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S L Asa

Publications and source records attributed to S L Asa.

At least 19 recordsLinked to original sources
PubMed2001

A soluble dominant negative fibroblast growth factor receptor 4 isoform in human MCF-7 breast cancer cells.

Fibroblast growth factor receptors (FGFRs) are receptor tyrosine kinases encoded by four closely related genes. FGFR 1, 2, and 3 have a number of isoforms derived by alternative splicing, alternative initiation and exon switching; however, FGFR4 has been reported to encode a single intact receptor with three extracellular immunoglobulin (Ig)-like domains, a transmembrane domain, and a split intracellular kinase. Here we describe a novel C-terminally truncated soluble isoform of FGFR4 expressed by human epithelial breast cancer MCF-7 cells. This isoform results from failure of splicing of intron 4 resulting in an mRNA species that encodes an in-frame premature stop codon. Cells transfected with the corresponding cDNA containing intron 4 express a truncated releasable protein that is identified in conditioned media. This soluble FGFR4 isoform (sFGFR4) abrogates the effect of FGF-1-induced MAPK phosphorylation and PRL gene activation. These findings represent the first description of an endogenous soluble C-terminally truncated FGFR4 isoform with FGF modulatory properties.

3T3 Cells↗
PubMed2001

How familial cancer genes and environmentally induced oncogenes have changed the endocrine landscape.

The gene responsible for MEN-2, the ret proto-ocogene, has elucidated mechanisms of endocrine tumorigenesis. Activating mutations of this transmembrane tyrosine kinase receptor represent the first known example of an inherited oncogene. This knowledge has altered our approach to affected patients by allowing in utero screening and prophylactic thyroidectomy rather than provocative testing and morphologic analysis of C cell hyperplasia--will it result in eradication of medullary carcinoma of thyroid? The lessons from Chernobyl taught us how radiation can induce chromosomal rearrangements that involve the same gene. This has led to a better understanding of papillary thyroid carcinoma and provides a novel immunohistochemical marker that widens our diagnostic armamentarium.

Adenocarcinoma↗
PubMed2001

Immunohistochemical diagnosis of papillary thyroid carcinoma.

In thyroid, the diagnosis of papillary carcinoma (PC) is based on nuclear features; however, identification of these features is inconsistent and controversial. Proposed markers of PC include HBME-1, specific cytokeratins (CK) such as CK19, and ret, the latter reflecting a ret/PTC rearrangement. We applied immunohistochemical stains to determine the diagnostic accuracy of these three markers. Formalin-fixed, paraffin-embedded tissue from 232 surgically resected thyroid nodules included 40 hyperplastic nodules (NH), 35 follicular adenomas (FA), 138 papillary carcinomas (PC; 54 classical papillary tumors and 84 follicular variant papillary carcinomas [FVPC]), 4 follicular carcinomas (FC), 6 insular carcinomas (IC), 7 Hürthle cell carcinomas (HCC), and 2 anaplastic carcinomas (AC). HBME-1 and ret were negative in all NH and FA; some of these exhibited focal CK19 reactivity in areas of degeneration. Half of the FC and AC exhibited HBME-1 staining but no positivity for CK19 or ret. In PC, 20% of cases stained for all three markers. Classical PC had the highest positivity with staining for HBME-1 in 70%, CK19 in 80%, and ret in 78%. FVPC were positive for HBME-1 in 45%, for CK19 in 57%, and for ret in 63%; only 7 FVPC were negative for all three markers. The six IC exhibited 67% staining for HBME-1 and 50% positivity for CK19 and ret. The seven HCC had 29% positivity for HBME-1 and CK19, and 57% positivity for ret. This panel of three immunohistochemical markers provides a useful means of diagnosing PC. Focal CK19 staining may be found in benign lesions, but diffuse positivity is characteristic of PC. HBME-1 positivity indicates malignancy but not papillary differentiation. Only rarely are all three markers negative in PC; this panel therefore provides an objective and reproducible tool for the analysis of difficult thyroid nodules.

Adenocarcinoma, Follicular↗
PubMed2001

Growth hormone-releasing hormone (GHRH) and GHRH receptor (GHRH-R) isoform expression in ectopic acromegaly.

Bronchial endocrine neoplasms causing acromegaly due to ectopic production of growth hormone (GH)-releasing hormone (GHRH) have been reported. We describe the case of a 39-year-old man with clinical and biochemical acromegaly. Magnetic resonance imaging revealed an enlarged pituitary, which was confirmed histologically to harbour somatotroph hyperplasia. Further investigations identified a circumscribed central mass in the right lung which was surgically resected and histologically confirmed to be an endocrine tumour with strong immunopositivity for GHRH, synaptophysin and chromogranin; the lesion also exhibited mild positivity for peptide YY, calcitonin gene-related peptide (CGRP), glucagon-like peptide (GLP)-1, corticotrophin-releasing hormone (CRH), tyrosine hydroxylase, vasoactive intestinal peptide (VIP) and enkephalin. S100 protein was identified in stellate cells surrounding nests of epithelial tumour cells. The MIB-1 antibody labelled about 10% of the tumour cells. We established that the tumour not only produced GHRH but the GHRH-receptor (GHRH-R) as well. GHRH and GHRH-R mRNA were identified and the latter was characterized as two variants, a full-length transcript and a truncated splice variant that has been described in human pituitary somatotroph adenomas. We suggest that GHRH expression by this tumour and the presence of its receptor may be responsible for enhanced growth. The expression of a truncated splice variant that is unable to transduce GHRH signalling may be implicated in the less aggressive behaviour of well-differentiated endocrine tumours that produce GHRH compared with small-cell lung carcinomas that are very responsive to GHRH growth stimulation.

Acromegaly↗
PubMed2001

Distinct clonal composition of primary and metastatic adrencorticotrophic hormone-producing pituitary carcinoma.

The pathogenetic mechanisms underlying pituitary tumorigenesis are largely unknown. Previous reports have suggested that aggressive pituitary adenomas and/or carcinomas may be associated with genetic alterations that are distinct from those responsible for the more common and less aggressive pituitary adenomas. Here, we describe the clonal composition of a pituitary carcinoma, its recurrence and its metastasis. The samples studied were from a 48-year-old woman who presented with recurrent Cushing's syndrome. During the 8-year course of her disease, she had an ACTH-producing pituitary carcinoma requiring two transsphenoidal procedures and resection of a metastatic cervical lymph node. Her disease remained active despite surgical resection, external beam irradiation and medical treatment with ketoconazole. Ultimately, bilateral adrenalectomy was performed to control the hypercortisolism. Morphological and immunohistochemical studies revealed that the primary and recurrent pituitary tumours and the metastatic lesion were an endocrine tumour with ACTH and growth hormone immunoreactivity. Primary, recurrent and metastatic tumour DNAs were analysed for X-chromosome inactivation and loss of heterozygosity (LOH) at several microsatellite loci on chromosomes 9,10, 11, 13 and 22. All three lesions were monoclonal in composition as suggested by the pattern of X chromosome inactivation of the PGK-1 allele. Moreover, the primary, recurrent and metastatic lesions demonstrated LOH at the microsatellite allelic markers PYGM and D10S217. In contrast, however, the metastatic lesion showed a loss-to-retention pattern at two distinct loci (IFNA and D22S156) compared to the primary and recurrent pituitary tumours. These findings, while consistent with a clonal composition of the primary and metastatic pituitary lesions, show each clone to be distinct. This is the first description of a metastatic pituitary carcinoma with a distinct clonal composition from its primary source.

Adrenocorticotropic Hormone↗
PubMed2001

RET oncogene activation in papillary thyroid carcinoma.

The RET proto-oncogene encodes a cell membrane tyrosine-kinase receptor protein whose ligands belong to the glial cell line-derived neurotrophic factor. RET functions as a multicompetent receptor complex that includes alphaGFRs and RET. Somatic rearrangements of RET designated as RET/PTC (from papillary thyroid carcinoma) were identified in papillary thyroid carcinoma before RET was recognized as the susceptibility gene for MEN2. There are now at least at least 15 types of RET/PTC rearrangements involving RET and 10 different genes. RET/PTC1 and RET/PTC3 are by far the most common rearrangements. All of the rearrangements are due to DNA damage and result in the fusion of the RET tyrosine-kinase (RET-TK) domain to the 5'-terminal region of heterologous genes. RET/PTC rearrangements are very common in radiation-induced tumors but have been detected in variable proportions of sporadic (i.e., non-radiation associated) papillary carcinomas. It is estimated that up to approximately half the papillary thyroid carcinomas in the United States and Canada harbor RET/PTC rearrangements, most commonly RET/PTC-1, followed by RET/PTC-3 and occasionally RET/PTC-2. The cause of these rearrangements in sporadic papillary carcinomas is not known, but the close association between their presence and the papillary carcinoma phenotype indicates that they play a causative role in tumor development. The proposed mechanisms of RET/PTC-induced tumorigenesis and the clinical and pathologic implications of RET/PTC activation are discussed.

Carcinoma, Papillary↗
PubMed2001

Infundibulohypophysitis in a man presenting with diabetes insipidus and cavernous sinus involvement.

Infundibulohypophysitis is an unusual inflammatory condition that affects the infundibulum, the pituitary stalk, and the neurohypophysis and may be part of a range that includes lymphocytic hypophysitis. Lymphocytic hypophysitis occurs mainly in women and most often presents in the later stages of pregnancy. Infundibulohypophysitis usually presents with diabetes insipidus and the cause remains unclear. The case of a 46 year old man with a 12 week history of polyuria and polydipsia is reported. Cranial diabetes insipidus was diagnosed on the basis of a water deprivation test. Initial cranial and pituitary imaging studies were normal. He subsequently developed symptoms of panhypopituitism over a period of 6-9 months and then, more acutely, developed diplopia secondary to a fourth nerve palsy. Further brain imaging studies disclosed an enhancing pituitary stalk and a left cavernous sinus lesion. An initial trial of immunosuppressive treatment did not help symptoms significantly. The diagnosis of infundibulohypophysitis was made on histological evidence. The patient was treated with prednisolone and methotrexate. At 9 months he is well, without symptoms, and the radiological abnormalities have resolved.

Anti-Inflammatory Agents↗
PubMed2001

The spectrum and significance of primary hypophysitis.

Hypophysitis can present clinically as a mass lesion of the sella turcica. Secondary hypophysitis occurs in cases where a definite etiologic agent or process inciting the inflammatory reaction can be identified. In contrast, primary hypophysitis refers to inflammation confined to the pituitary gland with no identifiable etiologic associations. We report three cases of primary hypophysitis to illustrate the spectrum of three clinicopathological entities that encompass this disease: lymphocytic hypophysitis, granulomatous hypophysitis, and xanthomatous hypophysitis. Our three patients underwent surgery, with variable response. However, conservative, supportive treatment with or without surgical decompression is generally favored over aggressive and extensive surgical resection that results in hypopituitarism. We conclude that the optimal management of patients with hyophysitis requires a high index of suspicion before extensive surgical resection. Histological confirmation of the diagnosis of hypophysitis can be obtained by performing a biopsy or by requesting an intraoperative frozen section consultation.

Adult↗
PubMed2001

Analysis of ret/PTC gene rearrangements refines the fine needle aspiration diagnosis of thyroid cancer.

Papillary carcinoma (PC) represents the most common malignancy of the thyroid gland. Therefore, the assessment of fine needle aspiration biopsies of thyroid nodules rests heavily on the identification of nuclear features of PC. The ret/PTC oncogene, formed by several gene rearrangements, is specific for PC among thyroid tumors. In this study we examined thyroid aspirates for the presence of ret/PTC gene rearrangements by RT-PCR and Southern hybridization. We prospectively collected thyroid aspirates in Cytolyt solution and prepared slides for cytological examination using the ThinPrep method. All remaining material was then used for nucleic acid extraction with subsequent RT-PCR for the housekeeping gene PGK-1 to ensure ribonucleic acid integrity, for thyroglobulin to ensure the presence of follicular epithelial cells, and for the three most common ret/PTC gene rearrangements (ret/PTC-1, -2, and -3). The results of the first 73 cases with surgical follow-up were correlated with the cytological diagnosis and final histopathology. ret/PTC gene rearrangements were detected in 17 of 33 samples (52%) that were PC on histopathology; the presence of gene rearrangements was confirmed by molecular analysis of corresponding surgically resected frozen tissue. There were no false positives. The identification of ret/PTC gene rearrangements refined the diagnosis of PC in 9 of 15 specimens (60%) that would otherwise have been considered indeterminate and in 2 of 6 that were considered insufficient for cytological diagnosis. The results indicate that RT-PCR for ret/PTC is a specific marker that can be applied to fine needle aspiration biopsies and improves the diagnosis of malignancy when used as an adjunct to traditional cytology.

Biopsy, Needle↗
PubMed2001

Stage-sensitive blockade of pituitary somatomammotrope development by targeted expression of a dominant negative epidermal growth factor receptor in transgenic mice.

The epidermal growth factor receptor (EGFR) and its ligands EGF and transforming growth factor-alpha (TGF alpha) are expressed in the anterior pituitary, and overexpression of TGF alpha in the lactotrope cells of the pituitary gland in transgenic mice results in lactotrope hyperplasia and adenomata, suggesting a role for EGFR signaling in pituitary cell proliferation. To address the role of EGFR signaling in pituitary development in vivo, we blocked EGFR signaling in transgenic mice using the dominant negative properties of a mutant EGFR lacking an intracellular protein kinase domain (EGFR-tr). We directed EGFR-tr expression to GH- and PRL- producing cells using GH and PRL promoters, and a tetracycline-inducible gene expression system, to allow temporal control of gene expression. EGFR-tr overexpression in GH-producing cells during embryogenesis resulted in dwarf mice with pituitary hypoplasia. Both somatotrope and lactotrope development were blocked. However, when EGFR-tr overexpression was delayed to the postnatal period either by directing its expression with the PRL promoter or by delaying the onset of induction with tetracycline in the GH cells, no specific phenotype was observed. Lactotrope hyperplasia during pregnancy also occurred normally in the PRL-EGFR-tr mice. These data suggest that EGFR signaling is required for the differentiation and/or maintenance of somatomammotropes early in pituitary organogenesis but not later in life. (Molecular Endocrinology 15: 600-613, 2001)

Animals↗
PubMed2001

The endogenous fibroblast growth factor-2 antisense gene product regulates pituitary cell growth and hormone production.

Basic fibroblast growth factor (bFGF; FGF-2) is one of 19 related members of a growth factor family with mitogenic and hormone-regulatory functions. In Xenopus laevis oocytes, a 1.5-kb FGF-2 antisense (GFG) RNA complementary to the third exon and 3'-untranslated region (UTR) of FGF-2 mRNA has been implicated in FGF-2 mRNA editing and stability. The human homolog has been cloned, and we localized this gene by yeast artificial chromosome (YAC), somatic cell, and radiation hybrid panels to the same chromosomal site as FGF-2 (chromosome 4, JO4513 adjacent to D4S430), confirming this as a human endogenous antisense gene. The full-length GFG antisense RNA encodes a 35-kDa protein, which is highly homologous with the MutT family of antimutator nucleosidetriphosphatases (NTPases). We show that human pituitary tumors express FGF-2 and its endogenous antisense partner GFG. While normal pituitary expresses GFG but not FGF-2, pituitary adenomas express FGF-2 and have reduced levels of GFG; aggressive and recurrent adenomas expressed more FGF than GFG mRNA. To examine the effects of this antisense gene in the pituitary, we transfected the pituitary-derived GH4 mammosomatotroph cell line with constructs encoding the full-length human GFG cDNA. Transiently and stably transfected cells expressed the 35-kDa GFG protein that was localized to the cytoplasm. These cells exhibited enhanced PRL expression as documented by transiently transfected PRL-luciferase reporter assay and by endogenous PRL protein. GFG expression in these cells did not alter endogenous FGF-2 expression but increased the proportion of the higher molecular mass 22-kDa form of GH. Moreover, GFG expression inhibited cell proliferation as shown by [(3)H]thymidine incorporation, proliferating cell nuclear antigen (PCNA) nuclear staining, and cell cycle analysis. We conclude that the GFG-encoded protein has divergent hormone-regulatory and antiproliferative actions in the pituitary that are independent of FGF-2 expression. GFG represents a novel mechanism involved in restraining pituitary tumor cell growth while promoting hormonal activity.

Adenoma↗
PubMed2001

The mind's eye.

Explore the source record for details and available documents.

Adenoma↗
PubMed2001

Transgenic and knockout mouse models clarify pituitary development, function and disease.

Mouse models have been used to study various aspects of pituitary development, function and disease. Transgenic or knockout technology has been applied to examine the regulation of hormone gene expression and the pathophysiology of its alterations, to ascertain the factors that determine cell differentiation, and to manipulate oncogenesis. Transgenic mice have elucidated the necessary elements required for the tissue- and cell-specific expression of pituitary hormones. Transgenic and knockout technologies have derived mice with hormone overexpression or abrogation of hormone action, and have identified novel hormones. The role of precursor cells in cell differentiation has been confirmed by genetic ablation of cell lineages. Inactivation of transcription factors implicated in pituitary organogenesis and cytogenesis has proven their critical roles in pituitary development. Pituitary oncogenesis has been studied by promoter-directed oncogene expression or tumor suppressor gene ablation, by adenohypophysiotropic hormone overexpression, or by growth factor or receptor overexpression. The tumors have provided a number of cell lines for use in the continuing study of pituitary physiology and pathology. These models may also be used in the future to examine novel therapeutic strategies for the management of patients with pituitary disorders.

Animals↗
PubMed2000

Evidence for growth hormone (GH) autoregulation in pituitary somatotrophs in GH antagonist-transgenic mice and GH receptor-deficient mice.

Growth hormone (GH) modulates the hypothalamic release of somatostatin and GH-releasing hormone; however, there has been no evidence of GH autoregulation on the pituitary somatotroph. To determine the effects of GH on its own regulation, we examined the pituitaries of giant transgenic mice expressing a GH agonist (E117L), dwarf transgenic mice expressing a GH antagonist (G119K), and dwarf mice devoid of the GH receptor/binding protein (GHR/BP). In the E117L transgenic mice, the number and distribution of pituitary GH-immunoreactive cells were unchanged from nontransgenic littermate controls; an ultrastructural examination revealed typical, densely granulated somatotrophs. In contrast, the pituitaries of the G119K mice contained both moderately granulated somatotrophs and a sparsely granulated (SG) population with well-developed synthetic organelles and a distinct juxtanuclear globular GH-staining pattern. GHR/BP-deficient mice exhibited a marked reduction in the intensity of cytoplasmic GH immunoreactivity; however, prominent GH staining in the juxtanuclear Golgi was seen. GH-immunoreactive cells were increased in number, and the reticulin network pattern was distorted; stains for proliferating cell nuclear antigen confirmed mild hyperplasia. Electron microscopy showed that the somatotrophs were hyperactive SG cells with prominent endoplasmic reticulum membranes, large Golgi complexes, and numerous mitochondria. These findings are consistent with synthetic and secretory hyperactivity in pituitary somatotrophs due to the reduced GH feedback regulation. The changes are most striking in animals that are devoid of GHR/BP and less marked in animals expressing a GH antagonist; both models had reduced insulin-like growth factor-I levels, but the more dramatic change in the GHR/BP animals can be explained by abrogated GH signaling. This represents the first evidence of direct GH feedback inhibition on pituitary somatotrophs, which may have implications for the use of GH analogs in different clinical settings.

Animals↗
PubMed2000

Expression of prostate-specific antigen and human glandular kallikrein 2 in the thyroid gland.

Prostate-specific antigen (PSA) and human glandular kallikrein 2 (hK2) are two closely related kallikreins, primarily produced by the prostate. These serine proteases are now used as biomarkers for the diagnosis and management of prostate cancer. Until recently, PSA and hK2 were thought to be strictly expressed in the prostate; however, numerous studies confirmed their presence in various biological fluids as well as in many normal and malignant tissues. Using reverse transcription-polymerase chain reaction (RT-PCR), we screened RNA extracted from 26 different normal tissues and found that both genes are expressed in the thyroid. Subsequently, we analyzed 15 RNAs extracted from thyroid tissues (10 benign and 5 malignant lesions) and found that both kallikreins were expressed in five specimens (four benign lesions and one malignant). Sequencing of the PCR products confirmed the specificity of our experiments. Immunohistochemistry localized PSA in oxyphilic cells of thyroid tissue. These data confirm expression of both PSA and hK2 in thyroid tissue and suggest that oxyphils are the source of their production. The function of these two proteases in thyroid tissue is unknown.

Base Sequence↗
PubMed2000

Enteroendocrine localization of GLP-2 receptor expression in humans and rodents.

BACKGROUND & AIMS: Glucagon-like peptide (GLP)-2, a product of the proglucagon gene, is expressed in enteroendocrine cells of the small and large intestine and is trophic to the gastrointestinal mucosa. GLP-2 also inhibits gastric acid secretion and emptying and up-regulates intestinal hexose transport. GLP-2 acts via binding to a single G protein-coupled GLP-2 receptor (GLP-2R), but the cellular targets for the diverse actions of GLP-2 remain unknown. METHODS: GLP-2R expression in rodent and human tissues was examined using a combination of Northern blotting, reverse-transcription polymerase chain reaction (RT-PCR), and immunocytochemistry. RESULTS: A single major GLP-2R messenger RNA transcript was detected by Northern blot analysis in rodent stomach, duodenum, jejunum, ileum, and colon, but not in rodent esophagus. GLP-2R expression was also detected by RT-PCR in RNA from the hypothalamus, brain stem, and lung. Immunocytochemical localization of human GLP-2R expression using specific antisera detected GLP-2R immunopositivity in subsets of endocrine cell populations in the epithelium of the stomach and both the small and large bowel. CONCLUSIONS: These findings suggest that enteroendocrine-derived GLP-2 acts directly on endocrine cells to induce one or more downstream mediators of GLP-2 action in the gastrointestinal tract.

Animals↗
PubMed2000

Human skin expresses growth hormone but not the prolactin gene.

Using sensitive reverse transcriptase-polymerase chain reaction (RT-PCR) methods, we showed the expression of mRNA for growth hormone (GH) but not prolactin (PRL) in whole human skin (normal and basal cell carcinoma (BCC)). These RNAs for PRL and GH were below detectability in human epidermal keratinocytes and in human and hamster malignant melanocytes. This is in agreement with previous studies showing GH gene expression in dermal fibroblasts. GH peptide was not detected (by immunocytochemistry) in human skin specimens (normal and pathologic) in either dermal or epidermal compartments. The mRNA coding for the GH mediator insulin-like growth factor-1 (IGF-1) was detectable in whole skin and in malignant melanocytes. Therefore, in the present investigation of hormonal mediators of the cutaneous (epidermal) response to environmental stress, we have excluded the direct participation of PRL and GH in that reaction. Thus the analogy previously noted between the systemic (central) and skin responses to stress, as represented by cutaneous expression of hypothalamic-pituitary-adrenal axis components, does not extend to other pituitary hormones also involved in that response such as PRL and GH.

Adult↗