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M K Evans

Publications and source records attributed to M K Evans.

At least 19 recordsLinked to original sources
PubMed1999

Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps.

Altered mucin glycosylation and the de novo appearance of gastric mucin antigens have been described in colonic adenomas. The purpose of our study was to determine if expression of the gastric mucin genes MUC5AC and MUC6 occurs in colorectal adenomas and whether this correlates with histopathologic criteria of malignant potential. Immunohistochemical staining using antibodies against MUC5AC and MUC6 tandem repeat synthetic peptides was performed on specimens of normal colon mucosa (n = 26), hyperplastic polyps (n = 9) and adenomatous polyps (n = 111). Mucin mRNA levels were determined using RNase protection assays using riboprobes corresponding to unique non-repetitive sequences. MUC5AC and MUC6 staining were rarely detected and of low intensity in normal colon and hyperplastic polyps. The number of immunoreactive polyps and intensity of MUC5AC and MUC6 staining were greatest in larger adenomas of moderate villous histology and dysplasia. MUC5AC and MUC6 staining tended to decrease in highly villous polyps with severe dysplasia. Increased MUC5AC mRNA levels were found in 26/45 of adenomas tested compared with 0/9 normal colon specimens. MUC6 mRNA levels were found in 20/45 of adenomas compared with 1/9 normal colon specimens. MUC5AC and MUC6 mRNA were present more frequently and at higher levels in polyps with intermediate stages of size, villous histology and dysplasia. We conclude that aberrant expression of MUC5AC and MUC6 mucin genes is likely responsible for an expanded repertoire of mucin antigen expression in colorectal neoplasia.

Adenomatous Polyposis Coli↗
PubMed1999

Posturography does not test vestibulospinal function.

The clinical usefulness of posturography is unknown, despite its costing more than +500 per test in some areas of the United States, including Boston. We cross-sectionally and prospectively studied blinded vestibulo-ocular and vestibulospinal tests from 29 stable patients with chronic vestibular hypofunction; 22 patients were affected bilaterally (BVH), and 7 were affected unilaterally (UVH). Vestibulo-ocular function was assessed by electronystagmographic caloric stimulation and sinusoidal vertical axis rotation gains at 0.05 Hz. Vestibulospinal function was assessed by moving-platform and visualsurround posturography sensory organization tests (SOTs), paced and free gait in a gait laboratory, and clinical tests of timed gait and standing. Posturography SOT moving-platform tests 4 through 6, designed to assess vestibular function, correlated significantly (r < or = 0.72, P > or = 0.01) with vestibulo-ocular tests in 5 of 6 comparisons among BVH patients. Posturography SOT results, however, correlated poorly with other vestibulospinal measures: correlations were statistically significant for only 7 of 18 comparisons with clinical balance and gait function (r < or = 0.69, P > or = 0.01) and with 2 of 12 comparisons for gait laboratory dynamic stability measures (r < or = 0.55, P > or = 0.01) among the BVH patients. When both the platform and visual surround moved (SOT 6), however, correlations were statistically significant with static standing clinical measures (r = 0.51 to 0.69, P < 0.01) and with whole-body maximum moment arm during paced gait (r = 0.55, P < 0.01). Posturography scores for the UVH patients did not significantly correlate with any vestibulo-ocular or other vestibulospinal measures. These data indicate that among patients with BVH posturography SOT scores relate at best modestly with accepted measure of vestibulo-ocular function, less well with clinical measures of balance control, and poorly with dynamic gait-performance measures. We conclude that posturography SOT does not assess vestibulospinal function.

Adult↗
PubMed1999

Humoral immunity to commensal oral bacteria in human infants: salivary secretory immunoglobulin A antibodies reactive with Streptococcus mitis biovar 1, Streptococcus oralis, Streptococcus mutans, and Enterococcus faecalis during the first two years of life.

Secretory immunoglobulin A (SIgA) antibodies reactive with the pioneer oral streptococci Streptococcus mitis biovar 1 and Streptococcus oralis, the late oral colonizer Streptococcus mutans, and the pioneer enteric bacterium Enterococcus faecalis in saliva samples from 10 human infants from birth to age 2 years were analyzed. Low levels of salivary SIgA1 and SIgA2 antibodies reactive with whole cells of all four species were detected within the first month after birth, even though S. mutans and E. faecalis were not recovered from the mouths of the infants during the study period. Although there was a fivefold increase in the concentration of SIgA between birth and age 2 years, there were no differences between the concentrations of SIgA1 and SIgA2 antibodies reactive with the four species over this time period. When the concentrations of SIgA1 and SIgA2 antibodies reactive with all four species were normalized to the concentrations of SIgA1 and SIgA2 in saliva, SIgA1 and SIgA2 antibodies reactive with these bacteria showed a significant decrease from birth to 2 years of age. Adsorption of each infant's saliva with cells of one species produced a dramatic reduction of antibodies recognizing the other three species. Sequential adsorption of saliva samples removed all SIgA antibody to the bacteria, indicating that the SIgA antibodies were directed to antigens shared by all four species. The induction by the host of a limited immune response to common antigens that are likely not involved in adherence may be among the mechanisms that commensal streptococci employ to persist in the oral cavity.

Antibodies, Bacterial↗
PubMed1998

Clonal diversity of vancomycin-resistant enterococci from an outbreak in a tertiary care university hospital.

BACKGROUND: Enterococci have become important nosocomial pathogens and now account for approximately 12% of nosocomial infections. Enterococci can be transferred from patient to patient and from health care personnel to patient. We investigated the clonal diversity of vancomycinresistant enterococci (VRE) causing an outbreak of infections and attempted to determine the patterns of spread of these bacteria in a university hospital. METHODS: Ribotyping was used to examine the clonal diversity of 50 VRE isolates, including 23 from wounds, 14 from urine, 8 from blood, 3 from the rectum, 1 from drainage, and 1 from the cornea. RESULTS: Nine patients were infected with Enterococcus faecalis, 10 with Enterococcus faecium, 3 with both E faecalis and E faecium, and 1 with Enterococcus avium. The results suggest that the sources of the VRE infections included endogenous strains and strains acquired by transmission from attending staff or from the environment. Three patients were infected by both nosocomial and endogenous strains. CONCLUSIONS: These data suggest that the collection and analysis of several isolates from repeated specimens is necessary to obtain a fuller understanding of the epidemiology and population structure of antibiotic-resistant enterococci.

Anti-Bacterial Agents↗
PubMed1998

Humoral immunity to commensal oral bacteria in human infants: salivary antibodies reactive with Actinomyces naeslundii genospecies 1 and 2 during colonization.

The secretory immune response in saliva to colonization by Actinomyces naeslundii genospecies 1 and 2 was studied in 10 human infants from birth to 2 years of age. Actinomyces species were not recovered from the mouths of the infants until approximately 4 months after the eruption of teeth. However, low levels of secretory immunoglobulin A1 (SIgA1) and SIgA2 antibodies reactive with whole cells of A. naeslundii genospecies 1 and 2 were detected within the first month after birth. Although there was a fivefold increase in the concentration of SIgA between birth and age 2 years, there were no differences between the concentrations of SIgA1 and SIgA2 antibodies reactive with A. naeslundii genospecies 1 and 2 over this period. When the concentrations of SIgA1 and SIgA2 antibodies reactive with whole cells of A. naeslundii genospecies 1 and 2 were normalized to the concentrations of SIgA1 and SIgA2 in saliva, the A. naeslundii genospecies 1- and 2-reactive SIgA1 and SIgA2 antibodies showed a significant decrease from birth to 2 years of age. The fine specificities of A. naeslundii genospecies 1- and 2-reactive SIgA1 and SIgA2 antibodies were examined by Western blotting of envelope proteins. Similarities in the molecular masses of proteins recognized by SIgA1 and SIgA2 antibodies, both within and between subjects over time, were examined by cluster analysis and showed considerable variability. Taken overall, our data suggest that among the mechanisms Actinomyces species employ to persist in the oral cavity are the induction of a limited immune response and clonal replacement with strains differing in their antigen profiles.

Actinomyces↗
PubMed1996

DNA repair fine structure in Werner's syndrome cell lines.

Werner's syndrome (WS) is a human segmental progerioid disorder with an autosomal recessive pattern of inheritance. Patients with WS exhibit a number of symptoms resembling a premature aging phenotype. We have examined the fine structure of the DNA repair of UV-induced cyclobutane pyrimidine dimers in Epstein-Barr virus (EBV)-transformed WS lymphoblastoid cell lines and in a primary WS fibroblast cell line. The repair was measured at the level of the gene and also in the general genome. Gene-specific and strand-specific DNA repair was measured in the actively transcribed genes dihydrofolate reductase (DHFR), c-myc, and p53, and in the transcriptionally inactive regions, delta globin and the X-linked 754 domain. Both gene-specific repair and strand-specific repair were deficient in the transformed WS lymphoblastoid cell lines compared to normal controls. In normal cells, repair in the transcribed strand was 25 (4 h), 43 (8 h), and 72% (24 h); in the WS cells on average, repair in the transcribed strand was 18 (4 h), 27 (8 h), and 44% (24 h). However, in the primary WS fibroblast cell line, we found a pattern of preferential gene repair which was similar to that in normal human cells. In contrast to cells from patients with the gene-specific repair deficient disease Cockayne's syndrome, which show greatly delayed RNA synthesis recovery after UV irradiation, the WS cells had normal recovery of RNA synthesis. The DNA repair results differ for the different cell types, and our findings thus do not establish a general DNA repair phenotype for WS cells. The fibroblasts had proficient repair, but in the WS lymphoblasts we find a deficiency in DNA repair which could contribute to the reported hypermutability in these cells. The lymphoblasts are, however, transformed cells, and it raises the concern that biological findings in transformed cells may not reflect the situation in primary cells.

Blotting, Southern↗
PubMed1996

Gene-specific DNA repair and steady state transcription of the MDR1 gene in human tumor cell lines.

We have explored the relationship between DNA repair and transcription in vivo. A gene-specific repair assay has been employed to study removal of ultraviolet light-induced cyclobutane pyrimidine dimers in the MDR1 gene at different levels of MDR1 mRNA expression. The parental human adenocarcinoma cell line, KB-3-1, has very low levels of MDR1 mRNA expression, but its multidrug resistant derivatives KB-8-5 and KB-C1 have 42-fold and 3800-fold increases in MDR1 mRNA expression, respectively. In the KB-3-1 cell line that has a low level of MDR1 mRNA expression, we find a low level of MDR1 gene-specific repair and inefficient repair of the transcribed strand of the gene. In the KB-8-5 cell line that has a modest increase in MDR1 mRNA expression, we find only a minor increase in dimer repair in the MDR1 gene. Here, the repair in the transcribed strand is not significantly higher than that in the KB-3-1 cell line. However, in the KB-C1 derivative, where there is a 3800-fold increase in the level of MDR1 mRNA expression, we find a substantial increase in the level of dimer repair in the MDR1 gene. In addition, the MDR1 transcribed strand repair is markedly more efficient than the repair in the nontranscribed strand. Our data suggest that the rate of transcription in the MDR1 gene must be substantially increased before there is any measurable effect on DNA repair. Repair in the housekeeping gene, dihydrofolate reductase (DHFR), was similar in all three tumor cell lines. Repair in its transcribed strand was markedly lower than previously reported in normal human fibroblasts. We suspect that these human HeLa-derived tumor cell lines have deficient gene-specific DNA repair. This may be an important aspect of their malignant phenotype.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1995

p53 modulation of TFIIH-associated nucleotide excision repair activity.

p53 has pleiotropic functions including control of genomic plasticity and integrity. Here we report that p53 can bind to several transcription factor IIH-associated factors, including transcription-repair factors, XPD (Rad3) and XPB, as well as CSB involved in strand-specific DNA repair, via its C-terminal domain. We also found that wild-type, but not Arg273His mutant p53 inhibits XPD (Rad3) and XPB DNA helicase activities. Moreover, repair of UV-induced dimers is slower in Li-Fraumeni syndrome cells (heterozygote p53 mutant) than in normal human cells. Our findings indicate that p53 may play a direct role in modulating nucleotide excision repair pathways.

Adenosine Triphosphatases↗
PubMed1995

Caffeine inhibits gene-specific repair of UV-induced DNA damage in hamster cells and in human xeroderma pigmentosum group C cells.

We have studied the effect of caffeine on gene- and strand-specific DNA repair after exposure of Chinese hamster ovary cells and human xeroderma pigmentosum complementation group C (XPC) cells to ultraviolet irradiation (UV). In hamster cells, caffeine inhibited the repair of cyclobutane dimers (CPDs) in the dihydrofolate reductase (DHFR) gene by up to 66% after 8 h of repair incubation. This effect was dose-dependent, with more inhibition at 10 than at 1.5 mM caffeine. The inhibition was due to decreased repair in the transcribed strand of the hamster DHFR gene. This decrease in repair of CPDs in the DHFR gene correlated with an enhancement of UV-induced cell killing by caffeine. DNA repair was also measured in the overall genome by repair-replication analysis. In hamster cells, caffeine caused a modest enhancement of repair. Caffeine did not produce a significant effect on cell cycle progression up to 8 h after UV irradiation, but it caused a distinct block in early S phase during the 24 h post-irradiation period. In XPC cells, 10 mM caffeine inhibited the removal of CPDs from the transcribed strand of the DHFR gene by 92%. The removal of all photoproducts from the overall genome was inhibited by 26% in these cells. Since the residual repair in XPC cells is thought to occur in active genomic regions, we propose that caffeine preferentially inhibits gene-specific repair.

Animals↗
PubMed1994

Gene-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in some cancer-prone and premature-aging human syndromes.

We have examined the gene-specific DNA repair of UV-induced cyclobutane pyrimidine dimers (CPDs) in fibroblasts from the following cancer prone syndromes: familial dysplastic nevus syndrome (DNS), Gardner's syndrome (GS), and Bloom's syndrome (BS). These heritable human syndromes are associated with DNA damage hypersensitivity and have been considered as potentially DNA repair deficient. Previous determinations of DNA repair in these cell strains have been done solely at the level of the overall genome. That approach is not sensitive enough to detect deficiencies in repair at the level of the gene. Defective preferential repair of active genes may impair survival and affect genomic stability. This is exemplified by the disorder Cockayne's syndrome (CS) which is associated with a selective deficiency in the preferential repair of active genes. In this study, we have used a Cockayne's syndrome cell strain and also a normal human fibroblast cell line as a control. Repair was studied in the transcriptionally active gene dihydrofolate reductase (DHFR), the inactive delta globin gene, and in the c-myc protooncogene. In the DNS, GS and BS cell lines, we find preferential repair similar to that in normal cells. In Cockayne's syndrome cells, there is no preferential repair of the DHFR gene.

Abnormalities, Multiple↗
PubMed1994

Immunoglobulin A subclasses in infants' saliva and in saliva and milk from their mothers.

We sought to determine (1) the ontogeny of secretory IgA subclasses in saliva of breast- and formula-fed infants and (2) the influence of breast-feeding on the maturation of secretory salivary IgA subclasses. Secretory IgA and subclasses 1 and 2 concentrations were determined in saliva from 40 healthy, term infants from birth to age 18 months, and in parallel milk samples from the infants' mothers who were breast-feeding during the first 6 months after birth. Secretory IgA was detected in the neonates' saliva as early as 3 days after birth, increased rapidly during the next 6 months, but then stabilized at a level approximately one-sixth that of the mothers' salivary secretory IgA. Secretory IgA2 represented less than 15% of secretory IgA in saliva collected 2 weeks after birth but by 6 months represented 24.4% of secretory IgA, a value approaching that of the mothers' salivary secretory IgA2 (30.4%). This increase in the proportion of secretory IgA2 was temporally related to a reduction in the proportion of secretory IgA2 in milk throughout lactation. The secretory IgA concentration increased more rapidly during the first 6 months after birth in infants exclusively breast fed than in those exclusively bottle fed. We conclude that although secretory immunity is immature in infants, breast-feeding may aid in protection against pathogenic microorganisms by increasing the rate of mucosal IgA maturation.

Breast Feeding↗
PubMed1993

DNA strand bias in the repair of the p53 gene in normal human and xeroderma pigmentosum group C fibroblasts.

We have measured the gene-specific and strand-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in the p53 tumor suppressor gene in a normal, repair-proficient human fibroblast strain and in fibroblasts from a patient with the repair deficient disorder xeroderma pigmentosum, complementation xeroderma pigmentosum group C (XP-C). In both cell strains, repair was measured in the p53 gene and in its individual DNA strands. For comparison, the repair also was measured in other genomic regions in these human fibroblast strains, including the housekeeping gene dihydrofolate reductase, and two inactive genomic regions, the delta globin gene, and the 754 locus of the X chromosome. In both cell strains, we find that the p53 gene is repaired faster than the dihydrofolate reductase gene and much more efficiently than the inactive genomic regions. Selective repair of the transcribed DNA strand of p53 is observed in both human cell strains; the strand bias of repair is particularly distinct in XP-C. Mutations specific to the nontranscribed strand may occur due to replication errors at the sites of unrepaired DNA damage. Therefore, our results predict that the majority of mutations in skin cancers, especially those from patients with XP-C, would occur on the nontranscribed strand of the p53 gene. Indeed, Dumasz et al. (Proc. Natl. Acad. Sci. USA, in press, 1993) report such a strand bias of p53 mutation in skin cancers from XP-C patients.

DNA↗
PubMed1993

Gene-specific DNA repair in xeroderma pigmentosum complementation groups A, C, D, and F. Relation to cellular survival and clinical features.

We have examined the gene- and strand-specific DNA repair of UV-induced cyclobutane pyrimidine dimers in fibroblasts from normal individuals and from patients with the DNA repair-deficient disorder xeroderma pigmentosum (XP). Cells were studied from XP complementation groups A, C, D, and F. DNA repair was assessed in the essential, active gene, dihydrofolate reductase (DHFR), in the active c-myc protooncogene, and in the transcriptionally inactive delta-globin gene. In addition, repair was studied in the individual strands of the DHFR gene in normal and group C cells. In the two strains of group C cells, we find preferential DNA repair of the DHFR gene and a strand bias of the repair with more repair in the transcribed strand. This is in general accordance with previously published reports (Venema, J., van Hoffen, A., Natarajan, A.T., van Zeeland, A.A., and Mullenders, L.H.F. (1990) Nucleic Acids Res. 18, 443-448; Venema, J., van Hoffen, A., and Mullenders, L.H.F. (1991) Mol. Cell. Biol. 11, 4128-4134), but we now find that there is more repair in the nontranscribed strand and less in the transcribed strand than what has been observed previously. In XP group A and D strains, we find little or no gene-specific DNA repair. In cells from an individual in XP complementation group F, we find less repair of dimers in the active gene than what has been observed for the overall genome. We have also measured the colony-forming ability of the strains after treatment with UV and find that this measure of survival does not correlate with the level of gene-specific repair of dimers. Thus, XP group F represents a novel repair phenotype with little or no gene-specific repair of dimers, but with relatively high UV resistance. We also evaluate the XP patients' clinical features in relation to gene-specific repair of dimers.

Adult↗
PubMed1993

Deficient gene specific repair of cisplatin-induced lesions in Xeroderma pigmentosum and Fanconi's anemia cell lines.

Cisplatin is a chemotherapeutic agent known to cause DNA damage. The cytotoxicity of this drug is believed to result from the formation of DNA intrastrand adducts (IA) and DNA interstrand crosslinks (ICL). While there are many studies on DNA repair of cisplatin damage at the overall level of the genome in various human cell lines, there is little information on the gene-specific repair. In this report, we have measured the formation and repair of cisplatin induced DNA adducts in the dihydrofolate reductase (DHFR) and ribosomal RNA (rRNA) genes in three cell lines: normal human fibroblasts, Fanconi's anemia complementation group A (FAA) and Xeroderma pigmentosum complementation group A (XPA). It is generally thought that XPA cells lack nucleotide excision repair and that FAA cells are deficient in the repair of DNA ICL. We find that normal human fibroblast cells repair 84% of the ICL in the DHFR gene after 24 h, whereas XPA and FAA cell lines only repaired 32 and 50% of the ICL respectively. Furthermore, 69% of the cisplatin IA in the DHFR gene were repaired in 24 h in normal human fibroblasts compared to 22% for XPA and 24% for FAA cells. The repair of the rRNA gene was less efficient than in the DHFR gene, but the relative pattern between the different cell lines was similar to that of the DHFR gene. We thus find that FAA cells are deficient not only in the gene specific repair of cisplatin ICL, but also in the gene specific repair of the more common cisplatin IA. XPA cells are normally thought to be without any nucleotide excision repair capacity, but our data could support a slight ICL unhooking activity.

Cell Line↗
PubMed1990

Heterogeneity of DNA repair: implications for human disease and oncology.

DNA repair studies used to be confined to measurements representing an average over the entire mammalian genome. It is now possible to study repair processes at subgenomic levels including specific genes. We will describe such results and discuss the impact they may have on our understanding of important oncological processes. Also, we will describe and discuss some clinical conditions that may have some effect in DNA damage processing.

DNA↗