PubMed Health⌕ Search

Biomedical subjects

M A Nelson

Publications and source records attributed to M A Nelson.

At least 19 recordsLinked to original sources
PubMed2006

Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells.

The eukaryotic initiation factor 3f (eIF3f) is the p47 subunit of the multi-subunit eIF3 complex. eIF3 plays an important role in translation initiation. In the present study, we investigate the biological function of eIF3f in translation and apoptosis in tumor cells. We demonstrated for the first time that eIF3f is downregulated in most human tumors using a cancer profiling array and confirmed by real-time reverse transcription PCR in melanoma and pancreatic cancer. Overexpression of eIF3f inhibits cell proliferation and induces apoptosis in melanoma and pancreatic cancer cells. Silencing of eIF3f protects melanoma cells from apoptosis. We further investigated the biological function of eIF3f. In vitro translation studies indicate that eIF3f is a negative regulator of translation and that the region between amino acids 170 and 248 of eIF3f is required for its translation regulatory function. Ectopic expression of eIF3f inhibits translation and overall cellular protein synthesis. Ribosome profile and ribosomal RNA (rRNA) fragmentation assays revealed that eIF3f reduces ribosomes, which may be associated with rRNA degradation. We propose that eIF3f may play a role in ribosome degradation during apoptosis. These data provide critical insights into the cellular function of eIF3f and in linking translation initiation and apoptosis.

Apoptosis↗
PubMed2004

Modulation of the renin-angiotensin-aldosterone system for the secondary prevention of stroke.

Recurrent stroke is a major public health concern and new treatment strategies are needed. While modulation of the renin angiotensin aldosterone system (RAAS) has proven effective in reducing recurrent cardiac events, its role in preventing recurrent cerebrovascular events remains unclear. RAAS is both a circulating and tissue based hormonal system that regulates homeostasis and tissue responses to injury in both the CNS and the periphery, via the activity of angiotensin II (Ang II). Vascular and hematologic effects induced by Ang II including endothelial dysfunction, vascular structural changes, inflammation, hemostasis, and fibrinolysis are increasingly linked to the occurrence of cerebrovascular events. Animal models have shown that RAAS modulation may be protective in cerebrovascular disease. The HOPE and LIFE trials support the role of blood pressure independent mechanisms of RAAS modulation for improving outcomes in a broad range of patients with cardiovascular disease but do not specifically address recurrent stroke prevention. PROGRESS, a trial of secondary stroke prevention, demonstrates that blood pressure reduction with a combination strategy including the routine use of ACE inhibitors prevents recurrent stroke. Current evidence suggests that the RAAS plays an important role in the development and progression of cerebrovascular disease. Modulation of the RAAS holds promise for the secondary prevention of stroke, however, ongoing clinical trials will better define the exact role of ACE inhibitor and angiotensin II Type 1 receptor blocker therapy in stroke survivors.

Aged↗
PubMed2001

Robust and efficient synthetic method for forming DNA microarrays.

The field of DNA microarray technology has necessitated the cooperative efforts of interdisciplinary scientific teams to achieve its primary goal of rapidly measuring global gene expression patterns. A collaborative effort was established to produce a chemically reactive surface on glass slide substrates to which unmodified DNA will covalently bind for improvement of cDNA microarray technology. Using the p-aminophenyl trimethoxysilane (ATMS)/diazotization chemistry that was developed, microarrays were fabricated and analyzed. This immobilization method produced uniform spots containing equivalent or greater amounts of DNA than commercially available immobilization techniques. In addition, hybridization analyses of microarrays made with ATMS/diazotization chemistry showed very sensitive detection of the target sequence, two to three orders of magnitude more sensitive than the commercial chemistries. Repeated stripping and re-hybridization of these slides showed that DNA loss was minimal, allowing multiple rounds of hybridization. Thus, the ATMS/diazotization chemistry facilitated covalent binding of unmodified DNA, and the reusable microarrays that were produced showed enhanced levels of hybridization and very low background fluorescence.

Adsorption↗
PubMed2001

Graph models of oncogenesis with an application to melanoma.

We describe several analytical techniques for use in developing genetic models of oncogenesis including: methods for the selection of important genetic events, construction of graph models (including distance-based trees, branching trees, contingency trees and directed acyclic graph models) from these events and methods for interpretation of the resulting models. The models can be used to make predictions about: which genetic events tend to occur early, which events tend to occur together and the likely order of events. Unlike simple path models of oncogenesis, our models allow dependencies to exist between specific genetic changes and allow for multiple, divergent paths in tumor progression. A variety of genetic events can be used with the graph models including chromosome breaks, losses or gains of large DNA regions, small mutations and changes in methylation. As an application of the techniques, we use a recently published cytogenetic analysis of 206 melanoma cases [Nelson et al. (2000), Cancer Genet. Cytogenet.122, 101-109] to derive graph models for chromosome breaks in melanoma. Among our predictions are: (1) breaks in 6q1 and 1q1 are early events, with 6q1 preferentially occurring first and increasing the probability of a break in 1q1 and (2) breaks in the two sets [1p1, 1p2, 9q1] and [1q1, 7p2, 9p2] tend to occur together. This study illustrates that the application of graph models to genetic data from tumor sets provide new information on the interrelationships among genetic changes during tumor progression.

Chromosome Breakage↗
PubMed2001

Detection of three novel translocations and specific common chromosomal break sites in malignant melanoma by spectral karyotyping.

Chromosomal aberrations in malignant melanoma cells have been reported using standard chromosome banding analysis and comparative genomic hybridization. To identify marker chromosomes and translocations that are difficult to characterize by standard banding analysis, 15 early passage malignant melanoma cell lines were examined using spectral karyotyping. All 15 tumor cell lines had lost all or part of 1p and 10q. Losses of material on chromosome arms 4p (12/15), 6q (12/15), 9p (15/15), 12p (13/15), 12q (13/15), 13q (11/15), and 19q (14/15) were the next most frequent events. Gain of chromosome arms 1q (11/15), 6p (13/15), and 20q11 (14/15) was also observed. Interestingly, we identified translocations der(12)t(12;20)(q15;q11), der(19)t(10;19)(q23;q13), and der(12)t(12;19)(q13;q13) in 4/15 tumors. Three recurring translocations involving four of the most frequent break points were detected. The identification of recurring translocations and unique chromosome break points in melanoma will aid in the identification of the genes that are important in the neoplastic process.

Chromosome Breakage↗
PubMed2001

Analysis of the pdx-1 (snz-1/sno-1) region of the Neurospora crassa genome: correlation of pyridoxine-requiring phenotypes with mutations in two structural genes.

We report the analysis of a 36-kbp region of the Neurospora crassa genome, which contains homologs of two closely linked stationary phase genes, SNZ1 and SNO1, from Saccharomyces cerevisiae. Homologs of SNZ1 encode extremely highly conserved proteins that have been implicated in pyridoxine (vitamin B6) metabolism in the filamentous fungi Cercospora nicotianae and in Aspergillus nidulans. In N. crassa, SNZ and SNO homologs map to the region occupied by pdx-1 (pyridoxine requiring), a gene that has been known for several decades, but which was not sequenced previously. In this study, pyridoxine-requiring mutants of N. crassa were found to possess mutations that disrupt conserved regions in either the SNZ or SNO homolog. Previously, nearly all of these mutants were classified as pdx-1. However, one mutant with a disrupted SNO homolog was at one time designated pdx-2. It now appears appropriate to reserve the pdx-1 designation for the N. crassa SNZ homolog and pdx-2 for the SNO homolog. We further report annotation of the entire 36,030-bp region, which contains at least 12 protein coding genes, supporting a previous conclusion of high gene densities (12,000-13,000 total genes) for N. crassa. Among genes in this region other than SNZ and SNO homologs, there was no evidence of shared function. Four of the genes in this region appear to have been lost from the S. cerevisiae lineage.

Cloning, Molecular↗
PubMed2001

Costs and resources associated with the treatment of overactive bladder using retrospective medical care claims data.

The objectives of this study were to determine age- and gender-specific drug treatment prevalence rates for overactive bladder (OAB), and to compare resource use and costs among MCO members receiving drug treatment for OAB. Administrative claims data from seven affiliated health plans were analyzed for 8,661 members with a diagnosis or treatment indicative of OAB during 1998. Resource use and associated costs were analyzed over a four-month follow-up. In 1998, the prevalence of OAB among plan members was 1.1%. Of the patients with OAB, 71% did not receive pharmacotherapy. After multivariate analysis, treatment with tolterodine, oxybutynin, or other OAB treatment did not significantly affect the percent change in total per patient per month (PPPM) costs compared with the group not receiving a pharmacologic agent. Although the adjusted percent change in PPPM pharmacy costs was significantly higher within the tolterodine group, medical and total PPPM costs were not.

Benzhydryl Compounds↗
PubMed2000

The effects of dietary selenomethionine on polyamines and azoxymethane-induced aberrant crypts.

We evaluated the effects of dietary selenomethionine supplementation on colonic polyamine levels and the ability of L-selenomethionine supplementation to modulate the carcinogenic activity of azoxymethane (AOM) in the rat colon. Four-week-old male F344 rats were treated with 15 mg/kg body weight of AOM once a week for 2 weeks. Dietary selenomethionine at a concentration of either 1 or 2 ppm was administered in AIN-76A rodent diet to AOM-treated animals for 16 weeks. Aberrant crypt foci (ACF), precursor lesions of colon cancer, were investigated after the 16 week treatment course. Selenomethionine given in the diet at 2 ppm markedly reduced the number of aberrant crypt foci. The multiplicity of ACFs (i.e. the number of aberrant crypts/focus) and the percentage of microadenomas were also affected by selenomethionine in a dose dependent manner. However, evaluation of the colonic tissue polyamine levels between control and treated groups showed no significant difference. These results demonstrate that selenomethionine can modulate the development of AOM-induced premalignant lesions through a polyamine-independent mechanism.

Alanine Transaminase↗
PubMed2000

The external calcium-dependent NADPH dehydrogenase from Neurospora crassa mitochondria.

We have inactivated the nuclear gene coding for a putative NAD(P)H dehydrogenase from the inner membrane of Neurospora crassa mitochondria by repeat-induced point mutations. The respiratory rates of mitochondria from the resulting mutant (nde-1) were measured, using NADH or NADPH as substrates under different assay conditions. The results showed that the mutant lacks an external calcium-dependent NADPH dehydrogenase. The observation of NADH and NADPH oxidation by intact mitochondria from the nde-1 mutant suggests the existence of a second external NAD(P)H dehydrogenase. The topology of the NDE1 protein was further studied by protease accessibility, in vitro import experiments, and in silico analysis of the amino acid sequence. Taken together, it appears that most of the NDE1 protein extends into the intermembrane space in a tightly folded conformation and that it remains anchored to the inner mitochondrial membrane by an N-terminal transmembrane domain.

Adenosine Triphosphate↗
PubMed2000

Chromosome abnormalities in malignant melanoma: clinical significance of nonrandom chromosome abnormalities in 206 cases.

We report the cytogenetic abnormalities from a series of 206 primary malignant melanoma specimens referred to a single institution. A total of 169 out of 206 unique cases had chromosome breakpoints. A previously described statistical method was used to detect nonrandom distribution of chromosome breakpoints at the level of chromosome regions. Nonrandom occurrence of chromosome breakpoints (indicating that the observed number of breaks significantly exceeded the expected number of breaks) was detected in 28 regions, suggesting a hierarchy of genetic abnormalities in melanoma. Clinical variables and tumor characteristics were analyzed for associations with the presence of any nonrandom chromosome breakpoints; with individual, nonrandomly involved chromosome regions; and with paired, nonrandomly involved chromosome regions. No nonrandomly involved chromosome regions or pairs of regions appeared to significantly affect survival. These results identify recurring, nonrandom chromosome abnormalities in malignant melanoma. These results suggest that recurring, nonrandom chromosome alterations play a key role in the etiology and/or progression of malignant melanoma and identify targets within the genome for molecular genetic studies.

Chromosome Aberrations↗
PubMed2000

Effects of facial paralysis and audiovisual information on stop place identification.

This study investigated how listeners' perceptions of bilabial and lingua-alveolar voiced stops in auditory (A) and audiovisual (AV) presentation modes were influenced by articulatory function in a girl with bilateral facial paralysis (BFP) and a girl with normal facial movement (NFM). The Fuzzy Logic Model of Perception (FLMP) was used to make predictions about listeners' identifications of stop place based on assumptions about the nature (clear, ambiguous, or conflicting) of the A or AV cues produced by each child during /b/ and /d/ CV syllables. As predicted, (a) listeners' identification scores for NFM were very high and reliable, regardless of presentation mode or stop place, (b) listeners' identification scores for BFP were high for lingua-alveolar place, regardless of presentation mode, but more variable and less reliable than for NFM; significantly lower (overall at a chance level) for bilabial place in the A mode; and lowest for bilabial place in the AV mode. Conflicting visual cues for stop place for BFP's productions of /bV/ syllables influenced listeners' perceptions, resulting in most of her bilabial syllables being misidentified in the AV mode. F2 locus equations for each child's /bV/ and /dV/ syllables showed patterns similar to those reported by previous investigators, but with less differentiation between stop place for BFP than NFM. These acoustic results corresponded to the perceptual results obtained. (That is, when presented with only auditory information, on average, listeners perceived BFP's target /b/ syllables to be near the boundary between /b/ and /d/.)

Adult↗
PubMed2000

Large-scale comparison of fungal sequence information: mechanisms of innovation in Neurospora crassa and gene loss in Saccharomyces cerevisiae.

We report a large-scale comparison of sequence data from the filamentous fungus Neurospora crassa with the complete genome sequence of Saccharomyces cerevisiae. N. crassa is considerably more morphologically and developmentally complex than S. cerevisiae. We found that N. crassa has a much higher proportion of "orphan" genes than S. cerevisiae, suggesting that its morphological complexity reflects the acquisition or maintenance of novel genes, consistent with its larger genome. Our results also indicate the loss of specific genes from S. cerevisiae. Surprisingly, some of the genes lost from S. cerevisiae are involved in basic cellular processes, including translation and ion (especially calcium) homeostasis. Horizontal gene transfer from prokaryotes appears to have played a relatively modest role in the evolution of the N. crassa genome. Differences in the overall rate of molecular evolution between N. crassa and S. cerevisiae were not detected. Our results indicate that the current public sequence databases have fairly complete samples of gene families with ancient conserved regions, suggesting that further sequencing will not substantially change the proportion of genes with homologs among distantly related groups. Models of the evolution of fungal genomes compatible with these results, and their functional implications, are discussed.

Aspergillus nidulans↗
PubMed2000

American nursing scholars abroad, 1985-1995.

PURPOSE: To explore the international activities of American nursing scholars from 1985 to 1995, as indicated by their international teaching, scholarship, and consultation. METHODS: All faculty (N = 2,254) teaching in nursing doctoral programs in the United States were surveyed using an investigator-designed questionnaire. The professional characteristics of American nursing scholars who worked abroad and the dates, nature, and types of international activities they undertook were ascertained. From a total of 928 usable returns, 247 described international activity. FINDINGS: Data indicated a three-fold increase in international activity from 1985 to 1995 in the three major areas investigated. Universities in Western Europe and Asia were the most frequent recipients of nursing scholarly activity. The scholars or representatives of the host institutions made approximately half the initial contacts. The international hosts or U.S. universities were the predominant providers of funding. Nurses most likely to participate in international scholarly activity were senior faculty who were full professors in doctoral-granting institutions, published in international journals, presented educational topics, and were recognized by peers through membership in honorary organizations. CONCLUSIONS: A substantial increase in international nursing scholarship occurred during the decade studied, particularly related to teaching.

Faculty, Nursing↗
PubMed2000

Laparoscopic splenectomy for splenic sequestration crisis.

Medical and surgical advances have improved the treatment of splenic sequestration crisis in pediatric patients with sickle cell disease (SCD). Rapid enlargement of the spleen can result from sickled blood cels being trapped in the spleen, which can be life threatening. The laparoscopic splenectomy procedure using the lateral approach has been adapted successfully for the pediatric patient since 1993. Children with SCD who have a history of a splenic sequestration crisis usually are scheduled for an elective splenectomy procedure after the first documented crisis to reduce the risk of death. Some key benefits of this new surgical approach include a shortened hospital stay, decreased postoperative pain, and faster recovery and return to normal activities for the child with SCD.

Acute Disease↗
PubMed1999

Fas-induced apoptosis in human malignant melanoma cell lines is associated with the activation of the p34(cdc2)-related PITSLRE protein kinases.

The Cdc2L locus encoding the PITSLRE protein kinases maps to chromosome band 1p36 and consists of two duplicated and tandemly linked genes. The purpose of the present study was to determine whether diminution of PITSLRE kinases leads to deregulation of apoptosis. The human melanoma cell lines A375 (Cdc2L wild-type alleles) and UACC 1227 (mutant Cdc2L alleles) were tested with agonist anti-Fas monoclonal antibody. We found that exposure of these cells to anti-Fas for 24, 48, or 72 h resulted in differential sensitivity to Fas-induced apoptosis. In A375, cell death started at 24-48 h post-treatment, and it was maximal by 72 h. Conversely, UACC 1227 cells were resistant to Fas-mediated apoptosis. Induction of PITSLRE histone H1 kinase activity was observed in A375 anti-Fas treated but not in UACC 1227 cells. Also, the PITSLRE protein kinase activity in A375 anti-Fas-treated cells preceded maximal levels of apoptosis. Finally, fluorescence confocal microscopy revealed a nuclear localization of PITSLRE proteins in normal melanocytes and A375 cells but a cytoplasmic localization in UACC 1227 cells. The differences in PITSLRE protein and cellular localization between A375 and UACC 1227 cells appear to account for the differences in sensitivity of the two cells lines to anti-Fas and staurosporine. These observations suggest that alterations in PITSLRE gene expression and protein localization may result in the loss of apoptotic signaling.

Antibodies, Monoclonal↗
PubMed1999

Abnormalities in the p34cdc2-related PITSLRE protein kinase gene complex (CDC2L) on chromosome band 1p36 in melanoma.

The two genes encoding the PITSLRE protein kinase isoforms, CDC2L1 and CDC2L2, are localized to human chromosome band 1p36. The PITSLRE protein kinases are a part of the p34cdc2 supergene family. Several protein products of the CDC2L locus may be effector(s) in apoptotic signaling. The larger PITSLRE p110 isoforms appear to regulate some aspect of RNA splicing/transcription during the cell cycle. One or more of these genes may function as tumor suppressor genes in melanoma. Using fluorescence in situ hybridization, one allele of the CDC2L gene complex on chromosome 1 was either deleted or translocated in 8 of 14 different melanoma cell lines. We also observed mutations in the 5' promoter region of the CDC2L1 gene in four different cell lines relative to normal melanocytes using PCR-SSCP analysis and direct DNA sequencing. Western blot analysis revealed decreased level of PITSLRE protein expression in several cell lines, as well as in four surgical malignant melanoma specimens relative to normal melanocytes. Thus, the decreased PITSLRE protein expression appears to result from deletion of the CDC2L alleles and possibly by mutations within the 5' promoter region. We propose that aberrations in the CDC2L genes may contribute to the pathogenesis or progression of melanoma.

Base Sequence↗