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Biomedical subjects

C M Lewis

Publications and source records attributed to C M Lewis.

At least 55 records · Page 3Linked to original sources
PubMed1998

PMA alters folate receptor distribution in the plasma membrane and increases the rate of 5-methyltetrahydrofolate delivery in mature MA104 cells.

MA104 cells (a monkey kidney cell line) can internalize 5-methyltetrahydrofolate via a receptor mediated process termed potocytosis. Uptake is initiated by binding to an external folate receptor which cycles to an internal, but membrane bound compartment. These two pools can be measured by determining the amount of [3H]ligand removed by an acid-saline wash, i.e. acid labile and acid resistant pools. When assayed in confluent nonmitotic cells, 2/3 of the folate receptor pool is located in an internal (acid resistant) compartment, but phorbol 12-myristate 13-acetate (PMA) causes a shift such that 65-75% of the receptor pool resides on the surface of the plasma membrane. This new steady state is likely the result of an increased rate of receptor movement. In addition, PMA increases the rate of 5-methyl[3H]tetrahydrofolate delivery to the cytoplasm 1.8 fold. Using known inhibitors of potocytosis, we were able to show that the increased rate of delivery is receptor mediated. Comparison of the time courses of the PMA effects on folate receptor redistribution assessed by membrane binding of [3H]folic acid and 5-methyl[3H]tetrahydrofolate delivery to the cytoplasm suggests that PMA may be activating more than one protein kinase C independent signal transduction pathway. PMA is the first reported positive modulator of receptor mediated folate uptake.

Animals↗
PubMed1998

Response to radiation therapy and prognosis in breast cancer patients with BRCA1 and BRCA2 mutations.

BACKGROUND AND PURPOSE: The purpose of this study is to evaluate overall survival in BRCA1 or BRCA2 breast cancer patients, describe presenting stage, review histologic findings and evaluate response to radiotherapy. MATERIALS AND METHODS: A retrospective study was performed evaluating breast cancer patients with known mutations of BRCA1 or BRCA2. Patients from 12 different pedigrees were cross-referenced with the Utah Cancer Registry (UCR), histologic findings were verified and radiotherapy records were reviewed for acute response to treatment. Actuarial survival calculations were performed and patients were matched for age, date of diagnosis and tumor size. RESULTS: Thirty breast cancer patients with BRCA1 mutations were found to have 34 breast cancers (four had bilateral metachronous lesions) and 20 breast cancer patients with BRCA2 mutations were found to have 22 breast cancers (two had bilateral metachronous disease). The median age at diagnosis was 49 years (range 21-77 years) and 42 years (range 23-83 years), respectively, for BRCA1 and BRCA2 patients. Unusual histologic types of breast cancers were represented with 7% (4/56) medullary and 5% (3/56) lobular carcinomas. Complete staging was possible for 63% (35/56) of cancers. Stages I, II, III and IV represented 26, 63, 6 and 6% of cancers, respectively. The most severe radiation reaction was moist desquamation which was self-limiting and developed in 29% (6/21) of irradiated patients. The mean follow-up was 9.8 and 7.5 years for BRCA1 and BRCA2 cancers, respectively. Kaplan-Meier survival analysis demonstrated 5-year survival values of 75% for BRCA1 patients, 73% for BRCA2 patients, 70% for matched controls and 69% for UCR controls. No statistically significant differences were evident between the groups at 5 or 10 years. CONCLUSIONS: Despite their younger age at presentation, breast cancer patients harboring BRCAI or BRCA2 mutations present at a similar stage, display a normal acute reaction to radiotherapy and have a similar prognosis when compared with sporadic breast cancer patients.

Adult↗
PubMed1998

The effect of family structure on linkage tests using allelic association.

We considered the problem of testing a marker for linkage with a disease, using tests based on the transmission-disequilibrium test (TDT). The power of such tests was investigated for a number of possible family types, for which the families were classified by the disease status of family individuals. We show that parental disease status greatly affects the power, with families containing a single affected parent often preferred over families in which neither parent is affected. Families with a pair of affected sibs are of great value for all situations considered, but extension of the TDT to allow inclusion of information from unaffected sibs rarely increases power, if the parents have been genotyped.

Adult↗
PubMed1997

Age, genetic, and nongenetic factors influencing variation in serum sex steroids and zonal volumes of the prostate and benign prostatic hyperplasia in twins.

BACKGROUND: We have observed that hereditary and environmental factors have a substantial influence on the plasma content of sex steroids in normal male twins and in men of families with prostatic disease. METHODS: The contribution of genetic and nongenetic familial factors on the variation of plasma sex steroid concentrations and of the volume of zones of the prostate measured by transrectal ultrasound (TRUS) has now been investigated in pairs of male monozygotic (MZ) and dizygotic (DZ) twin pairs between age 25-75 years. Bioelectric impedance permitted quantitation of body fat, lean body mass, and water. Morphometrics and testicular volume were also determined. RESULTS: The intraclass correlation (rI) was > 0.40 for the variation of the total volume (TV), the transition zone (TZ), the peripheral zone (PZ), and the ratio of TZ/PZ in both MZ and DZ twins, and heredity affected 22% of the variation of the PZ and TZ and 30% of the ratio of TZ/PZ. None of the TV and environmental factors influenced the remainder of the variation. Heredity accounted for 25% or more of the variation of dihydrotestosterone (DHT), and the ratios of DHT/testosterone (T), estradiol (E2)/T, androstanediol glucuronide, sex hormone-binding globulin (SHBG)-bound T, T/SHBG, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and dehydroepiandrosterone sulfate (DHEA-S). In MZ twin pairs the variation of the volumes of the prostate became greater with age. In contrast, the variation of the sex hormone concentrations did not show greater variation with age. Heredity also affected > 30% of the variation for waist measurement, weight, body fat, body mass, water and lean body mass, body mass/fat, and testicular size. CONCLUSIONS: Our results indicated that both MZ and DZ twin pairs had zonal prostate volumes more like their twin pair than like unrelated twins. However, nongenetic factors exerted stronger influences than genetic factors on zonal volumes of the prostate. In contrast, hereditary factors had stronger influences on determining the variation of many sex hormones and morphometric characteristics than did nongenetic factors.

Adult↗
PubMed1997

Multilocus quantitative trait analysis using the multipoint identity-by-descent method.

The multipoint identity-by-descent method (MIM) was extended to test for evidence of quantitative trait loci in two independent genetic regions. This method is a fast and feasible implementation of a multiple-marker, two-region linkage analysis for quantitative traits. It tests for significant evidence of quantitative trait loci (QTL) in neither, one or both genetic regions tested, and could be extended to an arbitrary number of independent genetic regions. A two-stage analysis was used for the nuclear family data from GAW10. Initially, an analysis of the genomic search was carried out using single-region MIM, with sets of six adjacent markers. Chromosomal regions that showed some evidence of linkage were identified and used in a two-region MIM analysis.

Chromosome Mapping↗
PubMed1997

Linkage studies in dominant optic atrophy, Kjer type: possible evidence for heterogeneity.

Dominant optic atrophy, Kjer type, is an autosomal dominant disorder causing progressive loss of visual acuity and colour vision from early childhood. The gene (OPA1) has variable expressivity, a penetrance of 0.98, and the locus has been localised to 3q28-29. We have genotyped nine British families with the disease using 12 polymorphic microsatellite markers from this region. Linkage and haplotype analysis shows the OPA1 gene to be located in a 2.3 cM interval between markers D3S1601 and D3S2748. One family showed no evidence of linkage with the chromosome 3 markers, suggesting for the first time that locus heterogeneity for this disease may exist, although exclusion for linkage is based on unaffected subjects. In addition, analysis of recombinants has enabled us to order the 12 markers along chromosome 3.

Adolescent↗
PubMed1997

Effects of age and sex hormones on transition and peripheral zone volumes of prostate and benign prostatic hyperplasia in twins.

Benign prostatic hyperplasia has been shown to increase with age and be influenced by sex hormones. The relationship between aging and hormonal influences on growth of zones of the prostate is unresolved. We studied the relationship of age and sex hormones on volume of prostate zones in 214 male twins between 25 and 75 yr old. Volumes of the total prostate (TV), transition zone (TZ), and peripheral zones (PZ) were measured using transrectal ultrasound, and sex steroid concentrations were measured using RIA. Using transformed data corrected for age, TV (r = 0.54, P < 0.00001), TZ (r = 0.58, P < 0.00001), and PZ (r = 0.39, P < 0.00001) volumes increased with age. However, the PZ volume rose more rapidly than the TZ before age 50, and TZ showed a steeper increase after age 50 yr than the PZ volume. The TZ, PZ, and ratio TZ/PZ correlated significantly (r = 0.87, 0.90, and 0.52, respectively; P < 0.00001). After a TV exceeded 30 g, the rise of the PZ became attenuated, and the slope of the TZ became steeper. Age-adjusted sex hormone concentration was not evaluated in men with larger prostate volumes. Men with American Urological Association symptom scores above 10 had significantly (P < 0.001) larger total prostate volume (TV) and TZ volume, but not PZ volumes, than men with scores below 10. Prostate volumes correlated inversely with age-adjusted serum testosterone (T), dihydrotestosterone, sex hormone binding globulin, and sex hormone binding globulin-bound T concentrations. These results demonstrate that before age 50 yr or before a prostate weight exceeds 30 g, prostate growth may be mainly from enlargement of the PZ and after age 50, the TZ. In addition, elevated T and dihydrotestosterone concentrations do not predispose men to prostate enlargement or symptoms of benign prostatic hyperplasia.

Adult↗
PubMed1996

Genetic heterogeneity and unmapped genes for colorectal cancer.

Colorectal cancer (CRC) has a strong familial component. Candidate genes for colorectal cancer have been identified through mutations in four mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) and genes that are deleted or mutated in tumors (DCC, APC, and p53). Linkage analysis of candidate loci/regions was performed in 10 kindreds ascertained for common colorectal cancer from the Utah Population Database. Evidence for linkage to candidate genes was assessed using two- or three-point logarithm of the odds ratio scores with markers spanning the region of localization. One kindred is linked to hMSH2 and also fits the criteria for hereditary nonpolyposis colorectal cancer, having early age of onset and high penetrance for CRC. The remaining nine kindreds are unlinked to the candidate genes tested. These kindreds have a later age of onset and a lower penetrance than hereditary nonpolyposis colorectal cancer kindreds. these results indicate that further unmapped susceptibility loci may be responsible for much of the familial aggregation of CRC.

Adult↗
PubMed1996

Genetic contribution to DZ twinning.

The genetic contribution to dizygotic (DZ) twinning was investigated using 6,596 twin pairs from the Australian Twin Registry who provided information on other twins in their families. Responses were classified by the zygosity (DZ; monozygotic [MZ]) of the proband twins and by the relationship and zygosity of related twins. MZ probands and MZ twins reported by DZ probands were used as controls and assumed to be independent of any genetic influence. Significantly higher proportions of DZ twins were found in the families of DZ probands compared to the families of MZ probands for the following relationships: sibs of probands, proband mothers, offspring of sisters of proband mothers, and offspring of female probands (P < 0.001 in each case). The latter 2 relationships were used to estimate risk ratios of 1.7 for sisters of mothers of DZ twins, and 2.5 for offspring of female DZ twins. No greater tendency to DZ twinning in close relatives was found in mothers who bore DZ twins at a younger age than at an older age.

Australia↗
PubMed1996

Genetic modelling of dizygotic twinning in pedigrees of spontaneous dizygotic twins.

The inheritance of spontaneous dizygotic (DZ) twinning was investigated in 1,422 three-generation pedigrees ascertained through mothers of spontaneous DZ proband twins. DZ twinning was modelled as a trait expressed only in women. The penetrance was modelled first as a parity independent and secondly as parity dependent. The observed frequencies of maternal and paternal grandmothers with DZ twins differed significantly from the expectations under an X-linked mode of inheritance. Complex segregation analysis showed that the parity-independent phenotype of "having DZ twins" was consistent with an autosomal monogenic dominant model, with a gene frequency of 0.035 and a female-specific lifetime penetrance of 0.10. Recessive, polygenic, and sporadic models were rejected. The autosomal dominant model revealed a strong robustness against a changing population prevalence and the loss of information due to the presence of same-sexed twin pairs of unknown zygosity. When DZ twinning was modelled as a parity dependent trait, the data were compatible with an autosomal dominant model with a gene frequency of 0.306 and a penetrance of 0.03 per birth for female gene carriers.

Cluster Analysis↗
PubMed1996

Risks from occupational and dietary exposure to mevinphos.

Mevinphos (trade name, Phosdrin), a category 1 organophosphorus insecticide, has been used mainly as a cleanup pesticide for vegetable crops. A risk assessment for occupational and dietary exposure to mevinphos was initiated because of the high acute toxicity of the compound. Repetitive dosing with mevinphos did not cause any discernible histopathological effects in mice or rats, nor was it oncogenic in either species. The principal toxic effects of mevinphos, both short- and long term, were due to inhibition of cholinesterase activity. Consequently, potential adverse effects from short-term exposures were the primary concern. A human no-observed-effect level (0.025 mg/kg) for cholinergic signs was used as the regulatory basis for calculating margins of safety (MOSs) for potential acute dietary and short-term occupational exposures. Estimates of exposure to mixer/loaders, pilots, and flaggers associated with aerial application of mevinphos were based on passive dosimetry. Because no acceptable exposure studies for work tasks associated with ground application of mevinphos were available, surrogate data based on ground application of oxydemeton-methyl were used. Exposure estimates for field workers and harvesters relied on measured dislodgeable foliar residues of mevinphos and transfer factors generated from studies of other active ingredients. MOSs for mean acute occupational exposure of mixer/loader/applicators associated with ground application and of harvesters working in fruit trees were less than the value conventionally recommended to protect people from the toxic effects of mevinphos. MOSs for the 95th percentile of short-term worker exposure for all mixer/loader work categories associated with mevinphos application were also inadequate. Calculated MOSs for potential acute dietary exposure to measured residue levels of mevinphos were adequate for the various population subgroups. However, 25 of the USEPA tolerances for mevinphos on agricultural commodities were not adequate to protect for the toxic effects of mevinphos from theoretical acute dietary exposure to one or more population subgroups if commodities are consumed with residues at the tolerance level. When the mean short-term occupational exposures were combined with potential acute dietary exposure, the MOSs for mixer/loaders engaged in aerial applications, as well as ground applications, were inadequate to protect people from the toxic effects of mevinphos. As mitigation of the estimated excessive occupational exposures did not appear possible, both California and the USEPA were preparing to cancel registration of the product. However, an agreement was worked out between the manufacturer and the two agencies that ended production for domestic use but allowed existing stocks in the channels of trade to continue to be used for a limited period.

Animals↗
PubMed1996

Interobserver concordance in discriminating clinical atypia of melanocytic nevi, and correlations with histologic atypia.

BACKGROUND: The clinical features attributed to atypical (formerly ¿dysplastic") nevi and to the atypical multiple mole melanoma syndrome have been used in clinical practice, as well as experimentally, to assign melanoma risk. Little information is available, however, on the interobserver reliability in assessing those features. OBJECTIVE: Our purposes were to quantify interobserver and intraobserver concordances in recognizing certain atypical characteristics of nevi and to correlate the clinical assessments with the histologic characteristics. METHODS: Three observers evaluated clinical photographs of 100 pigmented lesions (predominantly melanocytic nevi, with some lentigines and seborrheic keratoses) from 95 subjects, of whom 85 were family members of four multiple melanoma kindreds and 10 were spouses. Each lesion was rated for border irregularity, color variegation, surface contour irregularity, pigment diffusion, and macularity versus papularity. Predictions were made as to the histologic diagnoses and presence of melanocytic atypia for those lesions judged to be nevi. RESULTS: The pair-wise concordances before agreement on specific criteria were quantified by kappa statistics, which indicated slight to fair agreement in judging the atypical clinical characteristics; concordances increased to moderate levels after consensus development of criteria for color variegation and assessment of macularity, but agreement on the other features remained limited. Whereas macularity and color variegation did correlate somewhat with higher grades of histologic atypia, correlations were generally low between the clinical and histologic diagnoses. CONCLUSION: There is limited interobserver reliability in the clinical assessment of nevus atypia, although correlations do exist between some atypical characteristics and grades of histologic atypia. Because of the low concordances, the clinical discrimination of the melanoma-associated atypical nevus phenotype should rely more on quantitative aspects of the trait, such as total numbers or maximal sizes of nevi, rather than on the subjective determinations of atypia.

Dermatitis, Seborrheic↗
PubMed1995

Screening for linkage using a multipoint identity-by-descent method.

The multipoint identity-by-descent method (MIM) was used to analyze simulated data for quantitative traits from GAW9. A two-stage method of implementation was used. First, polymorphic markers spaced 6-12 cM apart were used to identify chromosomes of interest for each trait Q1-Q4; and second, for each of these chromosomes, markers spaced 2 cM apart were used to confirm the linkage detected and refine the region for the susceptibility loci. MIM performed well at both levels of mapping, correctly detecting major genes for trait Q3 on chromosome 2, trait Q2 on chromosome 1, and trait Q4 on chromosome 5.

Analysis of Variance↗
PubMed1995

Use of a novel mutagenesis strategy, optimized residue substitution, to decrease the off-rate of an anti-gp120 antibody.

We have developed a novel strategy to decrease the antibody:antigen off-rate which we call optimized residue substitution. This strategy employs alanine substitution to first identify residues non-optimal for binding, as evidenced by a decrease in off-rate upon alanine replacement. These positions are then individually randomized to all amino acids, and the best replacement for each position determined. Finally, a construct which combines all optimized substitutions is generated and evaluated. We applied this strategy to the heavy chain CDR3 of P5Q, a scFv antibody which recognizes an epitope on the V3 loop of HIV gp120. We identified two amino acid substitutions that together decrease the off-rate by nearly ten-fold. The contributions by the two substitutions were near additive, indicative of independent affects on binding. We suggest that this strategy can be generalized to strengthen protein:ligand and protein:protein interactions in other systems.

Alanine↗
PubMed1994

Penetrance and expressivity of the chromosome 9p melanoma susceptibility locus (MLM).

A susceptibility locus for familial melanoma has been localized to the short arm of chromosome 9. Penetrance of melanoma was estimated by calculating the Kaplan-Meier function and fitting a log normal hazard function in 124 gene carriers in three 9p-linked kindreds. The penetrance of the gene for melanoma was estimated to be 53% by age 80. Additionally, nevus counts, skin type, and sun exposure histories were gathered for 119 individuals in two kindreds. Gene carriers were found to have higher nevus counts and nevus densities than non-gene carriers. Among gene carriers, individuals with melanoma were found to have more sun exposure within each skin type than gene carriers without melanoma. These analyses suggest that the 9p melanoma susceptibility is related to total number of nevi and that it interacts with other genetic and environmental factors to produce melanoma.

Adult↗
PubMed1994

Localization of the 9p melanoma susceptibility locus (MLM) to a 2-cM region between D9S736 and D9S171.

A familial melanoma susceptibility locus (MLM) was identified on the short arm of chromosome 9 in a set of Utah and Texas kindreds. Subsequent confirmation was reported for a set of 26 Australian kindreds, a set of 7 Dutch kindreds, and a set of 13 NIH melanoma kindreds. The original localization report placed the locus near the IFNA-D9S126 interval on chromosome 9p. We report further localization using D9S171 and a newly developed marker, D9S736, both of which lie in the IFNA-D9S126 interval. Analysis of this set of kindreds places the melanoma susceptibility locus in a 2-cM region that is proximal to D9S736 and distal to D9S171.

Adult↗
PubMed1994

A large kindred with 17q-linked breast and ovarian cancer: genetic, phenotypic, and genealogical analysis.

BACKGROUND: Mutation of a specific, but as yet unidentified, gene BRCA1 on chromosome 17q results in increased susceptibility to breast and ovarian cancer. It is important to know the effects of this gene in terms of the age-specific risks of these cancers and the potential interaction of this gene with other known risk factors. PURPOSE: We performed detailed studies on a large multigenerational family, in which there is known 17q-linked breast and ovarian cancer, in order to characterize the effects of the BRCA1 mutation on development of breast and ovarian cancer. METHODS: Data from the Utah Population Database were used to identify a family (identified as K2082) with a cluster of premenopausal breast cancer and ovarian cancer at any age. Blood samples from 195 members of the family were obtained and these individuals were genotyped for a series of four chromosome 17q polymorphic markers. Information on reproductive history, cancer incidence and treatment, and lifestyle factors was collected on 72 women in the family by questionnaire or through contact with living relatives. RESULTS: Odds in favor of linkage of breast and ovarian cancer in this family to the BRCA1 region of chromosome 17q are greater than 10(8) to 1. The estimated risks for breast or ovarian cancer because of the BRCA1 mutation in this family are 40% by age 50 years and 90% by age 70. No differences between affected and unaffected older BRCA1 gene carriers were observed for a number of known epidemiologic risk factors for these cancers. The gender of the parent from whom the mutant BRCA1 allele was inherited was significantly associated with phenotypic expression (P = .04). A recombinant which places BRCA1 distal to the marker Mfd191 was observed. CONCLUSIONS: Women with the BRCA1 mutation are at increased risk of developing breast and ovarian cancer. In our study population, the mutation appears to confer a lower risk of cancer at younger ages than found in previous studies. Continued interaction with family K2082 will be useful in longitudinal follow-up studies and in studies of the psychosocial implications of providing DNA diagnosis of BRCA1.

Adult↗