Biomedical subjects
R White
Publications and source records attributed to R White.
Colon cancer genetics.
The terms "hereditary," "sporadic," and "familial" colorectal cancer (CRC) suggest a knowledge of causation; however, current understanding of CRC does not permit categorization of differing CRC risks in accord with their cause per se. Despite these serious shortcomings, these terms are defined operationally on the basis of a family history of cancer, and when available, additional phenotypic information. The sporadic type occurs in the absence of a family history of CRC in a first-degree relative. The familial type occurs when at least one first-degree relative has CRC. Both these categories require the exclusion of hereditary CRC. In the case of hereditary CRC, this type is defined as a family history of CRC occurring in a pattern that indicates autosomal-dominant inheritance, which also may involve certain phenotypic signs (depending on the specific disorder, i.e., florid adenomatous polyps, benign and malignant extracolonic lesions, cancer of unusually early onset, and multiple primary cancer, particularly synchronous and metachronous CRC). Although this operational classification does not produce etiologically homogeneous groups, it is believed to have pragmatic utility with respect to planning targeted surveillance and management strategies. Because of the distinctive natural history of CRC in hereditary syndromes, it is of paramount clinical importance to identify hereditary CRC when it does occur. Even in patients with no evidence of hereditary CRC syndrome, their family history may be second only to age in determining the best CRC screening program for those who are asymptomatic. In an attempt to provide a perspective on the clinical evaluation of CRC risk, research was reviewed on pathologic features and biomarkers that may be related to CRC causes, especially the genetic basis of CRC susceptibility. The long-term objective of studies on the genetic epidemiology of CRC is primary and secondary prevention through development of targeted management and surveillance recommendations (based on an understanding of CRC causation) that is relevant to hereditary, familial, and sporadic CRC.
Antiestrogen ICI 164,384 reduces cellular estrogen receptor content by increasing its turnover.
The ability of estrogens to stimulate the transcriptional activity of the estrogen receptor can be inhibited by a diverse range of estrogen antagonists. Here we show that the antiestrogen ICI 164,384, N-(n-butyl)-11-[3,17 beta-dihydroxy-estra-1,3,5(10)-trien-7 alpha-yl]N-methylundecanamide, rapidly reduces the levels of receptor protein transiently expressed in cells without affecting receptor mRNA abundance. The reduction in the levels of receptor protein is dose dependent, reversible by estradiol, and mediated by the hormone-binding domain of the receptor. Pulse-chase experiments indicate that the half-life of the receptor is reduced from approximately 5 hr in the presence of estradiol to less than 1 hr by ICI 164,384. A similar reduction in estrogen receptor levels is demonstrated in human breast cancer cells treated with ICI 164,384. We discuss the possibility that the increased turnover of the receptor might be a consequence of impaired receptor dimerization.
A CA repeat 30-70 Kb downstream from the adenomatous polyposis coli (APC) gene.
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Identification of a conserved region required for hormone dependent transcriptional activation by steroid hormone receptors.
The oestrogen receptor stimulates transcription by means of at least two distinct transcriptional activation domains, TAF-1 in the N-terminal domain and TAF-2 in the hormone binding domain. Here we show that TAF-2 activity requires a region in the C-terminus of the hormone binding domain between residues 538 and 552 in the mouse oestrogen receptor which is conserved among many nuclear hormone receptors. Point mutagenesis of conserved hydrophobic and charged residues significantly reduced ligand dependent transcriptional activation but had no effect on steroid or DNA binding. Mutation of the corresponding residues in the glucocorticoid receptor also abolished transcriptional activation. We therefore propose that the conserved region may be essential for ligand dependent transcriptional activation by other members of the nuclear receptor family.
BSO-induced reduction of glutathione levels increases the cellular radiosensitivity of drug-resistant human tumor cells.
Acquired resistance to cis-platinum and melphalan, in the human ovarian OAW42 tumor cell line, respectively, conferred a 3- and 1.5-fold decrease in photon sensitivity. Analysis of cell survival curves by the linear quadratic equation showed an accompanying 5- and 2-fold reduction in the magnitude of the initial slope (alpha). Treatment with the GSH depleting agent BSO restored the magnitude of alpha to a value similar to that of the parental line without evidence of dose modification in the high-dose region of the cell survival curve. This in conjunction with failure of alteration in GSH levels to affect parental OAW2 sensitivity and of the SER of BSO to reflect GSH levels suggest a possible GSH independent mechanism of action for BSO. If similar patterns occur in the clinic, the possibility exists of circumventing collateral resistance between chemotherapeutic agents and ionizing radiation, provided that tumor thiol levels can be preferentially depleted.
Characterization of human adenylate kinase 3 (AK3) cDNA and mapping of the AK3 pseudogene to an intron of the NF1 gene.
We have isolated cDNA clones for human adenylate kinase isozyme 3 (AK3) with a genomic probe from the neurofibromatosis type 1 (NF1) region. Three overlapping clones isolated from a human frontal-cortex cDNA library gave rise to a consensus sequence of 1.7 kb. The open reading frame identified in this sequence predicted a peptide of 223 residues. A database search revealed striking homology, about 58% amino acid sequence identity, between this predicted protein and bovine AK3. Human AK3 protein also showed significant homology to other members of the adenylate kinase family isolated from various species. Genomic Southern analysis suggested that multiple AK3 loci exist in the human genome, including one located in an intron of NF1 on chromosome 17. The chromosome-17 locus appears to be a processed pseudogene, since it is intronless and contains a polyadenylate tract; it nevertheless retains coding potential because the open reading frame is not impaired by any observed base substitutions.
Inherited cancer genes.
The identification of several genes associated with inherited cancer syndromes has opened a door to understanding mechanisms of carcinogenesis in common, non-inherited forms of cancer. Each of these genes appears to play a role in the control of cell growth and differentiation.
Peripheral myelin protein-22 gene maps in the duplication in chromosome 17p11.2 associated with Charcot-Marie-Tooth 1A.
Charcot-Marie-Tooth disease 1A (CMT1A) is a hereditary demyelinating peripheral neuropathy, associated with a DNA duplication on chromosome 17p11.2. A related disorder in the mouse, trembler (Tr), maps to mouse chromosome 11 which has syntenic homology to human chromosome 17p. Recently, the peripheral myelin protein-22 (pmp-22) gene was identified as the likely Tr locus. We have constructed a partial yeast artificial chromosome contig spanning the CMT1A gene region and mapped the PMP-22 gene to the duplicated region. These observations further implicate PMP-22 as a candidate gene for CMT1A, and suggest that over-expression of this gene may be one mechanism that produces the CMT1A phenotype.
Familial influence on plaque formation in the beagle brain.
Aged canines exhibit central neuropathological changes strikingly similar to those seen in patients with Alzheimer's disease. In this study, brain tissue from pure bred beagles raised in a controlled environment were examined for Alzheimer-like pathology. The mean age of the animals was 15.6 years. The incidence of plaques among these 29 dogs was 65.5%. Of the 19 samples that demonstrated Alzheimer-like pathology, 18 were characterized as diffuse and one as neuritic. Plaque density was found to be independent of age. Plaque numbers were highest in the perirhinal cortex and the adjacent temporal cortex. Familial influence on plaque development is supported by congruence within 15 of the 16 litters examined (p < 0.001). In this environmentally controlled group the diffuse plaques were rarely converted to the dense neuritic plaques found in Alzheimer's disease.
The neurofibromatosis type 1 (NF1) gene: identification and partial characterization of a putative tumor suppressor gene.
The NF1 gene has been isolated and partially characterized. The discovery that NF1 functions as a ras GTPase activator protein has led to new opportunities for understanding the pathology of this disease. The approximately 11 kilobase (kb) NF1 consensus cDNA sequence contains an open reading frame encoding a peptide of 2818 amino acids. DNA blot and polymerase chain reaction analysis indicate that the NF1 gene consists of over 50 exons spanning 300 kb of chromosome 17.
Asthma: a disease remodeling the airways.
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Reconstruction of skin deficits--assessing the options.
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Providing medical care for children.
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Homeless adults without apparent medical and psychiatric impairment: onset of morbidity over time.
A cross-sectional study compared characteristics of homeless adults with and without substance abuse, physical health problems, and history of psychiatric hospitalization when they first became homeless. Self-report data on demographic characteristics, adverse events in childhood, and history of medical disorders were collected from 1,399 homeless adults who used three shelters in Santa Clara County, California, during a five-month winter period in 1989 and 1990 (96 percent response rate). A total of 45.6 percent of the respondents reported no impairments when they first became homeless. They were distinguished from those with impairments at onset of homelessness by their younger age, minority status, lower educational attainment, and lower frequency of adverse events in childhood. Respondents who reported no impairments when they first became homeless were likely to develop addictive and psychiatric disorders over time. Those who had been homeless five years or more reported high rates of alcohol abuse (34.5 percent), illegal drug use (24.1 percent), and psychiatric hospitalization (20.7 percent).
Pneumocandins from Zalerion arboricola. I. Discovery and isolation.
HPLC bioautography of the directed biosynthesis of Zalerion arboricola led to the discovery of pneumocandin B0 (L-688,786), a new antifungal and anti-Pneumocystis carinii lipopeptide. Isolation techniques were developed to separate this component from pneumocandin A0 (L-671,329) in fermentations of a mutant of Zalerion arboricola. A number of related compounds were also isolated, which differ from pneumocandins A0 and B0 in the hydroxylation patterns on the ornithine, homotyrosine, and proline.
Thoracic organ transplants in the United States from October 1987 through December 1991: a report from the UNOS Scientific Registry for Organ Transplants.
1. In 1991 there were 2,127 heart, 402 lung, and 51 heart-lung transplants performed in the United States. These numbers reflect increases of 27% for heart, over 1000% for lung, and a decrease of 31% for heart-lung transplants since 1988. 2. The number of programs performing heart transplants has increased by 16% since 1988, whereas the number of programs performing lung transplants has tripled over that time. 3. The most frequent primary indications for thoracic transplantation were: cardiomyopathy (45%) and coronary artery disease (41%) for heart; primary pulmonary hypertension (43%) and congenital/Eisenmenger's for heart-lung; and emphysema/chronic obstructive pulmonary disease (28%) and Alpha-1 antitrypsin deficiency (20%) for lung. 4. Average cold ischemic time increased gradually between 1988 and 1991: 2.7 hours for hearts transplanted in 1991 compared with 3.3 hours for heart-lungs, and 4.3 for lungs. 5. Between 1988 and December 1991, the following percentages increased significantly: pediatric heart and lung transplantations; non-White thoracic transplant recipients and donors; the use of thoracic organs from younger (< or = 5 yrs) as well as older (> or = 45 yrs) donors; and local utilization of thoracic organs. 6. For the entire period covered by this report, 1-year recipient survival rates were: heart 81.6%, heart-lung 55.4%, and lung 67.2%. Patient survival was significantly lower in heart retransplants or when the primary indication for transplantation was the treatment of congenital disease. Between 1988 and 1991, 1-year survival appeared to have increased significantly for heart-lung and lung recipients.
Report of the second international workshop on human chromosome 5 mapping: consensus genetic map.
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