Combination chemotherapy for myelomatosis.
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Biomedical subjects
Publications and source records attributed to J Dunn.
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The flagellin gene from the P/Gau strain of Borrelia burgdorferi was cloned and sequenced. The translated P/Gau flagellin protein differed from the flagellin of the B31 strain at 13 of 336 amino acids. This includes seven differences between amino acids 190-234, an immunodominant and specific region for B. burgdorferi. The entire flagellin molecule, as well as peptides of the internal portion of the protein which is more specific for B. burgdorferi, has been expressed in Escherichia coli using a pET7HIS.2 expression system. These peptides may be of great value for the development of sensitive and specific recombinant-based serological assays.
Both melphalan and cyclophosphamide increase life expectancy in patients with myelomatosis, but few large randomised studies have compared combination chemotherapy regimens with these single agents. In the Vth MRC myelomatosis trial, the survival of 314 patients randomised to receive ABCM (adriamycin, BCNU, cyclophosphamide, and melphalan) as first-line treatment was significantly longer than that of 316 patients given intermittent melphalan (M7) (p = 0.0003). The 75%, median, and 25% survivals were 7, 24, and 42 months, respectively, with M7 and 10, 32, and 56 months, respectively, with ABCM. Stable disease with few symptoms (plateau) was achieved by 61% of patients given ABCM and 49% of those given M7 (p = 0.004). Myelotoxicity was comparable between regimens. Cross-trial analysis suggests that M7 is comparable to melphalan and prednisone or melphalan, prednisone, and vincristine; that the efficacy of ABCM in the Vth trial and VIth MRC trials is comparable; and that ABCM gave better survival than intermittent melphalan regimens in the prognostic groups analysed. The results indicate that ABCM is an acceptable regimen that is more effective than melphalan, with or without prednisone, for first-line treatment of myelomatosis.
Developmental changes in the pattern of family conversations and talk about feelings were examined in a longitudinal study of 50 families observed at home when the second-born children were 33 and 47 months old. Significant increases were noted in the total amount of talk and the frequency of talk about feelings between sibling pairs as well as decreases in the amount of mother-child conversation and references to feelings. Differences in whose feelings were discussed and in the context of references to feelings were found for mother-child and sibling-child dyads. Developmental changes in the children's use of feeling state language co-occurred with the increase in interaction between children and their siblings. The findings contrast the "complementary" nature of mother-child interaction and the "reciprocal" nature of child-sibling interaction and support the argument that the quality of particular relationships influences the use children make of their communicative competence.
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The prevalence and negative impact of life events and adversities over a 3-year period on 80 children participating in a longitudinal study of siblings was examined. The scenarios of 256 events were rated by a child psychiatrist for negative impact on both siblings (aged 6 and 8-10 years, respectively). Only one of the 80 children had not experienced at least one major event. The majority (69%) of life events with negative impact and adversities were not shared by siblings. The relations between the impact of these adversities and children's perceived self-competence, temperament, and their mothers' mood were examined. The number of life events with negative impact was negatively correlated with children's perceived self-competence, an association apparently not mediated by children's temperament nor by maternal mood.
The met proto-oncogene is the tyrosine kinase growth factor receptor for hepatocyte growth factor/scatter factor (HGF/SF). It was previously shown that, like the oncogenic tpr-met, the mouse met proto-oncogene transforms NIH 3T3 cells. We have established NIH 3T3 cells stably expressing both human (Methu) and mouse (Metmu) met proto-oncogene products. The protein products are properly processed and appear on the cell surface. NIH 3T3 cells express endogenous mouse HGF/SF mRNA, suggesting an autocrine activation mechanism for transformation by Metmu. However, the tumor-forming activity of Methu in NIH 3T3 cells is very low compared with that of Metmu, but efficient tumorigenesis occurs when Methu and HGF/SFhu are coexpressed. These results are consistent with an autocrine transformation mechanism and suggest further that the endogenous murine factor inefficiently activates the tumorigenic potential of Methu. The tumorigenicity observed with reciprocal chimeric human and mouse receptors that exchange external ligand-binding domains supports this conclusion. We also show that HGF/SFhu expressed in NIH 3T3 cells produces tumors in nude mice.
Granulocyte/macrophage colony-stimulating factor-interleukin 3 (GM-CSF-IL-3) fusion proteins were generated by construction of a plasmid in which the coding regions of human GM-CSF and IL-3 cDNAs were connected by a synthetic linker sequence followed by subsequent expression in yeast. Both GM-CSF-IL-3 and IL-3-GM-CSF fusion proteins were purified to homogeneity and shown to bind to cell-surface receptors through either their GM-CSF or IL-3 domains. The fusion proteins exhibited enhanced receptor affinity, proliferative activity, and hematopoietic colony-stimulating activity compared with either IL-3 and/or GM-CSF alone. This suggests that GM-CSF-IL-3 fusion proteins may hold future promise as therapeutic agents.
Bacteriophage T7 infection has been studied in Escherichia coli strains showing both increased and decreased ribosome fidelity and in the presence of streptomycin, which stimulates translational misreading, in an effort to determine effects on the apparent programmed translational frameshift that occurs during synthesis of the gene 10 capsid protein. Quantitation of the protein bands from SDS-PAGE failed to detect any significant effects on the amounts of the shifted 10B protein relative to the in-frame 10A protein under all fidelity conditions tested. However, any changes in fidelity conditions led to inhibition of phage morphogenesis in single-step growth experiments, which could not be accounted for by reduced amounts of phage protein synthesis, nor, at least in the case of decreased accuracy, by reduced amounts of phage DNA synthesis. Reduction in phage DNA synthesis did appear to account for a substantial proportion of the reduction in phage yield seen under conditions of increased accuracy. Similar effects of varying ribosomal fidelity on growth were also seen with phage T3, and to a lesser extent with phage T4. The absence of change in the high-frequency T7 gene 10 frameshift differs from earlier reports that ribosomal fidelity affects low-frequency frameshift errors.
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Individual differences in young children's understanding of others' feelings and in their ability to explain human action in terms of beliefs, and the earlier correlates of these differences, were studied with 50 children observed at home with mother and sibling at 33 months, then tested at 40 months on affective-labeling, perspective-taking, and false-belief tasks. Individual differences in social understanding were marked; a third of the children offered explanations of actions in terms of false belief, though few predicted actions on the basis of beliefs. These differences were associated with participation in family discourse about feelings and causality 7 months earlier, verbal fluency of mother and child, and cooperative interaction with the sibling. Differences in understanding feelings were also associated with the discourse measures, the quality of mother-sibling interaction, SES, and gender, with girls more successful than boys. The results support the view that discourse about the social world may in part mediate the key conceptual advances reflected in the social cognition tasks; interaction between child and sibling and the relationships between other family members are also implicated in the growth of social understanding.
Bacteriophage T7 capsid protein 10B has previously been proposed to arise by a translational frameshift near the 3' end of the capsid gene 10A coding sequence, adding an additional 53 amino acid residues to the carboxyl-terminal end of the protein. Here we show by peptide mapping experiments as well as by direct partial sequence analysis of an overlapping "junction" peptide, that 10B is in fact related to 10A by a -1 switch in reading frame in a narrow region near the carboxy terminus of 10A. Peptide mapping experiments demonstrate that 10A and 10B have the same amino terminus as well as virtually identical methionine-labeled peptide maps. However, the predicted unique carboxyl-terminal peptide from 10B was also identified. An overlapping peptide was isolated from 10B which spans the junction region in which the proposed translational frameshift is thought to occur. Partial sequencing of this junction peptide confirms a -1 frameshift within the last few codons of 10A.
A human skin explant model was used to investigate the role of cytokines in graft-versus-host reactions (GVHR). Responder cells from HLA mismatched mixed lymphocyte cultures (MLC) produced GVHR (Grades I-III) in skin explant assays. Cell-free supernatants from these experiments also induced similar histopathological changes in the skin. The greatest degree of correlation between the GVHR observed with responder cells and the supernatant was shown with CD4 enriched MLC (p less than 0.001). Supernatants were assayed for tumour necrosis factor-alpha (TNF alpha) and interferon-gamma (IFN gamma) and CD4 enriched MLC populations produced high levels of these cytokines. These results correlated with the grade of GVHR observed in skin explant assays. The GVHR produced by the supernatant alone could be inhibited by both anti-IFN gamma and anti-TNF alpha polyclonal antibodies. The results suggest that TNF alpha and IFN gamma are directly involved in tissue damage during graft-versus-host disease in allogeneic transplant in man.
Three patients are presented who developed delayed intracerebral hematomas after head injury. Two patients had essentially negative CT scans on admission and developed intracerbral hematomas within 24 h after injury. They required surgical treatment and had fatal outcomes. The third patient presented with an epidural hematoma on CT scan, developed an intracerebral hematoma 48 h after evacuation of the epidural hematoma, and did well with conservative management.
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