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Biomedical subjects

S Powers

Publications and source records attributed to S Powers.

At least 19 recordsLinked to original sources
PubMed2005

Generation and analysis of genetically defined liver carcinomas derived from bipotential liver progenitors.

Hepatocellular carcinoma is a chemoresistant cancer and a leading cause of cancer mortality; however, the molecular mechanisms responsible for the aggressive nature of this disease are poorly understood. In this study, we developed a new liver cancer mouse model that is based on the ex vivo genetic manipulation of embryonic liver progenitor cells (hepatoblasts). After retroviral gene transfer of oncogenes or short hairpin RNAs targeting tumor suppressor genes, genetically altered liver progenitor cells are seeded into the liver of otherwise normal recipient mice. We show that histopathology of the engineered liver carcinomas reveals features of the human disease. Furthermore, representational oligonucleotide microarray analysis (ROMA) of murine liver tumors initiated by two defined genetic hits revealed spontaneously acquired genetic alterations that are characteristic for human hepatocellular carcinoma. This model provides a powerful platform for applications like cancer gene discovery or high-throughput preclinical drug testing.

Animals↗
PubMed2001

Strategic management simulations is a novel way to measure resident competencies.

BACKGROUND: The Strategic Management Simulation (SMS) has been used extensively to test and train higher cognitive functions in persons who occupy professional and leadership positions (i.e., skills like those needed by a surgeon). METHODS: The SMS was used to predict surgical residents' competency in decision making. Skills required for integrative surgical decision making including critical thinking, crisis management, flexibility, factual knowledge, and team building were assessed. Surgical residents with at least 2 years of experience participated. In additional, attending faculty familiar with the residents' work evaluated each resident with a standard comprehensive rating scale. Simulation performance on multiple measures was compared with faculty ratings. RESULTS: A number of measures obtained on simulation performance (eg, activity level, response speed, initiative, adequate usage of and appropriate search for relevant information) generated high correlations with comprehensive faculty assessment (eg, measures of crisis management, team interactions, flexibility of approach). CONCLUSION: The simulation technique is able to accurately assess performance of surgical residents (on a number of parameters) in a relatively brief time period. Simulation data were highly similar to faculty ratings that were based on at least 2 years of experience with the resident.

Clinical Competence↗
PubMed2001

Identification of Ras-regulated genes by representational difference analysis.

In conclusion, RDA provides a fast, technically simple, and inexpensive way to characterize genes aberrantly expressed due to Ras transformation. The identification and characterization of these genes may provide insight not only into the mechanism by which Ras causes transformation, but also may identify novel targets for rational drug design and development of anticancer drugs.

Animals↗
PubMed2001

Volatile compounds from Salix spp. varieties differing in susceptibility to three willow beetle species.

The volatile compounds emitted by leaves of 10 willow varieties that differ in their susceptibility to damage by blue (Phratora vulgatissima), brassy (P. vitellinae), and brown (Galerucella lineola) willow beetles were examined both before and after mechanical damage and correlated with feeding preferences of these beetles determined under laboratory conditions. Three compounds were identified from intact undamaged leaves of six willow varieties, namely cis-3-hexenyl acetate, cis-3-hexenol, and benzaldehyde. After mechanical damage, the yield and number of volatile compounds increased for all varieties. There were significant differences among willow varieties for both the concentration of cis-3-hexenyl acetate and the relative proportion of this compound to cis-3-hexenol (green leaf volatile ratio). The 10 varieties collectively showed a significant negative correlation between the relative resistance of each variety to blue and brown willow beetles and the yield of cis-3-hexenyl-acetate from damaged plants. The green leaf volatile ratio of damaged plants was also negatively correlated with the relative resistance of willow variety to these two beetle species.

Animals↗
PubMed2000

Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis.

We previously demonstrated ferritin binding is specific to white matter in mouse and human brain tissue and is not found within Multiple Sclerotic plaques. These results suggest that ferritin receptors are selectively expressed on oligodendrocytes. The present studies were designed to test the hypothesis that oligodendrocyte progenitor cells selectively bind ferritin and internalize it by methods consistent with receptor-mediated endocytosis. Using a cell culture system enriched for oligodendrocyte progenitor cells, we determined, that oligodendrocyte progenitor cells bind ferritin in a saturable and competitive manner with a K(d) of 5 nM and a receptor density of 0.06 fmol bound/20,000 cells. FITC tagged ferritin is internalized by A2B5, O4 or CNPase expressing cells in the culture, but not by GFAP+ cells. The uptake of ferritin into the oligodendrocyte progenitors was inhibited by treating the cells with inhibitors of receptor mediated endocytosis (hypertonic medium, potassium deficient medium, ATP depletion, sulfhydryl reagents). In addition exogenous ferritin decreased iron responsive element/iron regulatory protein binding indicating that the iron within the internalized ferritin is released and contributes to the intracellular iron pool. Given the relatively high amount of iron that can be delivered via ferritin, and the selective distribution of ferritin receptors in the white matter tracts in vivo, we propose that ferritin is a major source of iron for oligodendrocytes.

Animals↗
PubMed2000

Detecting gene copy number fluctuations in tumor cells by microarray analysis of genomic representations.

In this work, we explore the use of representations in conjunction with DNA microarray technology to measure gene copy number changes in cancer. We demonstrate that arrays of DNA probes derived from low-complexity representations can be used to detect amplifications, deletions, and polymorphic differences when hybridized to representations of genomic DNA. The method is both reproducible and verifiable, and is applicable even to microscopic amounts of primary tumors. We also present a mathematical model for array performance that is useful for designing and understanding DNA microarray hybridization protocols. The future applications and challenges of this approach are discussed.

Breast Neoplasms↗
PubMed1999

Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains.

Delivery of iron to the brain traditionally has been considered the responsibility of transferrin. However, transferrin receptors in brain are located primarily within gray matter areas rather than in the iron rich white matter tracts. In this report we present the first demonstration of ferritin binding sites in human brain and provide evidence that these binding sites are primarily in white matter tracts. This distribution of ferritin binding is opposite of that seen for the distribution of the transferrin receptor in normal adult human brain. Ferritin binds to human brain tissue in a competitive and saturable manner with a dissociation constant of 0.35 nM and a binding site density of 116.7 fmol/mg protein. In brain tissue from multiple sclerotic (MS) patients the normal pattern of transferrin and ferritin binding distributions is disrupted. Ferritin binding is absent in the lesion itself and in the immediate periplaque region within the white matter but returns to normal as the distance from the lesion becomes greater. In direct contrast to ferritin binding, transferrin binding in the MS tissue is present in the white matter tracts, but only in the periplaque region. The periplaque region also contains transferrin receptor positive cells (as determined by immunocytochemistry) morphologically consistent with oligodendrocytes. Gray matter binding of transferrin in MS patients appears normal. These data provide the initial evidence of ferritin binding in human brain, address the enigma of the apparent absence of an iron delivery system to the iron-rich white matter, and suggest loss of ferritin binding is involved in or is a consequence of demyelination associated with MS.

Adult↗
PubMed1999

Localized hypertrophic neuropathy: magnetic resonance imaging findings and long-term follow-up.

Four patients with painless, progressive focal neurological deficits that localized to peripheral nerve or plexus were eventually found to have the relatively rare condition of localized hypertrophic neuropathy or intraneural perineurioma. Magnetic resonance imaging (MRI) was an excellent tool for aiding in the precise localization of the lesion, if specifically tailored with regard to imaging planes and specific MRI sequences. Fat-saturated T2-weighted and fat-saturated T1-weighted postgadolinium images provided the best visualization, particularly with a high-field magnet and phase array body coil. Two patients stabilized following resection of the lesion and sural nerve grafting, and 1 had partial improvement in a proximal muscle following neurolysis.

Adolescent↗
PubMed1999

Characterization and distribution of ferritin binding sites in the adult mouse brain.

Studies on iron uptake into the brain have traditionally focused on transport by transferrin. However, transferrin receptors are not found in all brain regions and are especially low in white matter tracts where high iron concentrations have been reported. Several lines of research suggest that a receptor for ferritin, the intracellular storage protein for iron, may exist. We present, herein, evidence for ferritin binding sites in the brains of adult mice. Autoradiographic studies using 125I-recombinant human ferritin demonstrate that ferritin binding sites in brain are predominantly in white matter. Saturation binding analyses revealed a single class of binding sites with a dissociation constant (K(D)) of 4.65 x 10(-9) M and a binding site density (Bmax of 17.9 fmol bound/microg of protein. Binding of radiolabeled ferritin can be competitively displaced by an excess of ferritin but not transferrin. Ferritin has previously been shown to affect cellular proliferation, protect cells from oxidative damage, and deliver iron. The significance of a cellular ferritin receptor is that ferritin is capable of delivering 2,000 times more iron per mole of protein than transferrin. The distribution of ferritin binding sites in brain vis-à-vis transferrin receptor distribution suggests distinct methods for iron delivery between gray and white matter.

Age Factors↗
PubMed1999

The educational attainments of deaf students in mainstream programs in England: examination results and influencing factors.

The author reports findings of an investigation into educational outcomes of 16-year-old deaf students in mainstream programs in England in 1995 and 1996. Data on examination results, communication competence, and social acceptance were collected by questionnaire and analyzed against several background factors. All the background factors investigated contributed an effect of about 20% on examination results, emphasizing the need to investigate the effect of other factors. Relatively strong predictors of examination success were family socioeconomic status, presence of any additional learning difficulty, whether English was used as a main language in the home, age at onset of deafness, and parents' hearing status. Degree of hearing loss did not appear to have an important effect on examination success but was linked to other outcomes. The discussion considers how different codings of examination success can affect the results obtained from statistical analysis. Findings on the ethnic status of deaf students are also noted.

Achievement↗
PubMed1996

Ganglion cell-containing tumors of the pituitary gland.

The ganglion cell-containing tumors of the pituitary are rare lesions of undetermined histogenesis and nosology. A review of the literature revealed 42 such tumors, including the 3 cases described below. On the basis of this review, the tumors were divided into two histologic groups, one consisting of both adenomatous and gangliocytic elements (32 cases), and the other of the gangliocytic component only (10 cases). The first group of tumors were more common in females (23 of 32 cases) and were often active endocrinologically (28 of 32 cases), and acromegaly was the most common manifestation (19 cases). The second group was also more common in females (7 of 10 cases) but was less frequently active endocrinologically (3 of 19 cases). We review histologic and immunocytochemical findings in these tumors and discuss their histogenesis. We propose that the term mixed pituitary adenoma-gangliocytoma be used for the first group and gangliocytoma for the second. The two groups should be kept separate until their histogenesis is better understood.

Adolescent↗
PubMed1995

Ras membrane targeting is essential for glucose signaling but not for viability in yeast.

Ras proteins are small GTP binding proteins that serve as critical relays in a variety of signal transduction pathways in eukaryotic cells. Like most metazoan Ras proteins, yeast Ras is post-translationally modified by addition of a farnesyl and a palmitoyl moiety, and these modifications are required for targeting the protein to the cytoplasmic face of the plasma membrane and for biological activity of the protein. We have constructed mutants of the yeast (Saccharomyces cerevisiae) Ras that are farnesylated in vivo but are not palmitoylated. These mutant proteins are not localized to the plasma membrane but function in the cell as well as the wild-type protein. Such mutants are viable but fail to induce a transient increase in intracellular cAMP concentration in response to glucose addition, although this deficiency does not yield a marked growth phenotype. These results are consistent with the hypothesis that the essential role of the farnesyl moiety on yeast Ras is to enhance productive interaction between Ras and its essential downstream target, adenylyl cyclase, rather than to localize Ras to the plasma membrane.

Alleles↗
PubMed1995

Mutations in the SHR5 gene of Saccharomyces cerevisiae suppress Ras function and block membrane attachment and palmitoylation of Ras proteins.

We have identified a gene, SHR5, in a screen for extragenic suppressors of the hyperactive RAS2Val-19 mutation in the budding yeast Saccharomyces cerevisiae. SHR5 was cloned, sequenced, and found to encode a 23-kDa protein not significantly homologous to other proteins in the current data bases. Genetic evidence arguing that Shr5 operates at the level of Ras is presented. We tested whether SHR5, like previously isolated suppressors of hyperactivated RAS2, acts by affecting the membrane attachment and/or posttranslational modification of Ras proteins. We found that less Ras protein is attached to the membrane in shr5 mutants than in wild-type cells and that the Ras proteins are markedly underpalmitoylated, suggesting that Shr5 is involved in palmitoylation of Ras proteins. However, shr5null mutants exhibit normal palmitoyltransferase activity measured in vitro. Further, shr5null mutations attenuate Ras function in cells containing mutant Ras2 proteins that are not palmitoylated or farnesylated. We conclude that SHR5 encodes a protein that participates in the membrane localization of Ras but also interacts in vivo with completely unprocessed and cytosolic Ras proteins.

Acyltransferases↗
PubMed1994

A mutation in the effector region of Ras2 can be partially suppressed by alteration of a 'nonessential' region of Ras.

Phenotypically normal revertants of budding yeast cells that contain the hyperactive RAS2Val19 allele often result from second-site mutations within the RAS2 locus itself. Several such intragenic revertants harboring a suppressed RAS2Val19 allele as their only RAS gene were analyzed. All such suppressors resulted from single amino acid substitutions that affected either: (i) the effector region of Ras2, (ii) the C-terminal CAAX box of Ras2, or (iii) residues known to be critical for GTP binding in Ras proteins. While these suppressor mutations completely suppressed the hyperactive phenotype induced by the Val19 substitution, they did not block the ability of Ras2 to promote growth at normal temperatures. These results suggest that in yeast, attenuation of Ras proteins can effectively block hyperactive phenotypes without completely blocking the growth-promoting function. A spontaneous intragenic mutation that restored function to an effector mutant was mapped to a 'nonessential' region of Ras proteins. Based on this genetic interaction with the effector region and the report that deletions of this region affect Ras/GAP interaction, we suggest that this region may have a functional role in Ras activation of target effectors.

Base Sequence↗
PubMed1994

Neurotensin is an autocrine trophic factor stimulated by androgen withdrawal in human prostate cancer.

After therapeutic hormone deprivation, prostate cancer cells often develop androgen-insensitive growth through mechanisms thus far undefined. Neuropeptides have been previously implicated as growth factors in some prostate cancers. Here, we demonstrate that androgen-sensitive LNCaP human prostate cancer cells produce and secrete neurotensin following androgen withdrawal. We show that while LNCaP cells express the neurotensin receptor, only androgen-deprived cells exhibit a growth response to exogenous neurotensin. We further demonstrate that androgen-stimulated cells may be refractory to exogenous neurotensin due to androgen induction of a metalloprotease active toward neurotensin. Thus, prostate cancer cells deprived of androgen develop an alternative autocrine growth mechanism involving neurotensin.

Androgens↗
PubMed1994

Determination of structural requirements for the interaction of Rab6 with RabGDI and Rab geranylgeranyltransferase.

The importance of geranylgeranylation to the interaction of Rab proteins with RabGDI was investigated with a set of Rab6 mutants post-translationally modified by all known C-terminal lipid combinations. Rab6 proteins geranylgeranylated on CXC or CC motifs were found to be significantly better substrates for membrane extraction by RabGDI than either Rab6 proteins geranylgeranylated on CAAL motifs or Rab6 proteins that were farnesylated and palmitoylated. The methylation status of the CXC motif did not significantly affect interaction of wild type Rab6 with RabGDI. Rab6 protein sequences required for RabGDI interaction were then identified. Consistent with the significant homology between Rab-GDI and the Rab escort protein, a subunit of Rab geranylgeranyltransferase (RabGGTase), we show that there is an overlap between Rab6 motifs required for RabGDI binding and RabGGTase processing. The effector domain, loop3/beta 3 and the hypervariable region of Rab6 are all required for RabGDI binding, whereas loop3/beta 3 and the hypervariable region but not the effector domain are required for efficient processing of Rab6 by RabGGTase. Interestingly, however, loop3/beta 3 of Rab6 when introduced into H-Ras is sufficient to allow some in vivo processing of a C-terminal CSC motif.

Alkyl and Aryl Transferases↗