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M W Anderson

Publications and source records attributed to M W Anderson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Bacillary angiomatosis in patients with AIDS: multiorgan imaging findings.

PURPOSE: To describe the varied clinical manifestations and imaging findings encountered in bacillary angiomatosis, an infectious complication of the acquired immunodeficiency syndrome (AIDS). MATERIALS AND METHODS: Clinical, imaging, and histopathologic findings in nine men (aged 26-50 years) with AIDS and bacillary angiomatosis were described. This condition often manifests as vascular skin lesions that resemble those of Kaposi sarcoma, fever, and anemia and is due to infection with Bartonella (Rochalimaea) henselae. RESULTS: Common imaging findings included lung nodules, mediastinal adenopathy, peripheral adenopathy, pleural effusions, ascites, abdominal adenopathy, soft-tissue masses, and low-attenuation lesions in the liver and/or spleen. Most notably, nodes and soft-tissue lesions were dramatically enhanced with injection of contrast material, which is presumably because the lesions are composed to a large extent of well-formed capillaries. CONCLUSION: Bacillary angiomatosis, a treatable infection, should be considered in patients with AIDS, particularly when Kaposi sarcoma is suspected clinically.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Considerations concerning the murine hepatocarcinogenicity of selected chlorinated hydrocarbons.

Of the chlorinated hydrocarbons discussed above, all six are associated with induction of hepatocellular neoplasia in mice. None of the six is considered to be potent mutagen and most are without any significant genotoxic activity as assessed by conventional in vitro testing schemes. Although some of the agents have biological effects in common (see Figure 4), there is no single biological response (mode of action) that they all share to provide a mechanistic basis for the observed murine hepatocarcinogenicity. Based upon the information currently available for each of the chlorinated hydrocarbons discussed above, it is probable that some modes of action may be more contributory to the rodent carcinogenic response than others; however, no mode of action, pathway, or mechanism should be considered to be mutually exclusive. The murine hepatocarcinogenic effect of TriCE is most probably contingent upon its species-specific metabolism to trichloroacetic acid and DCA. There is fairly consistent evidence that cytotoxicity and reparative hyperplasia are associated with doses of TriCE that cause induction of liver neoplasms. The possibility that peroxisome proliferation is playing a role in the induction of mouse hepatocellular neoplasia remains a tempting explanation, since higher intracellular steady states of H2O2 production would be consistent with observed enhanced cellular proliferation as well as the possibility of in vivo DNA damage. The mouse hepatocarcinogenicity associated with TetCE most probably is associated with species-specific metabolic production of trichloroacetic acid. As with TriCE, cytotoxicity and reparative hyperplasia may represent a potential mode of action for the observed hepatocarcinogenicity. Once again, the potential for enhanced peroxisome proliferation is consistent with enhanced cell proliferation and oxygen radical damage would help explain the random point mutations in ras proto-oncogenes documented in DNA from TetCE-induced mouse liver tumors. DCA-induced mouse hepatocellular neoplasia is probably influenced by cytotoxicity and reparative hyperplasia, but there is also recent evidence that DCA may directly damage DNA, implying an in vivo genotoxic mechanism may be operational. Likewise, altered expression of several genes suggests that subversion of signal transduction may play a role in the induction or progression of liver tumor development. As with TetCE and TriCE, a role for peroxisome proliferation is still a consideration, although the liver tumor response is obvious at doses too low to cause peroxisome proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1994

Allelotype analysis of mouse lung carcinomas reveals frequent allelic losses on chromosome 4 and an association between allelic imbalances on chromosome 6 and K-ras activation.

We generated allelotypes of 38 methylene chloride-induced lung carcinomas from female C57BL/6J x C3H/6J F1 (hereafter called B6C3F1) mice. Two or more polymorphic markers per autosome, most of them microsatellites, were examined for loss of heterozygosity. Allelic losses throughout the genome were generally infrequent except for markers on chromosome 4, which were lost in approximately one-half of the carcinomas. Analysis of lung adenomas indicated that chromosome 4 loss was associated with malignant conversion. In addition, chromosome 4 loss were specific for lung carcinomas based on comparison to methylene chloride-induced liver tumors and additional studies of lung tumors from a variety of treatment protocols and different mouse strains. Preferential loss of the maternal chromosome 4 was observed in B6C3F1 carcinomas. Analyses of additional tumors induced in mice from two reciprocal crosses, A/J x C3H/HeJ F1 (hereafter called AC3F1) and C3H/HeJ x A/J F1 (hereafter called C3AF1), provided evidence for the inactivation of one allele of the putative chromosome 4 tumor suppressor gene by parental imprinting. Most B6C3F1 tumors lost all chromosome 4 markers examined, suggesting nondisjunction events. In contrast, several C3AF1 and AC3F1 tumors appeared to have interstitial deletions that defined the smallest region of overlap as a 9-cM interval between Ifa-2 and D4Nds2. The homologous region on human chromosome 9p21-22 is frequently lost in a variety of tumors including lung cancers. A candidate tumor suppressor gene, MTS1, is located in this region, which is homozygously deleted or mutated in cell lines derived from a variety of human tumors. Finally, an association between K-ras gene activation and allelic imbalances on chromosome 6 was observed for B6C3F1 lung tumors.

Alleles↗
PubMed1994

Role of glutamine-61 in the hydrolysis of GTP by p21H-ras: an experimental and theoretical study.

The active GTP-bound form of p21ras is converted to the biologically inactive GDP-bound form by enzymatic hydrolysis and this function serves to regulate the wild-type ras protein. The side chain of the amino acid at position 61 may play a key role in this hydrolysis of GTP by p21. Experimental studies that define properties of the Q61E mutant of p21H-ras are presented along with supporting molecular dynamics simulations. We find that under saturating concentrations of GTP the Q61E mutant of p21H-ras has a 20-fold greater rate of intrinsic hydrolysis (kcat = 0.57 min-1) than the wild type. The affinity of the Q61E variant for GTP (Kd = 115 microM) is much lower than that of the wild type. GTPase activating protein does not activate the variant. From molecular dynamics simulations, we find that both the wild type and Q61E mutant have the residue 61 side chain in transient contact with a water molecule that is well-positioned for hydrolytic attack on the gamma phosphate. Thr-35 also is found to form a transient hydrogen bond with this critical water. These elements may define the catalytic complex for hydrolysis of the GTP [Pai et al. (1990) EMBO J. 9, 2351]. Similarly, the G12P mutant, which also has an intrinsic hydrolysis rate similar to the wild type, is found to form the same complex in simulation. In contrast, molecular dynamics analysis of the mutants G12R, G12V, and Q61L, which have much lower intrinsic rates than the wild-type p21, do not show this complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed1994

The second intron of the K-ras gene contains regulatory elements associated with mouse lung tumor susceptibility.

We have previously demonstrated the preferential activation of the K-ras gene from the susceptible A/J parent in lung tumors from F1 mouse hybrids. In the present study, the mechanism of this observation is further investigated. Higher levels of expression of A/J K-ras allele were detected in lung adenomas (30 of 30) from the C3A mouse. In addition, three K-ras alleles, designated as susceptible (Ks), intermediate (Ki), or resistant (Kr), were identified by sequence analysis of the second intron of the K-ras gene from 32 strains of mice. These K-ras alleles are associated with differences in mouse lung tumor susceptibility. All Kr alleles have a tandem 37-bp direct repeat (nt 282-355) in the second intron of the K-ras gene. Ks and Ki alleles have only one copy of the 37-bp sequence (nt 282-318). Ks strains have three base variations at nt 288, 296, and 494, and Ki strains have two base variations at nt 288 and 494 in the second intron of the K-ras gene. Differential protein-binding patterns were observed in gel-mobility-shift experiments between the duplicated 37-bp sequence of the Kr allele and the single 37-bp sequence of the Ks and Ki alleles. DNase I footprinting assay revealed protein binding sites in the second intron of the K-ras gene that correspond to the tandem repeat sequences. Our data suggest that higher expression of the A/J allele relative to C3H allele may be responsible for the allele-specific activation of the K-ras gene in lung tumors from F1 hybrid mice.

Adenoma↗
PubMed1994

ras proto-oncogene activation in dichloroacetic acid-, trichloroethylene- and tetrachloroethylene-induced liver tumors in B6C3F1 mice.

The frequency and mutation spectra of proto-oncogene activation in hepatocellular neoplasms induced by tetrachloroethylene, trichloroethylene and dichloroacetic acid were examined to help define the molecular basis for their carcinogenicity. H-ras codon 61 activation was not significantly different among dichloroacetic acid- and trichloroethylene-induced and combined historical and concurrent control hepatocellular tumors (62%, 51% and 69% respectively). The mutation spectra of H-ras codon 61 mutations showed a significant decrease in AAA and increase in CTA mutations for dichloroacetic acid- and trichloroethylene-induced tumors when compared to combined controls. The H-ras codon 61 mutation frequency for tetrachloroethylene-induced tumors was significantly lower (24%) than that of combined controls and also that of the two other chemicals. Mutations at codons 13 and 117 plus a second exon insert contributed 4% to the total H-ras frequencies for trichloroethylene and tetrachloroethylene. There was also a higher incidence of K-ras activation (13%) in tetrachloroethylene-induced tumors than in the other chemically induced or control tumors. Four liver tumors were found to contain insertions of additional bases within the second exon of K- or H-ras. These findings suggest that exposure to dichloroacetic acid, trichloroethylene and tetrachloroethylene provides a selective growth advantage to spontaneously occurring mutations in codon 61 of H-ras and, at the same time, is responsible for a small number of unique molecular lesions suggestive of either a random genotoxic mode of action or a non-specific result of secondary DNA damage. However, the absence of ras activation in many of the liver neoplasms suggests that alternative mechanisms are also important in B6C3F1 mouse hepatocarcinogenesis.

Animals↗
PubMed1994

Activation of H-ras is prevalent in 1,3-butadiene-induced and spontaneously occurring murine Harderian gland tumors.

Treatment of B6C3F1 mice with concentrations of 62.5-625 p.p.m. 1,3-butadiene by inhalation for up to 2 years causes a significantly increased incidence of Harderian gland (HG) neoplasms over untreated controls (Melnick,R., Huff,J., Chou,B.J. and Miller,R.A. Cancer Res., 50, 6592-6599, 1990). Since a specific K-ras mutation (codon 13 GGC-->CGC) had previously been described in lung and liver tumors from 1,3-butadiene-treated B6C3F1 mice, we analyzed 23 adenomas and six adenocarcinomas of the HG from mice exposed to 1,3-butadiene for this mutation and mutations in the H-ras gene. We also examined ras activation in 16 spontaneously occurring HG adenomas and one adenocarcinoma. DNA samples were prepared from paraffin-embedded tissues and analyzed by PCR followed by direct sequencing methods. Only one 1,3-butadiene-induced HG tumor contained the K-ras codon 13 mutation previously detected in lung and liver tumors. However, 16/29 HG tumors from the treated B6C3F1 mice contained H-ras codon 61 mutations. The mutations detected were: 12 CAA-->CGA transitions, two CAA-->CTA and two CAA-->AAA transversions. Eleven of 17 spontaneous HG tumors contained mutations in H-ras codon 61: five CAA-->CGA transitions, two CAA-->CTA transversions and four CAA-->AAA transversions. While the spectrum of ras mutations did not differ between the spontaneously occurring and chemically induced tumors, these data indicate that activation of H-ras contributes to the process of HG tumorigenesis in both groups of these neoplasms.

Animals↗
PubMed1994

Low frequency of H-ras mutations in hepatocellular adenomas and carcinomas and in hepatoblastomas from B6C3F1 mice exposed to oxazepam in the diet.

Oxazepam has been the subject of recent toxicological and carcinogenesis studies because it is a commonly prescribed tranquilizer and has been shown to cause tumors in rodents. In this study, male and female B6C3F1 mice received 0, 125, 2500 or 5000 p.p.m. oxazepam in the diet for up to 2 years. Hepatocellular adenomas and carcinomas, as well as hepatoblastomas, which developed in these mice, were examined for the presence of activated ras proto-oncogenes. DNA was isolated from 20 or more tumors from each exposure group and analyzed by oligonucleotide hybridization, single-stranded conformation polymorphism analysis and direct sequencing of PCR-amplified H-ras gene fragments for codon 61 mutations. Thirteen of 37 (35%) hepatocellular adenomas and carcinomas from the 125 p.p.m. exposure group had mutations in codon 61, while mutations were detected in only 2 of 25 or 8% of the liver tumors from the 2500 p.p.m. exposure group and none of the 22 tumors from the 5000 p.p.m. group. This compares to 63% of 126 historical control liver tumors and 55% of 20 liver tumors from unexposed B6C3F1 mice in this study. In addition, 12 hepatoblastomas from the two high dose groups were examined for H-ras mutations at codon 61, but none were detected. No tumor DNAs from any of the exposure groups tested had mutations in codons 12, 13 or 117 of the H-ras gene or codons 12 or 13 of the K-ras gene, the other known hotspots for ras activation in mouse liver tumors. These results, together with those from the National Toxicology Program study showing no evidence of cytotoxicity or genotoxicity by oxazepam, suggest that oxazepam preferentially promotes cells that have activating lesions other than ras.

Adenoma↗
PubMed1994

Ras mutations in methylclofenapate-induced B6C3F1 and C57BL/10J mouse liver tumours.

The majority of genotoxic carcinogen-induced liver tumours of the sensitive B6C3F1 mouse contain activated H-ras oncogenes. Such mutations also occur in hepatocarcinogenesis-resistant strains. In order to determine whether this is true of non-genotoxic carcinogen-induced tumours, liver tumours induced in B6C3F1 and C57BL/10J mice by methylclofenapate (MCP) were compared. Polymerase chain reaction (PCR) analysis revealed H-ras codon 61 mutations in 11/46 B6C3F1 and 4/31 C57BL/10J liver tumours. The nude mouse tumorigenicity (NMT) assay was used to analyse tumours without codon 61 mutations. Of the 12 B6C3F1 liver tumour DNAs subjected to this assay, one contained a H-ras codon 117 mutation. Further PCR analysis on frozen tumour samples (46 B6C3F1 and 15 C57BL/10J) revealed no codon 12 mutations; one additional codon 117 mutation was identified in a B6C3F1 tumour. Overall, then, H-ras codon 61 mutations were detected in MCP-induced B6C3F1 tumours less frequently than in genotoxin-induced tumours. Two B6C3F1 tumours contained codon 117 mutations similar to those previously found in tumours induced by ciprofibrate, furan and furfural, and in at least one spontaneous tumour. Ras mutations were also detected in some C57BL/10J tumours, providing further evidence that ras oncogenes can participate in hepatocarcinogenesis in resistant mice.

Alleles↗
PubMed1994

Magnetic resonance.

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Echo-Planar Imaging↗
PubMed1994

The 528th Combat Stress Control Unit in Somalia in support of Operation Restore Hope.

The 528th Combat Stress Control (CSC) Unit activated on December 16, 1992, and deployed to Somalia in support of Operation Restore Hope on January 6, 1993. The experiences of the first 90 days are discussed, to include (1) deployment issues, (2) stresses facing the troops in Somalia, and (3) patient data. The CSC had expected to work with service members traumatized by the sight of starving children and dead bodies. Instead, the stresses were similar to those of low-intensity guerrilla warfare. Overall there were very few soldiers and marines impaired by mental health issues, and minimal psychiatric evacuations from the theater.

Adaptation, Psychological↗
PubMed1994

A novel mechanism of in vivo ras gene activation involving tandem duplication of coding sequences.

A series of weakly transforming c-K-ras genes have been detected in spontaneously occurring and chemically induced mouse adenomas. DNA sequence analysis of these weakly transforming ras oncogenes showed that activation occurred by a novel mechanism involving duplication of nine or ten codon segments flanking codon 61 in exon 2. The codon repetitions in exon 2 are directly preceded by a number of potentially recombinogenic DNA sequences which may have been involved in the genesis of the codon repetitions through mechanisms involving recombination or DNA slippage. Duplication of DNA sequences such as those observed in the mouse c-K-ras gene may represent a new mechanism for both tumor suppressor gene inactivation and proto-oncogene activation.

3T3 Cells↗
PubMed1993

Molecular dynamics simulation of HIV-1 protease in a crystalline environment and in solution.

Simulations of the unbound form of the human immunodeficiency virus type 1 protease have been carried out to 200 ps in a crystalline environment and in solution. Solution simulations were performed with and without charge-balancing counterions. The results are compared with the 2.8-A crystallographic structure of Wlodawer et al. [(1989) Science 245, 616], and a proposed model for the solution structure which involves local refolding of the flap regions is presented. The simulations suggest the crystal packing environment of the protease dimer stabilizes the flaps in an extended conformation. Solvation of the dimer leads to local refolding of the flaps which contract toward the active site, forming increased overlap and stronger intersubunit hydrogn bonding at the tips. The degree to which the flaps overlap in solution is observed to depend on the charge state of the system.

Amino Acid Sequence↗
PubMed1993

The A/J mouse lung as a model for developing new chemointervention strategies.

The use of the A/J mouse lung as a model for developing new chemo-intervention strategies was investigated by first inducing lung tumors with a single dose of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone. Lungs were then staged for tumor development and intervention therapy was initiated 42 weeks after carcinogen treatment. At this time point, an average of 7 pulmonary lesions were present on a standard histological section and the relative frequency of lesions was distributed as alveolar hyperplasias (38%), adenomas (40%), and adenocarcinomas (22%). Mice were treated for 4 or 8 weeks with cis-platinum alone or in combination with either indomethacin, an inhibitor of prostaglandin synthesis, metoclopramide, an inducer of poly(ADP) ribosylation, or nifedipine, a calcium channel blocker. The effect of indomethacin, metoclopramide, and nifedipine on tumor growth was also determined. The most dramatic effects were observed in lungs from mice treated for 8 weeks. cis-Platinum treatment caused a 37% reduction in the size of carcinomas, while tumor mass was reduced by 50 to 60% with cis-platinum in combination with metoclopramide and/or indomethacin. The inclusion of indomethacin therapy in conjunction with cis-platinum significantly enhanced the effectiveness of cis-platinum for inhibiting the growth of adenocarcinomas. In contrast, nifedipine appeared to ameliorate any of the inhibitory growth effects seen with cis-platinum treatment. Although none of the therapeutic combinations affected the size of adenomas, morphological differences were observed among treatment groups. A moderate to marked decrease in cytoplasm was observed in adenomas from mice treated with cis-platinum in combination with indomethacin or metoclopramide, cis-platinum plus metoclopramide and indomethacin, or metoclopramide plus indomethacin. Taken together, the results from these studies demonstrate that the A/J mouse lung can be used as a model to study the effectiveness of new intervention therapies for controlling malignant tumor growth. This model should also be applicable for studying the effectiveness of cancer prevention therapies on the progression of pulmonary hyperplasia.

Adenocarcinoma↗
PubMed1993

Mutational specificities of environmental carcinogens in the lac1 gene of Escherichia coli, VII: The host-mediated assay and its comparison with in vitro mutagenesis induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.

To investigate the influence of different types of metabolic activation (9,000 x g supernatant (S9) activation vs. a host-mediated approach) on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced mutational specificity, we determined by DNA sequencing the distribution of forward mutations recovered in the N-terminal region of the lac1 gene of Escherichia coli. After activation with the S9 liver fraction from rats treated with Aroclor 1254, a diverse spectrum of mutations was recovered, with 55% of the events being G:C-->A:T transitions. In contrast, after the host-mediated assay in mice, G:C-->A:T transitions accounted for over 94% of the mutations recovered. Generally, NNK metabolism can proceed through two distinct pathways, involving either alpha-methyl or methylene hydroxylation. These two pathways produce different distributions of DNA damage. The difference in the mutational spectra we observed thus likely reflects the difference in the contributions of each pathway under the two different treatment conditions.

Base Sequence↗
PubMed1993

Comparison of pulmonary O6-methylguanine DNA adduct levels and Ki-ras activation in lung tumors from resistant and susceptible mouse strains.

The role of O6-methylguanine (O6MG) DNA adduct formation and persistence in the formation of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors from resistant C57BL/6 and susceptible A/J mice was investigated. In addition, the frequencies of pulmonary tumor formation and Ki-ras activation were defined in C57BL/6 mice treated with NNK or vinyl carbamate (VC), and the role of the p53 gene in pulmonary carcinogenesis in these resistant mice was examined. One day after treatment with 100 mg/kg NNK, O6MG adduct concentrations were twofold to eightfold higher in Clara cells and type II cells than in small cells or whole lungs from both mouse strains. The concentrations of O6MG in isolated cells decreased at a similar rate in the two strains of mice. Lung tumors were detected by 27 mo of age in 18% of the C57BL/6 mice after a single 100 mg/kg dose of NNK and in 46% of these mice after a single 60 mg/kg dose of VC. In contrast, the tumor incidence in untreated C57BL/6 mice was 4%. Only one of 22 lung tumors from C57BL/6 mice treated with NNK contained an activated Ki-ras gene that was associated with an O6MG DNA adduct, whereas previous studies detected activated Ki-ras oncogenes in most of the NNK-induced lung tumors analyzed from susceptible A/J and resistant C3H mice. The small differences in formation and persistence of the O6MG adduct in whole lung or isolated lung cells from A/J and C57BL/6 strains do not account for the differences in either susceptibility for tumor formation or activation of the Ki-ras gene between these strains. In contrast to the low number of NNK-induced tumors with Ki-ras mutations in the resistant mice, 11 of 20 lung tumors from VC-treated mice contained activated Ki-ras genes. Neither p53 tumor suppressor gene mutations nor overexpression of the p53 protein were detected in spontaneous or chemically induced lung tumors in C57BL/6 mice. Thus, although Ki-ras activation was detected in some tumors, pathways independent of ras activation and p53 inactivation also appear to be involved in lung tumorigenesis in this resistant mouse strain.

Animals↗