of this study was to determine whether variation in DNA repair genes is related to smokers' increased susceptibility to DNA damage, and the impact of high tea drinking on this. We designed a phase II randomised controlled, 3-arm tea intervention trial to study the effect of high consumption (4 cups per day) of decaffeinated green or black tea or water on oxidative DNA damage, as measured by urinary 8-hydroxydeoxyguanosine (8-OHdG), among heavy smokers over a 4-month period and to evaluate the roles of XRCC1 genotypes as effect modifiers. A total of 120 heavy smokers were included in the analysis. Multiple linear regression models were used to estimate the main effects and interaction effect of green and black tea consumption on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Finally, we studied whether the effect of treatment varied by XRCC1 status of the individual. In this randomised controlled trial among smokers, daily drinking of 4 cups of decaffeinated green tea was associated with statistically significant decrease in urinary excretion of 8-OHdG. We did find a greater effect of green tea consumption on urinary 8-OHdG levels among Arg399/Arg (p = 0.02) than among Arg399/Gln+Gln/Gln (p = 0.079) smokers. Decaffeinated black tea consumption had no effect on urinary 8-OHdG levels among heavy smokers. Our data show that consumption of 4 cups of tea per day is a feasible and safe approach and was associated with significant decrease in urinary 8-OHdG among green tea consumers after 4 months of use. Our results suggest that carriers of the polymorphic XRCC1 Gln399 allele may not significantly benefit from a green tea, and hence an antioxidant, intervention.
Molecular analysis of malignant astrocytomas demonstrated three distinct groups of tumors with ch... more Molecular analysis of malignant astrocytomas demonstrated three distinct groups of tumors with chromosome 17p abnormalities, which include (a) deletion of the p53 locus (17p13.1) and mutations in the remaining allele, (b) deletion of the p53 locus but no detectable mutations in the remaining allele, and (c) deletions not including the p53 locus but mutations in one of the alleles. Furthermore, deletion mapping analysis demonstrated allelic loss of genes distal to DI7S28/D17S5 markers (17p13.3) in group C tumors. The loss of heterozygosity of genes on chromosome 17 without detectable mutation (group B) or deletion (group C) in the p53 gene implies the presence of a second tumor suppressor gene in the telomeric region of 17p, the homozygous functional inactivation of which may play a role, either alone or in conjunction with p53, in the initiation and/or progression of astrocytic neoplasms.
Oncogene, 1999
Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either... more Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either from the progression of low grade precursor lesions or rapidly in a de novo fashion and contain distinct genetic alterations. There is, however, a third subset of malignant gliomas in which genetic lesions remain to be identi®ed. Following surgical resection, all gliomas appear to have an inherent tendency to recur. Comparative molecular analysis of ten primary malignant gliomas (three anaplastic astrocytomas and seven glioblastomas multiforme) with their recurrences identi®ed two distinct subgroups of recurrent tumors. In one group, primary tumors harbored genetic aberrations frequently associated with linear progression or de novo formation pathways of glial tumorigenesis and maintained their genetic pro®les upon recurrence. In the other subset with no detectable known genetic mutations at ®rst presentation, the recurrent tumors sustained speci®c abnormalities associated with pathways of linear progression or de novo formation. These included loss of genes on chromosomes 17 and 10, mutations in the p53 gene, homozygous deletion of the DMBTA1 and p16 and/ or p15 genes and ampli®cation and/or overexpression of CDK4 and alpha form of the PDGF receptor. Recurrent tumors from both groups also displayed an abnormal expression pro®le of the metalloproteinase, gel A, and its inhibitor, TIMP-2, consistent with their highly invasive behavior. Delineation of the molecular dierences between malignant glioblastomas and their subsequent recurrences may have important implications for the development of rational clinical approaches for this neoplasm that remains refractory to existing therapeutic modalities.
Journal of Clinical Endocrinology & Metabolism, 1996
Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroa... more Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.
growth factor receptors (PDGFR) and epidermal growth factor receptor (EGFR) in human malignant gl... more growth factor receptors (PDGFR) and epidermal growth factor receptor (EGFR) in human malignant gliomas showed amplification and overexpression of both receptors in distinct subsets of tumors. Amplification of the aPDGFR was detected in 4 of 50 glioblastomas (8%). EGFR was amplified in 9 of the 50 tumors (18%). Western blot analysis showed elevated expression of aPDGFR and EGFR proteins in 4 (24%) and 3 (18%), respectively, of 17 tumor specimens analyzed. Increased produc tion of aPDGFR as well as EGFR proteins was observed in the presence or absence of gene amplification. Three of the 4 tumors with elevated levels of aPDGFR also overexpressed the 0PDGFR, which was present as a single copy gene in all 50 tumors analyzed. Our findings suggest that the amplification and/or Overexpression either of EGFR or of the aPDGFR along with the coordinate Overexpression of the /3PDGFR can contribute to the malignant phenotype of distinct subsets of human glioblastoma.
Journal of Clinical Endocrinology & Metabolism, 1991
Endocrine Society JCEM ...
Oral Surgery Oral Medicine Oral Pathology Oral Radiology and Endodontology, 2005
Bifid condyle is a rare condition. Most initially reported cases were found in studies conducted ... more Bifid condyle is a rare condition. Most initially reported cases were found in studies conducted on skeletal specimens. While increasing numbers are being reported on living persons, most of them are asymptomatic and have been found on routine dental radiographic examination for other dental complaints. Most of the cases of bifid condyle reported so far have occurred unilaterally and predominantly on the left side. Bifid condyle associated with temporomandibular joint ankylosis is very rare with only 2 cases reported in the English-language literature as far as we know. An additional case of bifid condyle associated with temporomandibular joint ankylosis, involving the right side of mandible, is presented as well as a review of the literature on bifid condyles including those associated with temporomandibular joint ankylosis.
American Journal of Pathology, 2002
The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure... more The goal of this study was to develop a sensitive, simple, and widely applicable assay to measure copy numbers of specific mRNAs using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), and identify a profile of gene expression closely associated with angiogenesis. We measured a panel of nine potential angiogenesis markers from a mouse transgenic model of prostate adenocarcinoma (TRAMP) and a mouse skin model of vascular endothelial growth factor (VEGF)-driven angiogenesis. In both models, expression of VEGF correlated with expression of mRNAs encoding other angiogenic cytokines (angiopoietin-1 and angiopoietin-2), endothelial cell receptor tyrosine kinases (Flt-1, KDR, Tie-1), and endothelial cell adhesion molecules (VE-cadherin, PECAM-1). Relative to control, in dermis highly stimulated by VEGF, the Ang-2 mRNA transcript numbers increased 35-fold, PECAM-1 and VE-cadherin increased 10-fold, Tie-1 increased 8-fold, KDR and Flt-1 each increased 4-fold, and Ang-1 increased 2-fold. All transcript numbers were correspondingly reduced in skin with less VEGF expression, indicating a relationship of each of these seven markers with VEGF. Thus, this study identifies a highly efficient method for precise quantification of a panel of seven specific mRNAs that correlate with VEGF expression and VEGF-induced neovascularization, and it provides evidence that real-time quantitative RT-PCR offers a highly sensitive strategy for monitoring angiogenesis.
Annals of The New York Academy of Sciences, 1978
Management Science, 1986
IQBAL ALI, WADE D. COOK AND MOSHE KRESS Department of General Business, University of Texas, Aust... more IQBAL ALI, WADE D. COOK AND MOSHE KRESS Department of General Business, University of Texas, Austin, Texas 78712 Faculty of Administrative Studies, York University, Toronto, Ontario, Canada M3J 2R6 CEMA, PO Box 2250, Haifa, Israel This paper examines the ...
Management Science, 1986
Cook and Kress (Cook, Wade D., Moshe Kress. 1985. Ordinal ranking with intensity of preference. M... more Cook and Kress (Cook, Wade D., Moshe Kress. 1985. Ordinal ranking with intensity of preference. Management Sci. 31 (1) 26--32.) present a model for representing ordinal preference rankings, where the voter can express intensity or degree of preference. The consensus of a set of m rankings is that ranking whose distance from this set is minimal. The consensus problem is
Journal of Clinical Investigation, 1993
Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its abi... more Vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF) is unique in its ability to promote vascular permeability and endothelial cell growth, and its role in tumor development has received considerable attention. In this report, we describe the elevation of VIM-/ VEGF transcript expression in human hepatocellular carcinoma. Surgical samples of 23 patients with hepatocellular carcinoma were studied using reverse transcription-PCR analysis. The oligonucleotide primers were designed to amplify all four known splicing variants that could be ex pressed in the samples studied. Sixteen cases showed VPF/VEGF tran script expression in the tumor (16/23, 69.6%), whereas only 9 of the 23 patients showed it in the corresponding nontumoral part. There was no difference between the pattern of expression of VPF/VEGF isoforms in tumoral and nontumoral tissues. VPF/VEGF mRNA expression in the liver tumors was associated with fibrous capsule formation and septal formation (/' < 0.05 respectively, Fisher's exact /' test). In situ hybridiza tion confirmed the presence of VPF/VEGF mRNA expression in tumor cells and less intensely in hepatocytes of nontumoral liver. We also found that VPF/VEGF expression in the tumor cell was increased in the area adjacent to necrotic regions (presumably hypoxic regions). As a regulator of vascular permeability and endothelial cell growth factor, VPF/VEGF may play an important role in the development of hepatocellular carci noma.
has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating ... more has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins. The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinositol 3,4,5-triphosphate. The PTEN/MMAC1 gene is mutated in the germline of patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 gene in tumors from various tissues, especially endometrium, brain, prostate, and ovary, in which the gene is inactivated very frequently.
Journal of Neurosurgery, 1992
Glioblastoma multiforme, the most common and most lethal primary central nervous system neoplasm,... more Glioblastoma multiforme, the most common and most lethal primary central nervous system neoplasm, is noted for its phenotypic and biological heterogeneity. This heterogeneity may result from genetic alterations accumulated by a single transformed astrocyte as it evolves into a monoclonal tumor. Alternatively, it may be attributed to the presence of multiple biologically and genetically distinct astrocytic populations within a polyclonal tumor. To address the issue of clonal composition of glioblastoma multiforme the authors used two independent approaches: analysis of X-chromosome inactivation and analysis of chromosomes 10 and 17 for tumor-specific somatic deletions. The analysis included 10 tumors from nine female patients with glioblastoma multiforme (eight primary and two recurrent tumors), who were heterozygous at either of two X-chromosome genes (hypoxanthine phosphoribosyl-transferase or phosphoglycerate kinase). Nine glioblastomas multiforme demonstrated a monoclonal pattern on X-chromosome analysis; contamination with normal tissue obscured the analysis in one tumor. Somatic deletions on chromosomes 10 and/or 17 occurred in nine tumors, supporting a monoclonal composition for these tumors. These data suggest that glioblastoma multiforme is a monoclonal neoplasm, derived from the clonal expansion of a single transformed astrocyte that has, as a fundamental step in tumorigenesis, sustained a critical genetic alteration on chromosome 10 and/or 17.
Reduced DNA repair capacity is believed to increase susceptibility to smoking-related cancers. Po... more Reduced DNA repair capacity is believed to increase susceptibility to smoking-related cancers. Polymorphisms in several DNA repair genes have been reported but the role of these variants in generating DNA damage phenotypes in human populations has been less well studied. The aim of this study was to determine whether variation in DNA repair genes is related to smokers' increased susceptibility to DNA damage, and the impact of high tea drinking on this. We designed a phase II randomised controlled, 3-arm tea intervention trial to study the effect of high consumption (4 cups per day) of decaffeinated green or black tea or water on oxidative DNA damage, as measured by urinary 8-hydroxydeoxyguanosine (8-OHdG), among heavy smokers over a 4-month period and to evaluate the roles of XRCC1 genotypes as effect modifiers. A total of 120 heavy smokers were included in the analysis. Multiple linear regression models were used to estimate the main effects and interaction effect of green and black tea consumption on creatinine-adjusted urinary 8-OHdG, with or without adjustment for potential confounders. Finally, we studied whether the effect of treatment varied by XRCC1 status of the individual. In this randomised controlled trial among smokers, daily drinking of 4 cups of decaffeinated green tea was associated with statistically significant decrease in urinary excretion of 8-OHdG. We did find a greater effect of green tea consumption on urinary 8-OHdG levels among Arg399/Arg (p = 0.02) than among Arg399/Gln+Gln/Gln (p = 0.079) smokers. Decaffeinated black tea consumption had no effect on urinary 8-OHdG levels among heavy smokers. Our data show that consumption of 4 cups of tea per day is a feasible and safe approach and was associated with significant decrease in urinary 8-OHdG among green tea consumers after 4 months of use. Our results suggest that carriers of the polymorphic XRCC1 Gln399 allele may not significantly benefit from a green tea, and hence an antioxidant, intervention.
Molecular analysis of malignant astrocytomas demonstrated three distinct groups of tumors with ch... more Molecular analysis of malignant astrocytomas demonstrated three distinct groups of tumors with chromosome 17p abnormalities, which include (a) deletion of the p53 locus (17p13.1) and mutations in the remaining allele, (b) deletion of the p53 locus but no detectable mutations in the remaining allele, and (c) deletions not including the p53 locus but mutations in one of the alleles. Furthermore, deletion mapping analysis demonstrated allelic loss of genes distal to DI7S28/D17S5 markers (17p13.3) in group C tumors. The loss of heterozygosity of genes on chromosome 17 without detectable mutation (group B) or deletion (group C) in the p53 gene implies the presence of a second tumor suppressor gene in the telomeric region of 17p, the homozygous functional inactivation of which may play a role, either alone or in conjunction with p53, in the initiation and/or progression of astrocytic neoplasms.
Oncogene, 1999
Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either... more Malignant glial tumors (anaplastic astrocytomas and glioblastomas multiforme) arise mostly either from the progression of low grade precursor lesions or rapidly in a de novo fashion and contain distinct genetic alterations. There is, however, a third subset of malignant gliomas in which genetic lesions remain to be identi®ed. Following surgical resection, all gliomas appear to have an inherent tendency to recur. Comparative molecular analysis of ten primary malignant gliomas (three anaplastic astrocytomas and seven glioblastomas multiforme) with their recurrences identi®ed two distinct subgroups of recurrent tumors. In one group, primary tumors harbored genetic aberrations frequently associated with linear progression or de novo formation pathways of glial tumorigenesis and maintained their genetic pro®les upon recurrence. In the other subset with no detectable known genetic mutations at ®rst presentation, the recurrent tumors sustained speci®c abnormalities associated with pathways of linear progression or de novo formation. These included loss of genes on chromosomes 17 and 10, mutations in the p53 gene, homozygous deletion of the DMBTA1 and p16 and/ or p15 genes and ampli®cation and/or overexpression of CDK4 and alpha form of the PDGF receptor. Recurrent tumors from both groups also displayed an abnormal expression pro®le of the metalloproteinase, gel A, and its inhibitor, TIMP-2, consistent with their highly invasive behavior. Delineation of the molecular dierences between malignant glioblastomas and their subsequent recurrences may have important implications for the development of rational clinical approaches for this neoplasm that remains refractory to existing therapeutic modalities.
Journal of Clinical Endocrinology & Metabolism, 1996
Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroa... more Nelson's syndrome is the appearance and/or progression of ACTH-secreting pituitary macroadenomas in patients who had previously undergone bilateral adrenalectomy for Cushing's disease. Extremely high plasma ACTH levels and aggressive neoplastic growth might be explained by the lack of appropriate glucocorticoid negative feedback due to defective glucocorticoid signal transduction. To study the glucocorticoid receptor (GR) gene in Nelson's syndrome, DNA was extracted from pituitary adenomas and leukocytes of four patients with this condition and amplified by PCR for direct sequence analysis. In one of the tumors, a heterozygous mutation, consisting of an insertion of a thymine between complementary DNA nucleotides 1188 and 1189, was found in exon 2. This frame-shift mutation led to premature termination at amino acid residue 366 of the wild-type coding sequence, excluding the expression of a functioning receptor protein from the defective allele. The mutation was not detected in the sequence of the GR gene in the patient's leukocyte DNA, indicating a somatic origin. By lowering the receptor number in tumorous cells, this defect might have caused local resistance to negative glucocorticoid feedback similar to that caused by the presence of a null allele in a kindred with the generalized glucocorticoid resistance syndrome. P53 protein accumulation, previously reported in 60% of corticotropinomas, could not be detected in any of the four pituitary tumors examined by immunohistochemistry. We suggest that a somatic GR defect might have played a pathophysiological role in the tumorigenesis of the corticotropinoma bearing this mutation.
growth factor receptors (PDGFR) and epidermal growth factor receptor (EGFR) in human malignant gl... more growth factor receptors (PDGFR) and epidermal growth factor receptor (EGFR) in human malignant gliomas showed amplification and overexpression of both receptors in distinct subsets of tumors. Amplification of the aPDGFR was detected in 4 of 50 glioblastomas (8%). EGFR was amplified in 9 of the 50 tumors (18%). Western blot analysis showed elevated expression of aPDGFR and EGFR proteins in 4 (24%) and 3 (18%), respectively, of 17 tumor specimens analyzed. Increased produc tion of aPDGFR as well as EGFR proteins was observed in the presence or absence of gene amplification. Three of the 4 tumors with elevated levels of aPDGFR also overexpressed the 0PDGFR, which was present as a single copy gene in all 50 tumors analyzed. Our findings suggest that the amplification and/or Overexpression either of EGFR or of the aPDGFR along with the coordinate Overexpression of the /3PDGFR can contribute to the malignant phenotype of distinct subsets of human glioblastoma.
Journal of Clinical Endocrinology & Metabolism, 1991
Endocrine Society JCEM ...