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Biomedical subjects

L J Williams

Publications and source records attributed to L J Williams.

At least 37 records · Page 2Linked to original sources
PubMed1992

Complete inhibition of growth followed by death of human malignant melanoma cells in vitro and regression of human melanoma xenografts in immunodeficient mice induced by camptothecins.

The plant alkaloid camptothecin and three camptothecin derivatives were used to study responses of human malignant melanoma (BRO) cells xenografted in immunodeficient (nude) mice. Camptothecin and its derivatives 9-nitro-20(S)-camptothecin and 9-amino-20(S)-camptothecin inhibited growth of tumors and caused regression in all tumor-bearing mice. Tumor regression was accompanied by degenerative changes in the tumor cells, as assessed by microscopic observations of histological sections prepared from the tumors. No toxic effects were observed in the drug-treated mice, with or without xenografts. In parallel experiments, camptothecin, 9-nitro-20(S)-camptothecin, and 9-amino-20(S)-camptothecin inhibited proliferation of BRO cells in vitro and resulted in dramatic morphological cellular changes comparable to those observed in the sections of solid tumors. The derivative 12-nitro-20(S)-camptothecin had no effect on BRO tumors or cell cultures. The difference between 9-nitro-20(S)-camptothecin and 12-nitro-20(S)-camptothecin is the position at which the NO2 group is attached to the camptothecin molecule. In contrast to BRO melanoma cells, none of the camptothecin derivatives had any effect on cultured human melanocytes, the normal counterparts of melanoma cells. Taken together, the findings indicate that camptothecin and derivatives exert different effects on the growth and morphology of normal and malignant (BRO) melanocytes.

Animals↗
PubMed1992

Attachment of mitochondria to intermediate filaments in adrenal cells: relevance to the regulation of steroid synthesis.

The rate of steroid synthesis is regulated by the rate of transport of cholesterol from lipid droplets to mitochondria. We have previously demonstrated that lipid droplets in adrenal cells are tightly attached to intermediate filaments. Here we now show that mitochondria colocalize with intermediate filaments in modified double indirect immunofluorescence and by electron microscopy of extracted adrenal cells. Direct contact between mitochondria and intermediate filaments was established by examination of stereo pairs of electron micrographs from extracted cells. The attachment of both droplets and mitochondria to intermediate filaments suggests possible mechanisms for this form of intracellular transport of cholesterol to mitochondria and hence for the regulation of steroid synthesis.

Adrenal Glands↗
PubMed1992

Ornithine decarboxylase gene of Neurospora crassa: isolation, sequence, and polyamine-mediated regulation of its mRNA.

Ornithine decarboxylase (ODC), which initiates the biosynthesis of the polyamines putrescine, spermidine, and spermine, is encoded by the spe-1 gene of the fungus Neurospora crassa. This gene and its cDNA have been cloned and sequenced. The gene has a single 70-nucleotide intron in the coding sequence. The cDNA, comprising the entire coding region, recognizes a single 2.4-kb mRNA in Northern (RNA) blots. The mRNA transcript, defined by S1 mapping, has an extremely long, 535-base leader without strong secondary-structure features or an upstream reading frame. The translational start of the protein is ambiguous: a Met-Val-Met sequence precedes the Pro known to be the N terminus of the ODC polypeptide. The polypeptide encoded by the N. crassa spe-1 gene (484 amino acids) has 46% amino acid identity with that of Saccharomyces cerevisiae (466 amino acids) and 42% with that of mouse (461 amino acids). Alignment of the longer N. crassa sequence with S. cerevisiae and mouse sequences creates gaps in different sites in the S. cerevisiae and mouse sequences, suggesting that N. crassa ODC is closer to an ancestral form of the enzyme than that of either yeast or mouse ODC. N. crassa ODC, which turns over rapidly in vivo in the presence of polyamines, has two PEST sequences, found in most ODCs and other proteins with rapid turnover. In striking contrast to other eucaryotic organisms, the variation in the rate of ODC synthesis in response to polyamines in N. crassa is largely correlated with proportional changes in the abundance of ODC mRNA. Spermidine is the main effector of repression, while putrescine has a weaker effect. However, putrescine accumulation appears to increase the amount of active ODC that is made from a given amount of ODC mRNA, possibly by improving its translatability. Conversely, prolonged starvation for both putrescine and spermidine leads to the differentially impaired translation of ODC mRNA.

Amino Acid Sequence↗
PubMed1992

Attachment of steroidogenic lipid droplets to intermediate filaments in adrenal cells.

Light microscopy of living and extracted adrenal cells (Y-1 mouse adrenal tumour cells and cultured bovine fasciculata cells), using Nomarski optics and fluorescence with nile red to stain lipid, revealed in both cell types that lipid droplets remain attached to intermediate filaments when the cells are extracted to prepare these structures. Electron microscopy of thin sections shows the presence of lipid droplets in both cell types. The droplets differ in appearance but are, in both cases, surrounded by a complete capsule 5 nm wide. The droplets in Y-1 cells include those associated with lysosomes and crystalline structures in addition to typical rounded forms. Only the latter type is seen in bovine fasciculata. Intermediate filaments apparently ending in droplets can also be seen. Immunoelectron microscopy with anti-vimentin and Protein A conjugated to gold particles together with measurement of the diameter of these structures identifies them as intermediate filaments. When adrenal cells are permeabilised and extracted under mild or severe conditions using Triton X-100, thin sections showed that lipid droplets remain associated with the cytoskeleton and in particular intermediate filaments. Extraction under mild and severe conditions cleared the cell contents, revealing attachment of intermediate filaments to lipid droplets with greater clarity than in unextracted cells, i.e. homogenised cells or cells subjected to lysis. Such attachment was unequivocally demonstrated in stereo pairs. These observations support our earlier studies showing attachment of droplets to intermediate filaments, which suggests a role for these filaments in intracellular transport of cholesterol.

Adrenal Glands↗
PubMed1991

Heterotransplantation of human breast carcinomas in nude mice. Correlation between successful heterotransplants, poor prognosis and amplification of the HER-2/neu oncogene.

Four hundred and thirty-three human breast carcinomas and 23 cell lines derived from human breast carcinomas were heterotransplanted in nude mice. Twenty-eight tumors and 13 cell lines took and could be serially transplanted. Their human origin was established by isozyme analysis performed on successive passages. Sixteen primary infiltrating duct-cell carcinomas (PIDC) took, from a total of 262 transplanted (6.1%). This is in striking contrast to the greater than 50% rate of takes of most major cancers of epithelial origin. All 16 PIDC growing in nude mice were highly cellular and lacked desmoplastic hyperplasia. The clinical prognosis of the PIDC patients whose tumors were successfully transplanted was poor. Ten of 16 (63%) died of their disease within 3 years, compared to only 49 (20%) of the 246 PIDC patients whose tumors did not take in nude mice. This could not be attributed to later stage disease of the tumors that took, because only 15% of these patients had 4 or more positive axillary lymph nodes as opposed to 28% of the patients whose tumors did not take. Sixty-four percent of the breast carcinomas growing in nude mice exhibited amplification of the HER-2/neu oncogene which is also correlated with poor prognosis in human breast cancer. It is possible that the nude mouse is more susceptible to a population of highly invasive and lethal breast carcinomas.

Adult↗
PubMed1991

Comparative analysis of nucleotide sequences of the partial envelope gene (5' domain) among human T lymphotropic virus type I (HTLV-I) isolates.

Human T-cell lymphotropic virus type I (HTLV-I) is associated with adult T-cell leukemia/lymphoma (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The nucleotide sequences of 640 bp of the proviral genome (positions 5158-5797) derived from 11 HTLV-I-infected persons were analyzed using the polymerase chain reaction and M13-based sequencing techniques. Patterns of single nucleotide substitutions were characterized from the extracellular domain of the envelope gene (gp46). Compared with other retroviruses, the nucleotide sequences of the HTLV-I external envelope gene are highly conserved among the genotypes studied. We found no evidence of dual infections with HTLV-II among the seropositive asymptomatic persons or in patients with either ATL or HAM/TSP. No unique sequence differences were observed in the envelope gene of the HTLV-I isolates derived from patients coinfected with human immunodeficiency virus type 1 (HIV-1). However, comparative analysis of these data and other published HTLV-I envelope sequences indicated the presence of four subtypes of HTLV-I in relation to their geographic origin.

Base Sequence↗
PubMed1990

Placental examination can help determine cause of brain damage in neonates.

Intrapartum asphyxia rarely causes cerebral palsy. More than 90% of cases of cerebral palsy are now believed to result from an antecedent intrauterine developmental abnormality. It is now also known that there is an association between subacute and chronic intrauterine hypoxia (decreased uteroplacental blood flow) and brain damage. We present an evaluation protocol that includes clinical findings of the mother and infant combined with pathologic examination of the placenta. The purpose of this protocol is to better identify and separate cases of acute from chronic perinatal asphyxia. We believe that improved screening and identification of perinatal asphyxia will reduce the number of malpractice suits for infants with brain damage. The objective is to eliminate from litigation those cases due to antecedent developmental abnormality over which the clinician has no responsibility and should not be held medically liable.

Brain Damage, Chronic↗
PubMed1989

The intracellular association of B700 and B50 murine melanoma antigens and their role in tumor rejection.

B700 and B50 are melanoma-specific antigens originally isolated from B16 murine melanoma. B700, which elicits a strong tumor rejection response, is present on all murine melanomas tested to date. We now demonstrate the presence of B50 in the other murine melanomas and find that the 2 molecules are non-covalently complexed with each other within the cells. We also show that hosts immunized with intact, irradiated melanoma cells produce antibodies that specifically recognize the B700 and B50 tumor antigens. These results suggest that B50 may also participate in the host response to melanoma growth.

Animals↗
PubMed1988

Tunnel vision or general interference? Cognitive load and attentional bias are both important.

Accuracy of identification of single letters presented in the near periphery (2.2 degrees, 3.3 degrees, or 4.4 degrees) was adversely affected when subjects were given a simultaneous foveal visual task as part of the same display. The level of processing required by the foveal task as well as the attentional allocation instructions were both found to be important. Tunnel vision as opposed to general interference can be induced by a combination of high foveal cognitive load, a focused attention strategy, and speed stress.

Attention↗
PubMed1985

Exceptional lethality for nude mice of cells derived from a primary human melanoma.

BRO human melanoma cells, obtained from a biopsy of a highly aggressive and malignant primary tumor, were grown as xenografts in nude mice and in cell culture. These cells were exceptionally tumorigenic and malignant for nude mice. NIH-II nude mice survived 11.0 +/- 0.4 (S.E.) and 14.1 +/- 0.4 days after i.p. inoculation of 10(7) or 10(6) BRO cells, respectively, and lethal tumors developed in all mice inoculated i.p. with only 10(3) cells. The doubling time (2.3 days) of the volume of tumors formed after s.c. inoculation was comparable to the doubling time of these cells in culture. After i.p. or s.c. inoculation, BRO cells metastasized to the diaphragm and lungs, causing respiratory failure in most of the host mice. The original tumor and the cell line derived from it had undifferentiated structures with prominent nuclei and very large nucleoli. Karyotype abnormalities included a gigantic A group chromosome, a large D group chromosome, and an unusual double centromere chromosome not found typically in human melanoma cells. Due to the short and reproducible survival times of nude mice inoculated i.p. with BRO cells, this model system may be useful for rapidly determining the effects of experimental treatment on the survival of hosts bearing human tumor cells.

Animals↗
PubMed1984

Information processing in near peripheral vision.

The present study required that Ss name briefly exposed single lower-case letters that were presented at a total of 24 locations (8 meridians X 3 retinal eccentricities, 0.5 degrees, 2.75 degrees, and 5.0 degrees from a central fixation point, 0 degrees). One group of 12 Ss received a set size (load) of 2 letters, and another group of 12 Ss received a set size (load) of 24 letters. Ss given the larger load were significantly less accurate and significantly slower (longer vocal latencies) in naming the letters. In addition, significant main effects of retinal eccentricity and meridian were found. Ss performed more poorly as the stimuli were presented more eccentrically. Also, performance tended to be somewhat poorer above and below the fixation point than it did left or right of fixation. There was also some tendency toward a right visual field superiority. Unlike an earlier study, there was little evidence in favor of a "tunnel vision" interpretation, which would have required an interaction of load X retinal eccentricity. Possible reasons for the different results from the two studies are discussed in terms of a levels-of-processing interpretation.

Cognition↗
PubMed1983

Correlation between response to chemotherapy of human tumors in patients and in nude mice.

Human tumors serially heterotransplanted in nude mice have been tested for their response to chemotherapeutic agents. Fourteen melanomas, 14 colorectal carcinomas, and 14 breast carcinomas have been used. Each tumor originated in a different patient. The tumors were maintained by serial subcutaneous transplantation in nude mice. For the experiments in this study, each neoplasm was transplanted under the kidney capsule of 60 to 100 adult nude mice. The areas of the individual tumor implants were precisely measured immediately after insertion using a stereo microscope equipped with a micrometric ocular. The animals were then divided into groups of six to ten animals each. One group was injected daily with saline and served as controls. The mice in the remaining groups were injected daily for eight days with one of the following chemotherapeutic agents--Adriamycin (doxorubicin), 5-fluorouracil, methotrexate, Cytoxan (cyclophosphamide), Alkeran (melphalan), vincristine, vinblastine, methyl-CCNU, or BCNU--at optimum doses (the maximum dose tolerated that causes less than 10% weight loss). Treatment was initiated when the implants were well established, having roughly doubled their initial mass. The animals were then sacrificed and the tumors measured again. A drug was rate effective only if it inhibited growth of the tumor by 99% or more. The results so obtained were compared with the published results of various clinical trials. When the sensitivity of the human tumors in the mice was compared with the sensitivity of tumors of the same type that had been treated in human patients, a close correlation was found. The panel study detected nine of ten effective drugs, giving only two false-positive results. Our data strongly support the validity of heterotransplants of human tumors in the nude mouse as a predictive system for testing new anticancer agents and in determining optimal treatment schedules and combinations of known drugs.

Animals↗
PubMed1983

Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid.

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.

Adult↗
PubMed1982

Platelet size in health and hematologic disease.

In normal subjects, mean platelet volume (MPV) has an inverse, nonlinear relation with platelet count, while platelet volume heterogeneity has a direct, nonlinear relation with MPV. Compared with the reference range established for normal subjects, patients with chronic lymphocytic leukemia, atherosclerotic heart disease, diabetes mellitus, and chronic undifferentiated schizophrenia had normal platelet volume mean and heterogeneity. Patients treated with cytotoxic chemotherapy for acute nonlymphocytic leukemia, patients with megaloblastic anemia, and patients with aplastic anemia had abnormally small platelets with increased heterogeneity. Patients with chronic myelogenous leukemia had abnormally large platelets with increased heterogeneity.

Anemia, Megaloblastic↗