Showing papers by "Fred Hutchinson Cancer Research Center published in 1983"
TL;DR: The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.
Abstract: The promoter or regulatory region of the mouse gene for metallothionein-I was fused to the structural gene coding for human growth hormone. These fusion genes were introduced into mice by microinjection of fertilized eggs. Twenty-three (70 percent) of the mice that stably incorporated the fusion genes showed high concentrations of human growth hormone in their serum and grew significantly larger than control mice. Synthesis of human growth hormone was induced further by cadmium or zinc, which normally induce metallothionein gene expression. Transgenic mice that expressed human growth hormone also showed increased concentrations of insulin-like growth factor I in their serum. Histology of their pituitaries suggests dysfunction of the cells that normally synthesize growth hormone. The fusion genes were expressed in all tissues examined, but the ratio of human growth hormone messenger RNA to endogenous metallothionein-I messenger RNA varied among different tissues and different animals, suggesting that expression of the foreign genes is influenced by site of integration and tissue environment.
744 citations
TL;DR: The visualization of parvov virus, polyomavirus, herpes simplex virus, adenovirus, and retrovirus genetic material in infected cell cultures and herpessimplex and adenvirus DNA in paraffin-embedded autopsy tissues is reported.
715 citations
TL;DR: In this paper, three methods of cohort analysis are presented for a statistical model wherein the explanatory or exposure variables act multiplicatively on age × calendar year specific death rates, and all three approaches yield roughly equivalent estimates of the relative risk associated with arsenic exposure.
Abstract: Three methods of cohort analysis are presented for a statistical model wherein the explanatory or exposure variables act multiplicatively on age × calendar year specific death rates. The first method, which assumes that the baseline rates are known from national vital statistics, is a multiple regression analysis of the standardized mortality ratio. The second method is a variant of Cox's proportional hazards analysis in which the baseline rates are treated as unknown nuisance parameters. The third method consists of case-control sampling from the risk sets formed in the course of applying Cox's model. It requires substantially less computation than do the other two. In illustrative analysis of respiratory cancer deaths among a cohort of smelter workers, all three approaches yield roughly equivalent estimates of the relative risk associated with arsenic exposure. The discussion centers on the tradeoff between efficiency and bias in the selection of a particular method of analysis, and on practica...
543 citations
Journal Article•
TL;DR: A monoclonal antibody, designated 60.3, which reacts with a cell surface antigen expressed by most peripheral blood and bone marrow leukocytes, appears to be involved in a membrane-dependent cell activation pathway that is common to diverse functional systems and is shared by both lymphoid and myeloid cells.
Abstract: We have described a monoclonal antibody, designated 603, which reacts with a cell surface antigen expressed by most peripheral blood and bone marrow leukocytes Immunoprecipitation showed at least three major components with relative mw of 95,000, 130,000, and 150,000 under reducing conditions Antibody 603 inhibited several cell-mediated immune functions The lytic activity of both cytotoxic T cells and natural killer cells was blocked in the presence of the antibody The proliferative responses of T cells stimulated by soluble antigens, mitogens, or allogeneic cells were inhibited when antibody 603 was added at the initiation of culture, but not when added after 48 hr Antibody 603 also blocked the migration of neutrophilic granulocytes The antigen identified by antibody 603 thus appears to be involved in a membrane-dependent cell activation pathway that is common to diverse functional systems and is shared by both lymphoid and myeloid cells
299 citations
TL;DR: The ‘hit-and-run’ hypothesis is revisited and its implications for HSV-induced tumorigenicity are revisited.
Abstract: Experiments to determine the mechanism of transformation of herpes simplex virus (HSV) have identified fragments of viral DNA which are able to initiate transformation. No set of viral genes seems to be consistently retained or expressed in the transformed cells or in human cervical tumours, suggesting that viral DNA is not needed to maintain the transformed phenotype. In fact there is no conclusive evidence that initiation of neoplasia is mediated by a viral protein. Here we revisit the 'hit-and-run' hypothesis and its implications for HSV-induced tumorigenicity.
286 citations
TL;DR: The authors' analysis, using a binary logistic regression model, identified three factors predicting chronic graft-versus-host disease: moderate to severe acute graft-Versus- host disease with an estimated relative risk of 11.65; increasing patient age; and the use of viable donor buffy coat cells in addition to the marrow to prevent graft rejection.
Abstract: One hundred ten of 175 patients with aplastic anemia conditioned by cyclophosphamide had sustained engraftment of marrow from human leukocyte antigen (HLA)-identical siblings and lived for...
285 citations
TL;DR: A series of monoclonal antibodies that reacts with myeloids-associated determinants on committed myeloid stem cells and their progeny are generated and potential applications of these antibodies to studies of normal and malignant hematopoiesis are discussed.
268 citations
TL;DR: An antiserum against a synthetic dodecapeptide whose sequence corresponds to the C terminus of the MC29 v-myc protein, which specifically precipitates the known gag- myc fusion proteins produced by the defective leukemia viruses MC29, CMII, and OK10, but does not react with gag-precursor or product proteins.
240 citations
TL;DR: Chemical analysis of various Burkitt lymphoma cell lines revealed that the Burkittymphoma cells contained more than 100 times as much of the glycolipid antigen as was found in other human lymphoma and leukemia cell lines.
Abstract: The antigen defined by a rat monoclonal antibody directed to a Burkitt lymphoma cell line was identified as globotriaosylceramide [Gal alpha (1 leads to 4)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide]. The antibody demonstrated a strict steric specificity since it did not react with globoisotriaosylceramide [Gal alpha (1 leads to 3)-Gal beta (1 leads to 4)-Glc beta (1 leads to 1)-ceramide], the positional isomer of the antigen associated with the Burkitt lymphoma. Chemical analysis of various Burkitt lymphoma cell lines revealed that the Burkitt lymphoma cells contained more than 100 times as much of the glycolipid antigen as was found in other human lymphoma and leukemia cell lines.
234 citations
TL;DR: Evidence suggests that DNA sequences capable of forming S1-sensitive sites in supercoiled plasmids may bind nucleosomes poorly after reconstitution with histones.
216 citations
TL;DR: Analysis of the sequences of the genes and identification of at least three different classes of duplication units interspersed throughout the five gene cluster suggests that the cluster evolved quite recently and that the mechanism of gene duplication involved homologous but unequal exchange between middle repetitive elements of the Alu family.
Abstract: The structure of the human growth hormone gene cluster has been determined over a 78 kilobase region of DNA by the study of two overlapping cosmids. There are two growth hormone genes interspersed with three chorionic somatomammotropin genes, all in the same transcriptional orientation. One of the growth hormone genes lies in an active chromatin conformation in the pituitary and at least one of the chorionic somatomammotropin genes lies in an active chromatin conformation in the placenta. The two groups of genes are highly homologous throughout their 5' flanking and coding sequences, but diverge in their 3' flanking regions which raises the paradox of how genes so similar in structural and flanking sequences can be so differentially regulated. Analysis of the sequences of the genes and identification of at least three different classes of duplication units interspersed throughout the five gene cluster suggests that the cluster evolved quite recently and that the mechanism of gene duplication involved homologous but unequal exchange between middle repetitive elements of the Alu family.
TL;DR: A transforming gene detected by transfection of chicken B-cell lymphoma DNA has been isolated by molecular cloning and the nucleotide sequence of the cloned transforming gene suggests that it encodes a protein that is partially homologous to the amino terminus of Transferrin and related proteins although only about one tenth the size of transferrin.
Abstract: A transforming gene detected by transfection of chicken B-cell lymphoma DNA has been isolated by molecular cloning. It is homologous to a conserved family of sequences present in normal chicken and human DNAs but is not related to transforming genes of acutely transforming retroviruses. The nucleotide sequence of the cloned transforming gene suggests that it encodes a protein that is partially homologous to the amino terminus of transferrin and related proteins although only about one tenth the size of transferrin.
TL;DR: The transcription of the herpes simplex virus thymidine kinase gene on circular and linear plasmids after injection into Xenopus oocytes appears to be transcribed at least 500 times more efficiently than the linear plasids.
Abstract: We have assayed the transcription of the herpes simplex virus thymidine kinase gene on circular and linear plasmids after injection into Xenopus oocytes. The circular plasmids appear to be transcribed at least 500 times more efficiently than the linear plasmids. Moreover, when the circular templates are allowed to form functioning transcription complexes, and are then linearized in situ, the synthesis of accurate transcripts is substantially reduced.
TL;DR: The findings confirm the importance of transplanting early before transfusion and indicate that the greatest possible amount of donor marrow (supplemented by stem cells/lymphoid cells derived from the peripheral blood) should be obtained.
Abstract: Summary. One hundred and seventy-five consecutive patients with severe aplastic anaemia were given high-dose cyclophosphamide followed by marrow grafts from healthy, HLA-identical family members, and 168 lived long enough to show engraftment. In 38 patients the graft was rejected and 29 of these died. This analysis, using a binary logistic regression model, was aimed at identifying factors that predicted marrow graft rejection. Five factors correlated with graft rejection: (1) previous blood transfusion; (2) a positive relative response in mixed leucocyte culture indicating sensitization of patient against donor; (3) a low number of marrow cells used for transplantation; (4) marrow grafts from male donors; and (5) lack of infusion of viable donor buffy coat cells in addition to the marrow for transfused patients. The findings confirm the importance of transplanting early before transfusion and indicate that the greatest possible amount of donor marrow (supplemented by stem cells/lymphoid cells derived from the peripheral blood) should be obtained.
TL;DR: The chromatin structure of the chromosomal DNA regions containing the human G gamma, A gamma, delta, and beta genes are preferentially sensitive to mild digestion with DNase I, whereas these genes are as resistant as collagen genes in cells that do not express globin.
Abstract: We have investigated the chromatin structure of the chromosomal DNA regions containing the human G gamma-, A gamma-, delta-, and beta-globin structural genes in both fetal and adult erythropoietic tissues and in two human erythroleukemia cells lines before and after induction. Our results indicate that DNase I introduces specific cuts into the beta-globin gene cluster in erythroid cells but not in leukocytes. The predominant sites are located at the 5' sides of the G gamma-, A gamma-, delta-, and beta-globin genes, within 200 base pairs of the respective cap sites. Examination of fetal liver cells has revealed the presence of hypersensitive sites at the 5' side of all four genes, whereas analysis of adult bone marrow has revealed the characteristic sites near the delta- and beta-globin genes but no hypersensitive sites at the 5' termini of the G gamma- or A gamma-globin genes. The presence of delta and beta hypersensitive sites in fetal cells suggests that the increment in expression of the delta and beta genes during development most likely involves the modulation of another pathway to gene expression. Using isolated nuclei from HEL and K562 cells, we have found that the G gamma, A gamma, delta, and beta genes are preferentially sensitive [relative to the pro-alpha2(I) collagen gene] to mild digestion with DNase I, whereas these genes are as resistant as collagen genes in cells that do not express globin. These findings are discussed within the context of chromatin structural correlates of hemoglobin switching.
TL;DR: A major technical advance has had a substantial impact on cellular immunology and has allowed new strategies to be formulated for analysis of CTL, and the identification and characterization of aT-cell growth factor (TCGF), has allowed considerable insight into the manner in which the expansion of T-cell clones is regulated.
Abstract: We have, for some time, had a good overall appreciation of how cytotoxic Tcells (CTL) act (Brunner & Cerottini 1974, Berke 1980, Green & Henney 1981). Under appropriate in vitro conditions, membrane-membrane interactions occur which involve the engagement of antigen-specific recognition units on the killer cell by homologous antigens on the target cell-surface. Shortly thereafter, membrane permeability changes can be measured in the target cell and these herald the eventual destruction of the cell, most probably by colloid-osmotic lysis. The killer cell survives the lytic encounter unscathed and can readily engage new targets. Despite this appreciation ofthe lytic event, little is known of the phenomenon in molecular terms. The nature ofthe antigen recognition unit and the lytic event itself remain largely uncharacterized (recently reviewed in Clark & Golstein, 1982). Since studies on the mechanism of cytotoxic T-cells were last reviewed in these pages, however, a major technical advance has had a substantial impact on cellular immunology and has allowed new strategies to be formulated for analysis of CTL. This finding, the identification and characterization of aT-cell growth factor (TCGF, also termed Interleukin 2; IL-2), has allowed considerable insight into the manner in which the expansion of T-cell clones is regulated (see Immunological Reviews, volume 63, 1982). In a more practical setting,
TL;DR: It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men, and total-body irradiation prevents return ofnormal gonadotropin levels and menstruation in the majority of patients.
Abstract: One hundred thirty-seven patients had gonadal function evaluated 1-11 years after marrow transplantation. All 15 women less than age 26 and three of nine older than age 26 who were treated with 200 mg/kg cyclophosphamide recovered normal gonadotropin levels and menstruation. Five have had five pregnancies resulting in three live births, one spontaneous abortion, and one elective abortion. Three of 38 women who were prepared with 120 mg/kg cyclophosphamide and 920-1200 rad total-body irradiation had normal gonadotropin levels and menstruation. Two had pregnancies resulting in one spontaneous and one elective abortion. Of 31 men prepared with 200 mg/kg cyclophosphamide, 30 had normal luteinizing hormone levels, 20 had normal follicle-stimulating hormone levels, and 10 of 15 had spermatogenesis. Four have fathered five normal children. Thirty-six of 41 men prepared with 120 mg/kg cyclophosphamide and 920-1750 rad total-body irradiation had normal luteinizing hormone levels, ten had normal follicle-stimulating hormone levels, and 2 of 32 studied had spermatogenesis. One has fathered two normal children. It was concluded that cyclophosphamide does not prevent return of normal gonadal function in younger women and in most men. Total-body irradiation prevents return of normal gonadal function in the majority of patients.
TL;DR: A model which explains both the competition and the sink effects is discussed in which the 60/81 bp elements are attraction sites for a factor(s) which is needed to activate the gene promoter.
TL;DR: Investigation of transcription termination on a segment of Drosophila DNA that complements a yeast adenine-8 mutation indicates that this sequence is not required for polyadenylation, and similarities between termination in yeast and p-dependent termination in bacteria are suggested.
TL;DR: Investigation of the expression of the common acute lymphoblastic leukemia antigen by nonlymphoid cells, using a new murine monoclonal antibody, shows that differentiation markers that appear to be tumor or tissue specific may be found on cells of diverse origin.
TL;DR: It is shown here that the level of transcription of the injected ribosomal genes is strongly affected by spacer sequences far upstream of the promoter, and it is proposed that the upstreamSpacer sequences act to influence the frequency of promoter activation.
TL;DR: It is shown that monoclonal cytotoxic T lymphocyte (CTL) lines can be induced, by culture in high concentrations of spleen cell supernatant, to express a new lytic activity apparently identical with that of splenic cells NK activity.
Abstract: Reversible induction of natural killer cell activity in cloned murine cytotoxic T lymphocytes
TL;DR: Comparative observations with K562 cells indicate that TPA inhibits, as in HEL cells, spontaneous and induced globin synthesis, but induces minimal macrophage-like properties in these cells.
Journal Article•
TL;DR: Hybridomas were generated by fusing SP2/0 mouse myeloma cells with spleen cells from mice that had been immunized with cultured human melanoma cells, which secreted a monoclonal IgG1 antibody, 48.7, which binds to a cell surface antigen of cells from human melanomas and compound nevi.
Abstract: Hybridomas were generated by fusing SP2/0 mouse myeloma cells with spleen cells from mice that had been immunized with cultured human melanoma cells. One of the hybridomas secreted a monoclonal IgG1 antibody, 48.7, which binds to a cell surface antigen of cells from human melanomas and compound nevi. The presence of the target antigen in vivo was demonstrated immunohistologically by staining frozen sections of primary and metastatic melanoma by the peroxidase anti-peroxidase technique. Weak staining of some blood vessel cells was also seen, but other normal cells, including skin melanocytes, were unstained, as were cells from other tumor types. Antibody 48.7 immunoprecipitated polypeptides with apparent m.w. on sodium dodecyl sulfate-polyacrylamide gel electrophoresis of 250,000 and greater than 400,000.
TL;DR: Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction, and consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.
Abstract: The quantitative aspects of drug disposition in man of the commonly used antineoplastic agents, including cyclophosphamide, the nitrosoureas, cisplatin, methotrexate, cytarabine, 5-fluorouracil, doxorubicin, daunorubicin, bleomycin, vincristine, vinblastine, and vindesine are reviewed. Although the pharmacokinetic behaviour of these drugs has been adequately described in man, the chemical reactivity, the complexity of metabolism and disposition, the lack of simple, rapid and sensitive assays to measure plasma concentration, and the lack of defined therapeutic and toxic plasma concentrations have limited the application of routine drug monitoring in clinical oncology. With the exception of high dose methotrexate, drug doses and administration schedules remain empirical with a standard starting dose and subsequent dosage modifications determined by ensuing drug toxicities. However, many of the pharmacological characteristics of the drugs, such as their low therapeutic index, potentially life-threatening toxicities and wide individual variability in drug disposition, necessitate pharmacological monitoring. Comprehensive pharmacokinetic analysis of new and established antineoplastic agents does play a role in defining dosage, administration schedule, route of administration, and dosage modification in the presence of organ dysfunction. Consideration of the kinetics of these drugs in planning treatment regimens could lead to more rational, safer and possibly more efficacious use.
TL;DR: This highly conserved carbohydrate-defined determinant previously described on mouse embryonic and mouse and human carcinoma cells is also expressed as a tissue-specific differentiation antigen on normal human granulocytes.
TL;DR: Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of Salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salIVary sodium, albumin, and IgG.
Abstract: Whole saliva samples and lip biopsies were collected from 12 allogeneic bone marrow transplant recipients who developed extensive chronic graft-versus-host disease (GVHD) and from 10 healthy allogeneic and syngeneic recipients without GVHD. Six of ten biopsies from patients with chronic GVHD had lichenoid stomatitis or sialadenitis, or both, with sialodochitis. Seven of nine biopsies from patients free of chronic GVHD were entirely normal, and two had either mild glandular or mucosal changes. Salivary gland involvement in chronic GVHD was associated with decreased or absent levels of salivary IgA and inorganic phosphate, decreased salivary flow rates, and increased concentrations of salivary sodium, albumin, and IgG. The most striking abnormalities were found in patients with histologic evidence of sialadenitis. In contrast, marrow transplant recipients without chronic GVHD had normal salivary immunoglobulin and electrolyte levels. Secretory IgA deficiency may contribute to the frequent sinobronchial infections observed in patients with chronic GVHD.
TL;DR: With a minimum follow-up of more than 5 yr, an actuarial analysis shows a survival and apparent cure of 27% of the patients transplanted in remission and 15% ofthe patients transplants in relapse.
TL;DR: The p97 gene, like the transferrin and TR genes, is located on chromosome 3, and interspecies somatic cell hybrids derived from human fibroblasts or lymphocytes for expression of p97 and presence of human chromosomes are characterized.
Abstract: p97 is a 97,000 molecular weight cell-surface glycoprotein, which is present in human melanomas but in only trace amounts in normal adult tissues1–4 Amino acid sequence and iron binding studies have shown that p97 is structurally and functionally related to transferrin5 Reports that the genes for the transferrin receptor (TR)6–8 and possibly transferrin9–13 are located on chromosome 3 prompted us to investigate the chromosomal localization of the p97 gene Our strategy was to characterize interspecies somatic cell hybrids derived from human fibroblasts or lymphocytes for expression of p97 and presence of human chromosomes Although fibroblasts and lymphocytes express only small amounts of p973,4, we were able to type the hybrids for p97 by using monoclonal antibodies in highly sensitive and specific immunoassays Of 14 hybrids, 6 contained chromosome 3 and expressed p97, and 8 were negative for both We conclude that the p97 gene, like the transferrin and TR genes, is located on chromosome 3
TL;DR: These gangliosides were absent or present in very small quantity in normal tissue and may represent human cancer-associated markers in human colonic and liver adenocarcinoma.