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Biomedical subjects

S A Graham

Publications and source records attributed to S A Graham.

At least 19 recordsLinked to original sources
PubMed1999

Calcitonin driven v-Ha-ras induces multilineage pulmonary epithelial hyperplasias and neoplasms.

We initiated a transgenic model for primary pulmonary neuroendocrine cell (PNEC) hyperplasia/neoplasia using v-Ha-ras driven by the neural/neuroendocrine (NE)-specific calcitonin promoter (rascal). Previously, we showed that nitrosamine treated rodents develop PNEC hyperplasia but non-NE lung tumors, with variable outcomes presumably reflecting ras activation in multiple cell lineages. Interestingly, all rascal transgenic mouse lineages develop hyperplasias of NE and non-NE cells but mostly non-NE lung carcinomas, with rascal mRNA in differentiated PNECs and tumor cells. Analyses of embryonic lung demonstrate rascal mRNA in undifferentiated epithelium, consistent with expression in a common pluripotent precursor cell. These unexpected observations indicate that v-Ha-ras can lead to both NE and non-NE hyperplasia/neoplasia in vivo, opening new avenues for studies of lung carcinogenesis.

Adenocarcinoma↗
PubMed1999

Preschoolers' and adults' reliance on object shape and object function for lexical extension.

We investigated the developmental progression of reliance on object function versus object shape to extend novel words. In 3 experiments, 3-year-olds, 5-year-olds, and adults were presented with sets of objects consisting of a target, a same-shape/different-function match, a different-shape/same-function match, and a distracter. In Experiments 1 and 2, function was emphasized during the word learning phase and participants were given direct experience with the functions of target and test objects. In Experiment 3, function was emphasized both during the learning phase and when requesting a referent of the novel labels. Across all 3 experiments, 3- and 5-year-olds focused on shape while adults focused on function when extending the novel words. These results suggest a developmental change in the consideration of shape and function in lexical extension.

Adult↗
PubMed1999

CD10/neutral endopeptidase inhibition augments pulmonary neuroendocrine cell hyperplasia in hamsters treated with diethylnitrosamine and hyperoxia.

In previous studies, we demonstrated that pulmonary neuroendocrine cell (PNEC) hyperplasia in hamsters treated with diethylnitrosamine (DEN) plus 65% hyperoxia (DEN/O2) reflects predominantly neuroendocrine cell differentiation. Several peptides implicated in non-neoplastic PNEC hyperplasia are hydrolyzed by CD10/neutral endopeptidase 24.11 (CD10/NEP), an enzyme known to downregulate neurogenic inflammation of the lung by modulating locally effective concentrations of multiple bioactive peptides. In fetal mice, we observed that CD10/NEP inhibition by SCH32615 potentiates cell proliferation and type II cell differentiation in the lung in utero. Further, CD10/NEP messenger RNA levels parallelled relative PNEC numbers in DEN/O2-treated hamster lung, suggesting that the enzyme might mediate spontaneous regression of PNEC hyperplasia. The goals of the present study were: (1) to determine whether CD10/NEP inhibition would alter the extent of PNEC hyperplasia occurring in these hamsters, and (2) to analyze cellular mechanisms potentially involved in altering numbers of PNECs in this model. We administered SCH32615 chronically to a subset of DEN/O2-treated hamsters. Immunostaining of lungs from the CD10/ NEP-inhibited subset demonstrated significant acceleration of the development of PNEC hyperplasia, increased PNEC proliferation, and diminished PNEC apoptosis as compared with animals receiving no SCH32615. These observations indicate that PNEC hyperplasia can occur as a result of multiple cellular processes, including increased neuroendocrine cell differentiation, proliferation, and survival. CD10/NEP modulates PNEC numbers primarily by promoting cell differentiation and proliferation during lung injury, probably via increasing the half-life of bioactive peptides in the lung.

Animals↗
PubMed1998

Infants' expectations about object label reference.

The aim of this research was to examine whether infants at the early stages of lexical development were sensitive to the word-category linkage. In Experiment 1, 16-to 19-month-old infants were requested to match a target with either a basic-level or a thematic match, with or without a novel label. Stimuli were presented using the preferential looking paradigm. Infants in the Novel Label condition looked significantly longer at the basic-level match than infants in the No Label condition. In Experiment 2, infants were presented with a target, followed by a basic-level match and a superordinate-level match with or without a novel label. Again, infants in the Novel Label condition looked significantly longer at the basic-level match than infants in the No Label condition. Taken together, these findings indicate that infants initially assume that novel words label basic-level categories and thereby do honour the word-category linkage.

Child Development↗
PubMed1998

Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.

Previously, we identified macrophage-stimulating protein (MSP) as being expressed during hamster lung injury induced by nitrosamine carcinogens. Transient, generalized epithelial-cell hyperplasia during the preneoplastic period, and eventually nonneuroendocrine (non-NE) lung tumors, are known to develop in these nitrosamine-treated hamsters. We wished to test the hypothesis that MSP and its tyrosine kinase receptor, RON, might represent an autocrine/paracrine system involved in the pathogenesis of human nonneuroendocrine lung tumors, the non-small-cell carcinomas (NSCLCs). We found that this occurred in a paracrine fashion in three of eight primary human NSCLCs that expressed messenger RNA (mRNA) for MSP at high levels in histologically normal lung adjacent to the tumor, but not in the primary tumor, together with mRNA for RON in both normal and tumor tissue. MSP and RON could also constitute an autocrine/paracrine system in human NSCLC cell lines: five of 16 cell lines (squamous and adenosquamous) expressed both MSP and RON; and an additional five of 16 cell lines expressed RON without detectable MSP. Although three cases of primary squamous-cell carcinomas expressed MSP (two of three in the tumor and one of three in nonneoplastic lung), mRNA for RON was not detectable in these cases. RON was functional in all tested RON mRNA-positive cell lines, with exogenous MSP inducing RON-mediated tyrosine phosphorylation. Treatment of a RON-positive adenosquamous carcinoma cell line with MSP additionally resulted in increased motility in a cell-migration assay, suggesting that MSP might promote cell migration of some NSCLCs. In conclusion, MSP and RON might represent an autocrine/paracrine system involved in the pathogenesis of lung cancer, although the nature of the biologic responses in different cell types might vary considerably.

Carcinoma, Non-Small-Cell Lung↗
PubMed1997

Differential screening of a human chromosome 3 library identifies hepatocyte growth factor-like/macrophage-stimulating protein and its receptor in injured lung. Possible implications for neuroendocrine cell survival.

Transient pulmonary neuroendocrine cell hyperplasia and non-neuroendocrine lung tumors develop in nitrosaminetreated hamsters, which we hypothesized might modulate epithelial cell phenotype by expressing gene(s) homologous to human chromosome 3p gene(s) deleted in small cell carcinoma of the lung (SCLC). We differentially screened a chromosome 3 library using nitrosamine-treated versus normal hamster lung cDNAs and identified hepatocyte growth factor-like/macrophage-stimulating protein (HGFL/MSP) in injured lung. HGFL/MSP mRNA is low to undetectable in human SCLC and carcinoid tumors, but the HGFL/MSP tyrosine kinase receptor, RON, is present and functional on many of these neuroendocrine tumors. In H835, a pulmonary carcinoid cell line, and H187, a SCLC cell line, HGFL/ MSP induced adhesion/flattening and apoptosis. Using viable cell counts to assess proliferation after 14 d of treatment with HGFL/MSP, there is growth inhibition of H835 but not H187. Nitrosamine-treated hamsters also demonstrate pulmonary neuroendocrine cell apoptosis in situ during the same time period as expression of the endogenous HGFL/ MSP gene, immediately preceding the spontaneous regression of neuroendocrine cell hyperplasia. These observations suggest that HGFL/MSP might regulate neuroendocrine cell survival during preneoplastic lung injury, which could influence the ultimate tumor cell phenotype.

Animals↗
PubMed1995

Histochemical characterization of non-neuroendocrine tumors and neuroendocrine cell hyperplasia induced in hamster lung by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone with or without hyperoxia.

Lung tumors induced by 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK) with or without hyperoxia have frequent K-ras mutations but only rare p53 mutations, suggesting that this may be a model for non-small cell lung cancers. The goals of the present study were (1) to characterize the histopathology of lung tumors induced in hamsters by NNK with or without O2 and (2) as a corollary, to quantitate the pulmonary neuroendocrine cell hyperplasia in the different treatment groups early and late in the treatment period. Lung tumors induced by NNK with or without O2 were 71% adenomas, 22% adenocarcinomas, approximately 4% bronchoalveolar carcinomas, and approximately 4% squamous/adenosquamous carcinomas. One-half of all tumors were positive for the Clara cell antigen CC10 and 21% of NNK-induced tumors were mucin positive, compared with 2% of NNK/O2-induced tumors (P = 0.003). Immunostaining for PGP9.5 was positive in 5% of tumors induced by NNK alone, but in none of NNK/O2-induced tumors (P = 0.024). Abundant proliferating cell nuclear antigen occurred in 55% of NNK-induced tumors, compared with 19% of NNK/O2-induced tumors (P = 0.009). These data indicate that NNK with or without O2 induces non-neuroendocrine lung tumors. Hyperoxia appears to inhibit cell proliferation and suppress mucinous and partial neuroendocrine differentiation in some of these tumors.

Animals↗
PubMed1994

Quantification of mitral regurgitation by integrated Doppler backscatter power.

OBJECTIVES: We attempted to determine whether continuous wave Doppler backscatter power could be used to quantify mitral regurgitation. BACKGROUND: The power of a Doppler backscatter signal is proportional to the number of scatterers insonated and, hence, to the moving volume of blood. The relative power of the continuous wave Doppler signals from mitral inflow and aortic outflow is therefore proportional to the relative volumes of blood in motion. METHODS: Computer postprocessing was used to derive the relative power of the Doppler backscatter signal from the intensity of the pixels within the spectral display of anterograde aortic and mitral flow. The power ratio was used to calculate the regurgitant fraction in 20 patients (mean age 61.4 years) with mitral regurgitation. This Doppler regurgitant fraction was compared with that derived from angiographic left ventricular volume and thermodilution cardiac output. In addition, 12 normal control subjects were studied by the Doppler method. RESULTS: Mean (+/- SD) catheterization regurgitant fraction was 0.50 +/- 0.26, and mean Doppler regurgitant fraction was 0.47 +/- 0.25 (r = 0.89). The limits of agreement between the two methods by Bland-Altman analysis were -0.21 + 0.27. In normal control subjects with an expected regurgitant fraction of close to zero, mean Doppler regurgitant fraction was 0.03 +/- 0.05. CONCLUSIONS: Doppler backscatter power from mitral and aortic inflow provides a new and accurate method for quantifying mitral regurgitation.

Adult↗
PubMed1994

Modulation of oncogene and tumor suppressor gene expression in a hamster model of chronic lung injury with varying degrees of pulmonary neuroendocrine cell hyperplasia.

BACKGROUND: Intense pulmonary neuroendocrine cell (PNEC) hyperplasia occurs during preneoplastic lung injury in hamsters treated with diethylnitrosamine (DEN) plus hyperoxia. Alterations in oncogene and tumor suppressor gene expression during this process have not been explored. EXPERIMENTAL DESIGN: Our goals were: (a) to analyze expression of genes potentially involved in growth and differentiation of PNECs and/or nonneuroendocrine pulmonary epithelial cells (non-PNECs) in hamsters treated for up to 20 weeks with hyperoxia and DEN or the major tobacco-derived nitrosamine, 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanone (NNK); and (b) as a corollary, to determine which cells were most mitotically active by immunostaining for c-myc and proliferating cell nuclear antigen. RESULTS: Immunohistochemical analyses demonstrated intense PNEC hyperplasia after treatment with either DEN/O2 or NNK/O2. Whereas DEN/O2-induced PNEC hyperplasia spontaneously regressed, NNK/O2-induced PNEC hyperplasia continued to increase up to 20 weeks. Rb transcripts were decreased similarly in lungs from all treatment groups (NNK/O2 = DEN/O2 = DEN alone) in spite of large differences in PNEC hyperplasia between these groups. c-myc was overexpressed in lungs from animals treated with NNK/O2, DEN/O2 and DEN alone, in which c-myc protein immunostaining occurred predominantly in non-PNECs. Proliferating cell nuclear antigen immunostaining confirmed that non-PNECs were most mitotically active. CONCLUSIONS: These data indicate that PNEC hyperplasia is primarily due to PNEC differentiation, suggesting that this model is ideal for studying mechanisms of neuroendocrine differentiation. Paracrine effects of PNEC-derived growth factors may then contribute to dysregulation of non-PNEC growth preceding the ultimate development of non-neuroendocrine lung tumors in nitrosamine-treated hamsters.

Animals↗
PubMed1993

CD10/neutral endopeptidase 24.11 regulates fetal lung growth and maturation in utero by potentiating endogenous bombesin-like peptides.

Bombesin-like peptides (BLPs) are mitogens for bronchial epithelial cells and small cell lung carcinomas, and increase fetal lung growth and maturation in utero and in organ cultures. BLPs are hydrolyzed by the enzyme CD10/neutral endopeptidase 24.11 (CD10/NEP) which is expressed in bronchial epithelium and functions to inhibit BLP-mediated growth of small cell lung carcinomas. To determine whether CD10/NEP regulates peptide-mediated lung development, we administered a specific CD10/NEP inhibitor, SCH32615, to fetal mice in utero from gestational days e15-17. Fetal lung tissues were evaluated on e18 for: (a) growth using [3H]thymidine incorporation into nuclear DNA; and (b) maturation using: [3H]-choline incorporation into surfactant phospholipids, electron microscopy for type II pneumocytes, and Northern blot analyses for surfactant apoproteins A, B, and C. Inhibition of CD10/NEP stimulated [3H]thymidine incorporation into DNA (70% above baseline, P < 0.005), [3H]choline incorporation into surfactant phospholipids (38% above baseline, P < 0.005), increased numbers of type II pneumocytes (36% above baseline, P = 0.07), and fivefold higher surfactant protein A transcripts (P < 0.05). CD10/NEP-mediated effects were completely blocked by the specific bombesin receptor antagonist, [D-Phe12, Leu14]bombesin. These observations suggest that CD10/NEP regulates fetal lung growth and maturation mediated by endogenous BLPs.

Animals↗
PubMed1992

Effect of dietary butylated hydroxytoluene on nuclear envelope cytochrome P-450 during the initiation and promotion stages of hepatocarcinogenesis.

The anticarcinogenic effect of the dietary antioxidant butylated hydroxytoluene (BHT) correlates with a preservation of nuclear envelope (NE) cytochrome P-450 in rats undergoing chemically induced hepatocarcinogenesis. This effect of BHT on NE cytochrome P-450 was observed during both the initiation and the promotion stages of hepatocarcinogenesis. Complex interactions between the two different mechanisms of action of BHT (i.e., enzyme induction and antioxidant activity) may account for some of the differences between the patterns of response to BHT observed during initiation and promotion.

Animals↗
PubMed1992

Left ventricular energy in mitral regurgitation: a preliminary report.

Energy exchange based on Newtonian principles is the most appropriate way to express the function of any pump--including the heart. Using information obtained at cardiac catheterisation, we have measured the total work energy (ET) of the left ventricle (LV) (mean 1.63 F) in patients with severe mitral regurgitation (mean regurgitant fraction 0.66). ET was approximately 84% above normal. Of the regurgitant energy (RE) (mean 0.95 F), on average , 3/4 (73.6%) was kinetic (KE) and 1/4 (23.4%) potential (PE). Both components represent wasted LV energy: the kinetic energy associated with turbulence lost as heat, the potential energy responsible for a rise in Left Atrial (LA) pressure. The amount of PE as a percentage of total regurgitant energy (RE) varied considerably from one patient to another (10.5% to 54.4%). Hence, colour flow mapping which detects only KE of turbulent jet flow must underestimate LV energy loss and, because of patient to patient variation, cannot consistently reflect severity of regurgitation. Measurements of PE correlate well with wedge P-wave height. Corresponding non-invasive estimates were made using sphygmodynamometer-calibrated indirect carotid pulse tracings and echocardiographic measurements. These were not significantly different from the invasive measurements. Unfortunately, the calculation of PE is indirect and involves subtraction, so that measurements for individual patients were not accurate enough for clinical use. Part of the non-invasive calculation involved an estimate of left atrial pressure based on the blood pressure measurement and Doppler velocity of regurgitation; this should be a useful measurement in itself.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Prevention of 2-acetylaminofluorene-induced loss of nuclear envelope cytochrome P450 by the simultaneous administration of 3-methylcholanthrene.

Rats fed a basal diet containing 0.05% (w/w) 2-acetylaminofluorene (AAF) for 3 weeks showed a 50% loss of hepatic nuclear envelope cytochrome P450, whereas microsomal P450 remained at control levels. A similar dietary treatment with 0.004% (w/w) 3-methylcholanthrene (MC) caused moderate losses (20-25%) of cytochrome P450 in both nuclear envelopes and microsomes. Administration of the basal diet supplemented with a mixture of AAF (0.05%) plus MC (0.004%) resulted in a preservation of control levels of nuclear envelope cytochrome P450 and a 30% elevation of microsomal P450. Immunoblot analysis revealed that AAF alone, or in concert with MC, induced comparable levels of the P450d form. Induction of cytochrome P450c by dietary MC was detected only when MC was fed together with AAF. As previously found for butylated hydroxytoluene (BHT), the protective effect of dietary MC against hepatocarcinogenesis in AAF-fed rats correlated with a preservation of nuclear envelope cytochrome P450 content and with the induction of cytochrome P450c.

2-Acetylaminofluorene↗
PubMed1989

Induction of rat liver microsomal and nuclear cytochrome P-450 by dietary 2-acetylaminofluorene and butylated hydroxytoluene.

The influence of dietary 2-acetylaminofluorene (AAF) on the cytochrome P-450 content of rat liver microsomal and nuclear fractions was immunochemically probed with monoclonal and polyclonal antibodies to cytochromes P-450c and P-450d. Cytochrome P-450d but not P-450c was immunodetected in microsomes, nuclear envelopes, and nuclei from untreated rats. The levels of both cytochromes P-450c and P-450d were elevated after a diet of either 0.1% AAF for 1 week or 0.05% AAF for 3 weeks. However, the level of cytochrome P-450c relative to P-450d was lower after the more prolonged AAF feeding. Supplementation of AAF-containing diets with 0.3% butylated hydroxytoluene (BHT), which affords protection against AAF hepatocarcinogenesis in high-fat fed rats, protected and/or induced total (spectral) nuclear envelope cytochrome P-450 content. Immunochemical studies of liver fractions showed that BHT enhanced the AAF-dependent induction of cytochrome P-450c, but not of P-450d. This was a concerted effect of AAF + BHT since dietary BHT by itself did not affect the levels of cytochrome P-450c or P-450d as compared to control rats. Since 1- to 3-week dietary AAF had little effect on total (spectral analyses) microsomal cytochrome P-450 but markedly reduced total P-450 in nuclear envelopes, the coordinated induction of specific cytochrome P-450s in the different fractions suggests selective induction and depression of different forms of cytochrome P-450 and provides additional evidence for independent regulation of the drug-metabolizing system in nuclear envelope and microsomes. In addition, these results suggest that regulation of cytochrome P-450 may play a crucial role in the nutritional modulation of AAF hepatocarcinogenesis.

2-Acetylaminofluorene↗
PubMed1989

Cuphea: a new plant source of medium-chain fatty acids.

The plant genus Cuphea (family Lythraceae) promises to provide a new source of industrially and nutritionally important medium-chain fatty acids, especially of lauric acid now supplied exclusively by coconut and palm kernel oils from foreign sources. The seed lipids of Cuphea were first discovered in the 1960s to contain high percentages of several medium-chain fatty acids, including caprylic, capric, lauric, and myristic acid. Research is still in the early stages, but it is intensifying toward the goal of developing the genus into a new temperate climate crop for production of specialty oils. Given the diversity of Cuphea seed lipid composition and the wide ecological and distributional range of the genus, it may be possible to tailor crops to produce selected fatty acids on demand under a variety of growing conditions. Cuphea comprises about 260 species, most native to the New World tropics. Its morphology, classification, chromosome numbers, distribution, ecology, and folk uses are presented. Seed structure is described and seed lipid composition for 73 species is summarized. Problems in domestication and agronomic progress are reviewed. Knowledge of the biosynthetic mechanism controlling the lipids produced by Cuphea remains very limited. Future research in this area, and particularly successful employment of gene transfer techniques, may allow genes controlling the mechanism to be transferred to an already established seed oil producer such as rapeseed. Presently, both traditional plant breeding techniques and newer biotechnological methods are directed toward Cuphea oilseed development.

Fatty Acids↗
PubMed1985

The cephaloscapular projection. A special diagnostic aid.

The cephaloscapular roentgenographic projection is a new projection for diagnosing subluxation about the glenohumeral joint. When properly projected, the acromion, glenoid, humeral head, and coracoid can be seen in independent relief. The relatively radiolucent clavicle overlies the area but does not obscure the landmarks. This view should prove useful in diagnosing a variety of acute and chronic shoulder problems.

Adolescent↗