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Biomedical subjects

D Lovett

Publications and source records attributed to D Lovett.

17 recordsLinked to original sources
PubMed1993

Radium needle used to calibrate germanium gamma-ray detector.

A standard platinum-iridium needle that contains 374 MBq 226Ra was tested as a source for calibrating a portable germanium detector used with a gamma-ray spectrometer for environmental radioactivity measurements. The counting efficiencies of the 11 most intense gamma rays emitted by 226Ra and its short-lived radioactive progeny at energies between 186 and 2,448 keV were determined, at the full energy peaks, to construct a curve of counting efficiency vs. energy. The curve was compared to another curve between 43 and 1,596 keV obtained with a NIST mixed-radionuclide standard. It was also compared to the results of a Monte Carlo simulation. The 226Ra source results were consistent with the NIST standard between 248 and 1,596 keV. The Monte Carlo simulation gave a curve parallel to the curve for the combined radium and NIST standard data between 250 and 2,000 keV, but at higher efficiency.

Calibration↗
PubMed1993

Low-dose gallium nitrate for prevention of osteolysis in myeloma: results of a pilot randomized study.

PURPOSE: Since osteolysis is a major cause of morbidity in myeloma, we conducted a pilot study to evaluate whether the addition of gallium nitrate to standard antimyeloma treatment could preserve or increase bone mass in patients with osteolytic disease. METHODS: Patients stabilized on cytotoxic therapy were randomized to treatment with gallium nitrate for 6 months, or to observation only for the first 6 months followed by gallium nitrate treatment during the subsequent 6 months. Gallium nitrate was administered in monthly cycles by daily subcutaneous injections (30 mg/m2/d) for 2 weeks, followed by 2 weeks with no therapy, supplemented by an intravenous infusion (100 mg/m2/d) for 5 days every other month. RESULTS: Paired 6-month comparisons were available for seven observation periods and 13 gallium nitrate treatment periods. Total-body calcium assessed by delayed-gamma neutron activation (DGNA) decreased in four of seven patients during observation, but increased in nine of 13 patients during gallium nitrate treatment; the mean difference in total-body calcium (TBCa) between the two groups at 6 months was 3%. Median regional bone density assessed by dual-photon absorptiometry (DPA) declined by 1.4% in patients under observation (range, +6.7% to -18.3%), but was unchanged during gallium nitrate treatment (median change, 0%; range, -10.5% to +14.4%). The group mean vertebral fracture index assessed by lateral spine x-rays decreased by 27% during observation compared with 2% during gallium nitrate treatment. Mean body height decreased by 0.57 inches in the observation group and .06 inches in the gallium nitrate group. Patient self-assessment of bone pain showed that seven of 12 gallium nitrate-treated patients rated themselves as experiencing major reductions in bone pain, compared with zero of seven patients who were observed. One episode of hypercalcemia occurred in a patient under observation. CONCLUSION: Adjuvant treatment with low-dose gallium nitrate attenuates the rate of bone loss in myeloma and may be useful for ameliorating the consequences of skeletal morbidity in patients with cancer-related osteolysis.

Adult↗
PubMed1992

Interferon alfa-2a and fluorouracil in the treatment of patients with advanced esophageal cancer.

PURPOSE: The trial was undertaken to determine the response rate to and toxicities from the combination of interferon alfa-2a (IFN) and fluorouracil (FU) in patients with advanced esophageal cancer. MATERIALS AND METHODS: In this prospective phase II trial conducted at a large tertiary referral cancer center and university hospital, 40 patients with advanced locoregional, metastatic epidermoid, or adenocarcinoma of the esophagus were given FU 750 mg/m2 by 24-hour continuous intravenous infusion days 1 to 5, followed by weekly outpatient bolus FU 750 mg/m2 and IFN 9 x 10(6) U three times per week from day 1. Dose was attenuated for fatigue, neurotoxicity, gastrointestinal toxicity, and myelosuppression. RESULTS: Complete and partial responses were seen in 10 of 37 assessable patients with esophageal cancer (27%; 95% confidence interval, 0.13 to 0.41). Although substantial, toxicity was tolerable and primarily involved fatigue and mild myelosuppression. The median duration of response was 6.4 months (range, 2.8 to 14+ months). CONCLUSION: The combination of IFN and FU is an active regimen in the treatment of advanced esophageal cancer with a response rate similar to that reported for cisplatin-containing combinations in similar patient populations. Further studies based on this combination are indicated.

Adenocarcinoma↗
PubMed1992

Glomerular epithelial cells secrete a glomerular basement membrane-degrading metalloproteinase.

Cultured rat glomerular epithelial cells (GEC) were examined for their ability to release extracellular matrix-degrading proteinases with [3H]gelatin as substrate. GEC-conditioned media, under serum-free conditions, contained modest amounts of gelatinase activity (1 to 10 U/mg of protein); the activity was maximal at neutral pH, was inhibited by zinc chelators, was not inhibited by tissue inhibitor of metalloproteinase-2, and could not be further activated by trypsin or organomercurials. Gelatin substrate sodium dodecyl sulfate-polyacrylamide gels of GEC-conditioned medium revealed several zones of lysis, with molecular sizes of 150 kd (major band), and 220, 86 to 93, and 52 to 54 kd (minor bands). Northern blot analysis demonstrated that the GEC metalloproteinase(s) were distinct from the 68- to 72-kd type IV collagenase/gelatinase present in mesangial cells or the 92-kd type IV collagenase present in neutrophils. The GEC gelatinolytic activity also degraded insoluble type IV collagen in glomerular basement membrane in a dose-dependent manner. The major metalloproteinase activity responsible for the type IV collagen degradation has a molecular size of 150 kd with a type IV collagen substrate gel. Thus, GEC produce several neutral metalloproteinases, which, by virtue of their substrate specificity, may play an important role in glomerular basement membrane remodeling and in glomerular diseases characterized by alterations in basement membrane permeability.

Animals↗
PubMed1991

Interleukin-1 rapidly stimulates lysophosphatidate acyltransferase and phosphatidate phosphohydrolase activities in human mesangial cells.

Phosphatidic acid (PA) is a cytokine in a variety of cell types, and an intermediary in cell activation. It is produced from membrane phospholipids by either lysophosphatidate acyl-CoA:acyltransferase (lyso-PA AT) or phospholipase D. Interleukin-1 (IL-1) stimulation of human mesangial cells (HMC) induced activation of lyso-PA AT, and synthesis of new PA species with significant increase in PA mass. These PA species were enriched in long-chain unsaturated acyl side chains (C18:1, C18:2, C20:5, and C22:6) in both the sn-2 and sn-1 positions, and stimulated the action of the lyso-PA AT as a positive feedback mechanism. Gas-liquid chromatography and mass spectrometry demonstrate that the acyl composition of phosphatidic acid does not resemble that of the major phospholipid fractions of this preparation and therefore is not the product of phospholipase D. The PA species were rapidly converted to 1,2-sn-diacylglycerols by phosphatidate phosphohydrolase, which also was activated by IL-1 via a separate mechanism involving a pertussis-sensitive G-protein. The activities of lyso-PA AT and phosphatidate phosphohydrolase were associated with plasma membrane enriched and refined microsomal fractions. IL-1 stimulation of a murine T cell (thymoma) line, EL-4, also caused stimulation of lyso-PA AT, resulting in PA formation. EL-4 mutants with defective IL-1 receptors did not demonstrate stimulation of lyso-PA AT, showing the necessity of intact IL-1 receptors for activation of this enzyme. We conclude that PA is a significant signaling intermediary for IL-1 via activation of lyso-PA AT and a G-protein, which activates phosphatidate phosphohydrolase. This system suggests a novel mechanism whereby a low intensity signal may be translated into cellular activation.

Acyltransferases↗
PubMed1991

A phase II trial of carboplatin and vinblastine in the treatment of advanced squamous cell carcinoma of the esophagus.

Cisplatin-containing regimens are active in the treatment of esophageal cancer, with response rates of 25% to 35% in advanced disease. Carboplatin is less toxic than cisplatin; as a single agent, several responses were seen against esophageal tumors. To better define the role of carboplatin in esophageal cancer, the authors treated 19 chemotherapy-naive patients with advanced squamous cell carcinoma of the esophagus with carboplatin and vinblastine. Carboplatin (450 mg/m2 intravenously [IV] on days 1, 29, 57, and every 6 weeks thereafter) was given with vinblastine (5 mg/m2 IV on day 1 and then every 2 weeks). No major responses were seen. No significant renal toxicity and only mild gastrointestinal toxicity (emesis, diarrhea) were observed. Hematologic toxicity was more severe in patients with prior radiation therapy (RT), with three of six patients with prior RT exhibiting Grade 4 hematologic toxicity. Although generally less toxic than cisplatin-containing regimens, carboplatin and vinblastine is also less active in the treatment of squamous cell carcinoma of the esophagus. Hematologic toxicity with this regimen was severe in patients who had received prior RT.

Adult↗
PubMed1991

A phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide.

Ten patients with myeloid leukemias were treated in a phase I trial with escalating doses of mouse monoclonal antibody (mAb) M195, reactive with CD33, a glycoprotein found on myeloid leukemia blasts and early hematopoietic progenitor cells but not on normal stem cells. M195 was trace-labeled with iodine-131 (131I) to allow detailed pharmacokinetic and dosimetric studies by serial sampling of blood and bone marrow and whole-body gamma-camera imaging. Total doses up to 76 mg were administered safely without immediate adverse effects. Absorption of M195 onto targets in vivo was demonstrated by biopsy, pharmacology, flow cytometry, and imaging; saturation of available sites occurred at doses greater than or equal to 5 mg/m2. The entire bone marrow was specifically and clearly imaged beginning within hours after injection; optimal imaging occurred at the lowest dose. Bone marrow biopsies demonstrated significant dose-related uptake of M195 as early as 1 hour after infusion in all patients, with the majority of the dose found in the marrow. Tumor regressions were not observed. An estimated 0.33 to 1.0 rad/mCi 131I was delivered to the whole body, 1.1 to 6.1 rad/mCi was delivered to the plasma, and up to 34 rad/mCi was delivered to the red marrow compartment. 131I-M195 was rapidly modulated, with a majority of the bound immunoglobulin G (IgG) being internalized into target cells in vivo. These data indicate that whole bone marrow ablative doses of 131I-M195 can be expected. The rapid, specific, and quantitative delivery to the bone marrow and the efficient internalization of M195 into target cells in vivo also suggest that the delivery of other isotopes such as auger or alpha emitters, toxins, or other biologically important molecules into either leukemia cells or normal hematopoietic progenitor cells may be feasible.

Adult↗
PubMed1986

Interleukin 1 induces specific phosphorylation of a 41 kDa plasma membrane protein from the human tumor cell line K 562.

An in vitro system was established to investigate the early effects of interleukin 1 (IL 1) on a clearly defined subcellular system, the plasma membrane. Murine IL 1 was obtained from the macrophage tumor line P 388 D1 and purified to apparent homogeneity. Plasma membranes from the human leukaemic tumor cell line K 562 were highly purified by differential ultracentrifugation. The monokine induced the specific phosphorylation of a 41 kDa plasma membrane protein. This could be demonstrated by incubating the plasma membranes in the presence of IL 1 and (gamma-32P)-ATP, separating the proteins by SDS-PAGE and subsequent autoradiography. A first biochemical reaction caused by IL 1 in the target organelle of the cell, the plasma membrane, was discovered, yielding a clue of how signal transmission may take place finally resulting in the stimulation of the responding cell.

Cell Line↗
PubMed1986

Macrophage cytotoxicity: interleukin 1 as a mediator of tumor cytostasis.

Purified macrophage interleukin 1 (IL 1) induced a concentration-dependent inhibition of the proliferation of two commonly used tumor cell target lines, the human myeloid K562 and the murine T lymphoma Eb. In contrast, mastocytoma-derived P815 cells were not inhibited. The cytostatic action of IL 1 was not associated with direct cytotoxicity and was only partially reversible. PGE or interferon did not appear to mediate these effects. IL 1 treatment of the multipotential K562 cells revealed no morphologic evidence for the induction of specific differentiation. FACS analysis of IL 1-treated K562 cells showed a rapid decrease in transferrin receptor density, and a more delayed, but highly significant, increase in HLA-A,B,C antigen density. These findings provide one explanation for the frequently reported macrophage cytostatic actions against tumor cells, and indicate as well that IL 1, like interferon, may enhance the expression of Class I MHC antigens. These observations further extend the range of IL 1 actions and underscore the fundamental and direct role of this monokine in macrophage antitumor activity.

Animals↗
PubMed1985

Studies on the mechanism whereby cyclosporin A inhibits T-lymphocyte activation.

The immunosuppressive drug Cyclosporin A (CyA) inhibited the ConA-induced DNA synthesis in C57B1/6 spleen cells at a concentration of 40 ng/ml totally; this inhibition could not be overcome by the addition of highly purified interleukin-1. ConA-induced RNA synthesis was also inhibited by concentrations of 40 or 200 ng/ml CyA, although total inhibition could not be achieved. In contrast, lipopolysaccharide-induced proliferation could not be inhibited. CyA at a concentration of 40 ng/ml also inhibited the ConA-induced production of interleukin-2 by mouse spleen cells, this inhibition was not due to a toxic mechanism. On the contrary, the proliferative response of T cell blasts from a long-term T cell line (M2) to interleukin-2 containing supernatants was not inhibited by concentrations of 40 or 200 ng/ml CyA; only at 20-100-fold higher concentrations partial inhibition could be observed. One of the earliest events in the course of lymphocyte activation, the enhanced incorporation of unsaturated fatty acids into the lymphocyte plasma membranes; was also inhibited by concentrations of CyA, which abrogated the ConA-induced DNA synthesis. The inhibition of the enhanced incorporation of 14C-oleic acid and 14C-linoleic acid, which are incorporated by the membrane-bound lysolecithin-acyltransferase, thus suggests a molecular site of action for CyA.

Animals↗