Search PubMed⌕ Search

Biomedical subjects

A Arnold

Publications and source records attributed to A Arnold.

At least 73 records · Page 4Linked to original sources
PubMed1997

Mutation analysis of glial cell line-derived neurotrophic factor, a ligand for an RET/coreceptor complex, in multiple endocrine neoplasia type 2 and sporadic neuroendocrine tumors.

Causative germline missense mutations in the RET proto-oncogene have been associated with over 92% of families with the inherited cancer syndrome multiple endocrine neoplasia type 2 (MEN 2). MEN 2A is characterized primarily by medullary thyroid carcinoma (MTC) and pheochromocytoma, both tumors of neural crest origin. Parathyroid hyperplasia or adenoma is also seen in MEN 2A, but rarely in MEN 2B, which has additional stigmata, including a marfanoid habitus, mucosal neuromas, and ganglioneuromatosis of the gastrointestinal tract. In familial MTC, MTC is the only lesion present. Somatic RET mutations have also been identified in a subset of sporadic MTCs, pheochromocytomas, and rarely, small cell lung cancer, but not in sporadic parathyroid hyperplasias/adenomas or other neuroendocrine tumors. Glial cell line-derived neurotrophic factor (GDNF) and its receptor molecule GDNFR-alpha, have recently been identified as members of the RET ligand binding complex. Therefore, the genes encoding both GDNF and GDNFR-alpha are excellent candidates for a role in the pathogenesis of those MEN 2 families and sporadic neuroendocrine tumors without RET mutations. No mutations were found in the coding region of GDNF in DNA samples from 9 RET mutation negative MEN 2 individuals (comprising 6 distinct families), 12 sporadic MTCs, 17 sporadic cases of parathyroid adenoma, and 10 small cell lung cancer cell lines. Therefore, we find no evidence that mutation within the coding regions of GDNF plays a role in the genesis of MEN 2 and sporadic neuroendocrine tumors.

DNA Mutational Analysis↗
PubMed1997

Parathyroid tumor suppressor on 1p: analysis of the p18 cyclin-dependent kinase inhibitor gene as a candidate.

Loss of chromosome arm 1p DNA is the most common molecular defect thus far observed in human parathyroid adenomas, suggesting that 1p is the location of a putative tumor suppressor gene (or genes) whose inactivation contributes frequently to parathyroid tumorigenesis. To narrow the genomic location of this tumor suppressor gene, we analyzed 25 sporadic parathyroid adenomas for allelic loss of polymorphic DNA loci on chromosome 1 using 11 microsatellite markers not previously scored for this set of tumors. Allelic loss on chromosome arm 1p DNA was observed in 8 of 25 adenomas. Marker deletion patterns showed some complexity, with the regions most commonly deleted in these tumors being 1p36 and 1p35-p31. The 1p35-p31 region contains an excellent candidate tumor suppressor gene, p18, whose product is a cell cycle regulator that inhibits the cyclin D1-associated kinase CDK6. Given that cyclin D1 is a parathyroid oncogene, inactivation of an inhibitor of cyclin D1 function, like p18, might also cause excessive parathyroid growth. To examine the involvement of p18 in parathyroid tumorigenesis, we analyzed 25 parathyroid adenomas for mutations of the p18 coding exons by single strand conformational polymorphism analysis and sequencing. No point mutations were found in any of the 25 adenomas. These observations indicate that inactivating mutation of the p18 gene occurs uncommonly, if at all, in parathyroid adenomas. In addition, the data raise the important possibility that more than a single tumor suppressor gene on 1p could contribute to parathyroid neoplasia.

Adenoma↗
PubMed1996

Expression of the retinoblastoma protein in low-grade B-cell lymphoma: relationship to cyclin D1.

The product of the retinoblastoma tumor-suppressor gene (pRB), a nuclear phosphoprotein that regulates transcription factors such as E2F, is involved in cell cycle control and differentiation. Its activity is regulated by phosphorylation; the underphosphorylated form inhibits transcription whereas the highly phosphorylated form is inactive. Cyclin D1 and its associated kinase (CDK 4/6) phosphorylate pRB in vitro, and therefore are thought to contribute to the regulation of pRB function. To examine the effect of cyclin D1 overexpression on pRB in primary tumor tissue, we studied pRB expression in low-grade B-cell neoplasms, with particular regard to mantle cell lymphoma, which is characterized by cyclin D1 (bcl-1) overexpression. pRB expression was studied by immunostaining with a well-characterized anti-pRB antibody; the phosphorylation status of pRB was examined by immunoblots; and the functional binding capacity of pRB was examined by in vitro binding to adenovirus E1A protein. We studied 3 reactive lymph nodes, 28 low grade B-cell lymphomas, 4 cases of hairy cell leukemia (HCL) and 3 plasmacytomas. Reactive lymph nodes showed intense pRB staining of germinal centers, with strongest (2+) staining in the large cells (centroblasts) of the proliferating (dark) zone and weak or no staining of small lymphocytes, including those of the mantle zone. In B-chronic lymphocytic leukemia (B-CLL) (4 cases), follicular lymphoma (3 cases) and mucosa-associated (MALT) lymphoma (3 cases) strong (2+) pRB staining was limited to centroblasts in reactive and neoplastic follicles and occasional proliferation centers, with only faint staining of small lymphoid cells. In contrast, 15 of 16 cases of mantle cell lymphoma showed strong (1-2+) staining of most cells; one blastoid mantle cell lymphoma showed only faint pRB staining. All cases of (HCL) and plasmacytoma showed strong pRB staining. Although most lymphomas with strong pRB expression were cyclin D1(+), three cyclin D1(+) cases showed only weak pRB expression (1 B-CLL, 1 blastoid mantle cell, 1 unclassifiable low grade B-cell lymphoma). Conversely, of the 4 pRB(+) HCLs and 3 pRB(+) plasmacytomas, only 1 of each was cyclin D1(+). pRB appeared to exist primarily in the underphosphorylated (fastest migrating) form on Western blot, despite the fact that cyclin D1 was complexed to CDK4, a form in which it normally phosphorylates pRB. In addition, pRB appeared to be unmutated, because it bound normally to the adenovirus E1A protein and showed nuclear localization by immunostaining. We conclude that most cases of mantle cell lymphoma, HCL, and plasmacytoma show high levels of pRB in contrast to follicle center lymphoma and small lymphocytic lymphoma; however, pRB expression does not appear to be consistently related to cyclin D1 overexpression. The pRB appears to be unmutated and underphosphorylated, and therefore should be in its active form. Our data from primary lymphoma tissue suggests that overexpression of cyclin D1, whereas tumorigenic, does not lead to pRB loss or hyperphosporylation. Thus, the mechanism by which cyclin D1 contributes to tumorigenesis and the significance of the restricted expression of pRB in low-grade lymphoid neoplasms remain to be determined.

Amino Acid Sequence↗
PubMed1996

Genomic localization of novel candidate tumor suppressor gene loci in human parathyroid adenomas.

Only one oncogene, cyclin D1/PRAD1, has an established role in parathyroid tumorigenesis, and parathyroid tumor suppressor genes on chromosome arms 1p and 11q, which still have not been identified, have also been implicated by loss of heterozygosity analysis. To investigate whether other putative tumor suppressor genes are involved in the pathogenesis of parathyroid adenomas, we performed a more comprehensive analysis of allelic losses in these tumors. Using 39 polymorphic markers, we examined each chromosome arm, excluding the short arms of the acrocentric chromosomes. In 25 parathyroid adenomas, frequent loss of heterozygosity, in > 25% of the informative cases, was observed on chromosome arms 6q (30%), 11p (27%), and 15q (35%), in addition to previously reported 1p (30%) and 11q (38%) allelic losses. To more specifically localize the smallest shared regions of molecular genetic deletion, we examined the following chromosomes in greater detail: chromosome 6 (9 additional markers), chromosome 11 (8 additional markers), and chromosome 15 (15 additional markers). The regions most commonly deleted in these tumors were 6q22-23, 6q26-27, 11q13, 15q11-21, and 15q26-qter. All tumors with 11p loss had patterns consistent with monosomy for chromosome 11. These findings provide novel evidence for the existence of tumor suppressor genes on chromosome arms 6q and 15q that contribute commonly to the pathogenesis of parathyroid adenomas.

Adenoma↗
PubMed1996

Experimental erbium laser surgery in the guinea pig cochlea: its use in the study of afferent cochlear neurotransmitters.

Microiontophoretic techniques were used to examine the changes in activity of inner half cell afferents in the guinea pig following circumscribed penetration of cochlear bone with erbium:YSGG laser pulses. Neuronal responses to the application of the glutamate agonists N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) before laser use and after return to normal spontaneous activity were equivalent, implying total reversibility of the changes occurring. Suppression of laser-induced hair cell activity was possible with NMDA and AMPA receptor antagonists and lasted 10-15 min. These findings suggest a transmitter-related increase of neuronal activity. Our results show that use of the erbium laser in inner ear microsurgery might be possible with low risk if the amount of energy applied is kept under a safe limit of 10 J/cm2.

6-Cyano-7-nitroquinoxaline-2,3-dione↗
PubMed1996

CD5+ extranodal marginal zone B-cell (MALT) lymphoma. A low grade neoplasm with a propensity for bone marrow involvement and relapse.

Three cases of extranodal marginal zone B-cell lymphoma (low grade B-cell lymphoma of mucosa-associated lymphoid tissue [MALT] type) in which the neoplastic B cells expressed the CD5 antigen are reported. The patients included 2 men and 1 woman, aged 44, 62, and 77 years. In all three cases, the histologic features were typical of marginal zone/MALT lymphoma, with reactive follicles, marginal zone (centrocyte-like) cells, and plasma cells. Pseudofollicles, prolymphocytes, and paraimmunoblasts were absent. In all cases, lymphoma from one or more sites expressed monotypic immunoglobulin (2 IgM kappa, 1 IgM lambda), pan B cell antigens and CD5. Two of 3 cases expressed CD43; one case expressed CD23. No case showed overexpression of the bcl-1 protein, cyclin D1. Interphase cytogenetic analysis revealed trisomy 3 in one of two cases examined. The two male patients presented with lymphoma in the ocular adnexa. One of them had marrow involvement, cervical lymphadenopathy and peripheral blood involvement at presentation; 24 months later, he developed a relapse in subcutaneous tissue. The second patient had marrow involvement 3 years later, at the time of recurrence of his orbital disease. The third patient presented with lymphoma at the base of the tongue. She subsequently developed lymphoma involving the left upper eyelid and right lacrimal sac and duct, the marrow, and the nasopharynx between 63 and 95 months after initial presentation. All of these patients presented with disease involving sites in the head and neck and all had multiple relapses or recurrences with bone marrow involvement at the time of presentation (1 case) or at relapse (2 cases). The presence of CD5 may be a marker for cases of MALT lymphoma with a tendency for persistent or recurrent disease, for dissemination to the marrow and other extranodal sites, and for leukemic involvement of the peripheral blood.

Adult↗
PubMed1996

Oncogenic collaboration of the cyclin D1 (PRAD1, bcl-1) gene with a mutated p53 and an activated ras oncogene in neoplastic transformation.

Cyclin D1 is one of the key regulators in G1 progression in the cell cycle and is also a candidate oncogene (termed PRAD1 or bcl-1) in several types of human tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated form of p53 (p53-mt) in neoplastic transformation. Transfection of cyclin D1 alone or in combination with ras or with p53-mt was not sufficient for focus formation of rat embryonic fibroblasts. However, focus formation induced by co-transfection of ras and p53-mt was enhanced in the presence of the cyclin D1-expression plasmid. Co-transfection of ras- and p53-mt-transformants with the cyclin D1-expression plasmid resulted in reduced serum dependency in vitro. Furthermore, the transformants expressing exogenous cyclin D1 grew faster than those without the cyclin D1 plasmid when injected into nude mice. These observations strengthen the significance of cyclin D1 overexpression through gene rearrangement or gene amplification observed in human tumors as a step in multistep oncogenesis; deregulated expression of cyclin D1 may reduce the requirement for growth factors and may stimulate in vivo growth.

Animals↗
PubMed1996

Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study.

BACKGROUND AND PURPOSE: Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people. METHODS: Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information. RESULTS: Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P < .01) and independently associated with increased grade were greater age, clinically silent stroke on MRI, higher systolic blood pressure, lower forced expiratory volume in 1 second (FEV1), and income less than $50,000 per year. If excluded, FEV1 was replaced in the model by female sex, history of smoking, and history of physician-diagnosed hypertension at the baseline examination. Many clinical features were correlated with the white matter grade, especially those indicating impaired cognitive and lower extremity function. CONCLUSIONS: White matter findings were significantly associated with age, silent stroke, hypertension, FEV1, and income. The white matter findings may not be considered benign because they are associated with impaired cognitive and lower extremity function.

Age Factors↗
PubMed1996

Loss of chromosome arm 9p DNA and analysis of the p16 and p15 cyclin-dependent kinase inhibitor genes in human parathyroid adenomas.

Rearrangement and overexpression of the PRAD1/cyclin D1 oncogene, a cell cycle regulator, have been implicated in the pathogenesis of a subset of parathyroid adenomas. Recently, two cell cycle regulators that inhibit the cyclin D1-associated kinases cdk4 and cdk6 have been identified: p16 and p15, the products of the INK4A (also known as CDKN2, MTS1) and INK4B (also known as MTS2) putative tumor suppressor genes located on 9p21. Because inactivation of the p16 or p15 genes might be expected to result in oncogenic consequences similar to those from cyclin D1 overexpression, we examined 25 parathyroid adenomas for 1) allelic loss of polymorphic DNA loci on chromosome arm 9p, 2) homozygous deletions of the p16 and p15 genes by Southern blot analysis, and 3) mutations of the p16 and p15 genes by single strand conformational polymorphism analysis. Heterozygous allelic loss at 9p was observed in 4 of 25 adenomas (16%); their smallest shared region of deletion was 9p21-pter, which includes both the p16 and p15 genes. However, single strand conformational polymorphism analysis of all 3 exons of the p16 gene and both exons of the p15 gene failed to demonstrate mutation in any of the 25 cases, and homozygous deletions of the p16 and p15 genes, which are present in some human cancers, were not found in any parathyroid tumors. These observations indicate that inactivating mutations or homozygous deletions of the p16 and p15 genes occur uncommonly, if ever, in parathyroid adenomas; however, loss of a different tumor suppressor gene (or genes) on 9p appears to contribute to the pathogenesis of a significant percentage of these tumors.

Base Sequence↗
PubMed1996

Cyclin D1/PRAD1 expression in parathyroid adenomas: an immunohistochemical study.

The cyclin D1 (PRAD1) oncogene is rearranged with the PTH gene and is transcriptionally activated in a subset of parathyroid adenomas. Because of heterogeneity in rearrangement breakpoints, the true percentage of adenomas with cyclin D1 deregulation is unknown. Overexpression of the cyclin D1 protein in parathyroid adenomas appears to be a unifying consequence of all cyclin D1 gene rearrangements and can, therefore, be examined to more comprehensively identify adenomas in which cyclin D1 is pathogenetically important. We studied cyclin D1 expression in 65 parathyroid adenomas (from 64 patients), 51 normal parathyroid glands (from the same patients), and 4 parathyroid carcinoma specimens (from 3 patients) using a microwave-enhanced immunohistochemical method and affinity-purified cyclin D1 polyclonal antiserum. When available, data on adenoma mass, intact PTH level, and concurrent serum calcium level were also collected. Twelve of the 65 adenomas (18%) showed diffuse nuclear staining of approximately 30-70% of the tumor cells. All 51 normal glands were negative, except 1 gland that showed scattered cells ( < 10%) with positive nuclear staining. In addition, scattered positive cells were seen in the compressed rim of histologically normal parathyroid tissue surrounding 2 adenomas that were cyclin D1 negative. No significant differences in adenoma mass, intact PTH levels, or concurrent calcium levels were found between positive and negative tumors. Two of 4 parathyroid carcinoma specimens from 2 of 3 patients showed strong nuclear staining for cyclin D1. Overexpression of the cyclin D1 oncogene in 18% of our cases, due to the cyclin D1/PTH translocation and/or other mechanisms, suggests that overexpressed cyclin D1 plays a role in the pathogenesis of a much larger proportion of parathyroid adenomas than previously appreciated. Cyclin D1 overexpression is a feature of typical parathyroid adenomas and is not confined to unusually large, symptom-causing adenomas as had been suggested by early DNA studies. Although only three patients with parathyroid carcinoma were studied, two of the patients' tumors stained for cyclin D1, raising the possibility that the frequency of cyclin D1 overexpression may be even greater in carcinomas. Cyclin D1 overexpression appears to highlight a central pathway in parathyroid neoplasia.

Adenoma↗
PubMed1996

Role of the RET proto-oncogene in sporadic hyperparathyroidism and in hyperparathyroidism of multiple endocrine neoplasia type 2.

Parathyroid tumors occur either sporadically or as part of inherited syndromes such as multiple endocrine neoplasia (MEN) types 2A and 2B. The development of both of these familial syndromes has been related to specific germline gain-of-function mutations predominantly in exons 10 and 11 (MEN 2A) and 16 (MEN 2B) of the RET proto-oncogene. The same mutations have also been implicated in the pathogenesis of sporadic medullary thyroid carcinoma and sporadic pheochromocytoma. The RET mutations are thought to have a transforming effect only in cells of neural crest origin such as thyroid parafollicular (C-cells) and adrenal chromaffin cells, which normally express the RET proto-oncogene. Expression of RET messenger RNA has not yet been studied in the parathyroid, however, we demonstrate in this study by a sensitive, semiquantitative RT-PCR technique and in situ hybridization, that RET is expressed in MEN 2A parathyroid tumors and in sporadic adenomas. Although DNA from a parathyroid tumor of a MEN 2A patient displayed an expected mutation, none of the previously described MEN 2A or 2B mutations were found in DNA of 34 sporadic adenomas. Our data suggest that parathyroid disease is an integral part of the MEN 2A syndrome, but that MEN 2 mutations in RET rarely play a part in the pathogenesis of sporadic parathyroid tumors.

Adenoma↗
PubMed1996

Spirometry reference values for healthy elderly blacks. The Cardiovascular Health Study Research Group.

Pulmonary function was assessed by spirometry in 497 black and 2,980 white ambulatory elderly male and female participants of the Cardiovascular Health Study. The quality assurance program prompted technicians to exceed American Thoracic Society recommendations for spirometry. A "healthy" subgroup of 235 black and 1,227 white participants age 65 years and older was identified by excluding current and former smoker, and those with self-reported asthma or emphysema, congestive heart failure, and poor-quality results of spirometry tests, since those factors were associated with a lower FEV1. Reference equations and normal ranges for elderly blacks for measurements of FEV1, FVC, and the FEV1/FVC ratio were then determined from the healthy group. These elderly blacks had an FVC about 6% lower than elderly whites, even after correcting for standing height, sitting height (trunk length), and age. The popular use of spirometry reference values from studies of middle-aged white subjects by applying a 12% race correction factor for black patients appears to overestimate predicted values.

Aged↗