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Biomedical subjects

H Lazarus

Publications and source records attributed to H Lazarus.

At least 37 records · Page 2Linked to original sources
PubMed1988

P & T Committee interview: Establishing and maintaining a dynamic formulary.

In an exclusive interview with Hospital Formulary, Dr. Stephen Rostand and Mr. Herman Lazarus--the P & T Committee Chairman and Secretary of the University of Alabama Hospital--share their experiences in establishing an effective, functional formulary system. Discussed in this interview are the current activities of this Committee which include: reviewing adherence to an established Committee guideline on an effective antibiotic dosing regimen, creating a more effective adverse drug reaction reporting system, and establishing a computerized program to alert prescribers to the possibility of drug-drug interactions. By their willingness to cooperate, communicate, and remain flexible to medical staff requests, this 15-member Committee has been able to maintain a dynamic formulary.

Alabama↗
PubMed1987

Vascular graft-associated complement activation and leukocyte adhesion in an artificial circulation.

Complement-associated leukocyte adhesion appears to be a consistent in vitro and in vivo finding for many types of polymers; however, very little work has been done on the interaction of leukocytes with vascular graft materials. An in vitro perfusion system was used to study complement and leukocyte activation associated with the following vascular graft materials when tested with human blood: expanded polytetrafluoroethylene (ePTFE), crimped Dacron Bionit (DB) and preclotted Dacron Bionit. A decrease in the total leukocyte concentration with perfusion time was seen for all materials tested, and paralleled leukocyte adhesion to the graft surface as observed by scanning electron microscopy. The most dramatic decrease in leukocyte concentration was observed for the interaction of heparinized whole blood with Dacron. This was due to a selective decrease in neutrophils and monocytes, and was correlated with an increase in both leukocyte adhesiveness and complement activation, as measured by C5a elevation. Inhibiting complement activation by use of the anticoagulant, sodium citrate, curtailed Dacron-induced leukocyte adhesion. Little leukocyte or complement activation was observed for ePTFE or the silicone rubber control regardless of the anticoagulant used.

Adult↗
PubMed1987

Ganglioside GD2 specific monoclonal antibody 3F8: a phase I study in patients with neuroblastoma and malignant melanoma.

The murine IgG3 monoclonal antibody (MoAb) 3F8, specific for the ganglioside GD2, activates human complement, is active in antibody-dependent cell-mediated cytotoxicity (ADCC), and can target specifically to human neuroblastoma in patients with metastatic disease. In a phase I study, 3F8 was administered intravenously (IV) to 17 patients with metastatic GD2 positive neuroblastoma or malignant melanoma at doses of 5, 20, 50, and 100 mg/m2. Serum 3F8 levels achieved were proportional to the dose of 3F8 infused. However, serum antimouse antibody levels did not increase with the amount of 3F8 administered. Toxicities included pain, hypertension, urticaria, and complement depletion. All acute side effects were controllable with symptomatic therapy. No long-term side effects were detected in patients observed for more than 14 months. None of the 17 patients received any antitumor therapy postantibody treatment. Antitumor responses occurred in seven of 17 patients. These ranged from complete clinical remissions to mixed responses. The murine monoclonal antibody (MoAb) 3F8 has clinical utility for the diagnosis and therapy of neuroblastoma and melanoma.

Adolescent↗
PubMed1987

Unique proliferation-associated marker expressed on activated and transformed human cells defined by monoclonal antibody.

The expression, tissue distribution, and preliminary characterization of a cell surface molecule, apparently a glycolipid, recognized by a monoclonal antibody, anti-PAA, were described. This antibody (anti-PAA) was produced by the fusion of myeloma cells NS-1 with spleen cells from a BALB/c mouse, which were sensitized with activated human T-cells generated by allogeneic stimulation in mixed-lymphocyte culture (MLC). Resting human peripheral blood T-cells, B-cells, and monocytes demonstrated weak anti-PAA binding. Binding of proliferating T-cells (phytohemagglutinin- and MLC-activated T-cells) and thymocytes to anti-PAA was two to six times greater than that of resting T-cells. A fifteenfold-increased binding was observed with acute lymphocytic leukemia T-cell lines. Epstein-Barr virus-transformed B-cell lines bound anti-PAA up to sixteenfold greater than resting B-cells. Tumor cell lines of various nonlymphoid origins demonstrated marked reactivity with this antibody. Both benign and malignant cells in hyperplastic tissues, of various origins, bound anti-PAA, whereas their normal, nonproliferating counterparts did not. Normal proliferating cells in these tissues, including cells of the placental chorionic villi and trophoblasts, also bound anti-PAA. Of all lymphoid and nonlymphoid cell lines examined, only chronic lymphocytic leukemia (CLL) cells and some cell lines derived from Burkitt's lymphoma showed weak or no binding. This antibody also failed to react with a variety of nonprimate cell lines. Anti-PAA antibody did not immunoprecipitate any protein from lymphoid tumor cell lines to which it demonstrated a quantitatively high degree of binding, nor did protease treatment of these lines decrease antibody binding. Anti-PAA did, however, bind to glycolipids extracted from these cell lines. Binding of this monoclonal antibody to a minor neutral glycolipid, isolated from the erythroleukemia cell line K562, was about sixfold greater than that of any other K562 neutral glycolipid or ganglioside. Anti-PAA demonstrated weak or undetectable binding to purified, predominant, lymphoid cell membrane's neutral glycolipids and gangliosides. The monoclonal antibody anti-PAA appeared, therefore, to recognize a unique, proliferation-associated, neutral glycolipid present on normal as well as on benign and malignant proliferating cells. The antigen appeared to be universally expressed on proliferating cells from all human tissues with the exception of some Burkitt's cell lines and CLL cells. Nonhuman cell lines, except those for closely related primates, did not express PAA.

Antibodies, Monoclonal↗
PubMed1986

Industrial safety: Acoustic signals for danger situations in factories.

To clarify which types of acoustic signals should be used for what danger situations, the relationships between acoustic signals already used in factories and danger situations are investigated. Compatibilities between 20 danger signals (horns, sirens, etc) and 36 situations (e g, fire, accident, etc) are determined with the help of a compatibility scale. Based on mean ratings of 48 subjects, some of these signals can be grouped if the compatibilities between signals and danger situations are similar. Rules for selection of signals are given.

Journal Article↗
PubMed1984

Human-human hybrids secreting pneumococcal antibodies.

Starting with a nonimmunoglobulin producing human myeloma cell line, we have constructed a human myeloma "analog" (LSM 2.7) which supports the synthesis and secretion of human immunoglobulin in vitro upon fusion with human peripheral blood and spleen mononuclear cells. Fusions between LSM 2.7 and spleen cells obtained from patients immunized against pneumococcal capsular polysaccharides consistently gave rise to hybrids which synthesized and secreted human immunoglobulin. In three of ten independent fusions a large proportion of the hybrid cultures produced specific pneumococcal antibodies. All three spleens which yielded antibody producing hybrids were from patients immunized 3 to 4 days prior to staging splenectomy for Hodgkin's disease. Antibody secreting hybrid cells ceased producing immunoglobulin 28 to 42 days post fusion. However, fusion of a HAT sensitive clone derived from a hybrid which had secreted antibody, with peripheral blood mononuclear cells, resulted in reactivation of specific antibody secretion.

Antibodies, Bacterial↗
PubMed1984

Methotrexate analogues. 21. Divergent influence of alkyl chain length on the dihydrofolate reductase affinity and cytotoxicity of methotrexate monoesters.

n-Octyl, n-dodecyl, and n-hexadecyl alpha- and gamma-esters of methotrexate (MTX) were compared with the previously described alpha- and gamma-n-butyl esters and with MTX as inhibitors of dihydrofolate reductase (DHFR) and human leukemic lymphoblasts (CEM cells) in culture. The overall order of activity in both test systems was MTX greater than MTX gamma-esters greater than MTX alpha-esters. In the DHFR assay the activity of the alpha-esters followed the order C4 greater than C8 congruent to C12 greater than C16, whereas for the gamma-esters this order was C4 congruent to C8 greater than C12 greater than C16. On the other hand, the order of cytotoxic activity in culture in both series was C16 greater than C12 greater than C8 greater than C4. Increasing the alkyl chain length in the ester moiety therefore decreases DHFR affinity but increases cytotoxicity. The most potent member of the compounds tested was the gamma-n-hexadecyl ester, whose IC50 against CEM cells was 0.11 microM as compared with 0.025 microM for MTX. In a comparison of the effect of treatment with the gamma-n-hexadecyl ester (10(-5) M, 1 h) on DNA synthesis in CEM and CEM/MTX cells, the latter of which are 120-fold resistant to MTX by virtue of a transport defect, the ester produced only 4-fold less inhibition in the resistant line than in the parental line. These results suggest possible use of this compound or related derivatives in the treatment of MTX-resistant tumors with impaired transport.

Animals↗
PubMed1983

A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer.

The murine monoclonal antibody OC 125 reacts with an antigen (CA 125) common to most nonmucinous epithelial ovarian carcinomas. An assay has been developed to detect CA 125 in serum. By this assay, only 1 per cent of 888 apparently healthy persons and 6 per cent of 143 patients with nonmalignant disease had serum CA 125 levels above 35 U per milliliter. In contrast, 83 of 101 patients (82 per cent) with surgically demonstrated ovarian carcinoma had elevated levels of antigen. In 38 patients with epithelial ovarian carcinoma monitored on 2 to 18 occasions during 2 to 60 months, antigen levels ranged from less than 1 to more than 8000 U per milliliter. Rising or falling levels of CA 125 correlated with progression or regression of disease in 42 of 45 instances (93 per cent). Determination of CA 125 levels may aid in monitoring the response to treatment in patients with epithelial ovarian cancer.

Adenocarcinoma↗
PubMed1983

Comparison of a rabbit heteroantiserum and a murine monoclonal antibody raised against a human epithelial ovarian carcinoma cell line.

An ovarian carcinoma cell line (OVCA 432) and a B-lymphocyte line (LAZ 446) were established from the same donor. A heteroantiserum (D-100) was prepared in rabbits against OVCA 432 and absorbed with LAZ 446, human AB erythrocytes, and the CX-1 colorectal cell line. After absorption, D-100 reacted by indirect immunofluorescence with six of six epithelial ovarian carcinoma cell lines and cryostat sections of 18 of 18 epithelial ovarian tumors but bound to zero of 12 nonovarian tumor cell lines. Despite a lack of reactivity with nonovarian tumor cell lines, D-100 reacted with epithelial components of normal ovary, fallopian tube, endometrium, endocervix, breast, colon, and epididymis. A murine monoclonal antibody (OC 133) was also raised against OVCA 432 and selected for lack of reactivity with the autologous B-lymphocyte line LAZ 446. OC 133 reacted with six of six ovarian carcinoma cell lines and cryostat sections of seven of 19 ovarian tumors, but it also reacted with five of five nonovarian tumor cell lines. Of 12 normal tissues examined, OC 133 reacted with endometrium and endocervix only. Whereas D-100 bound to serous, mucinous, endometrioid, and clear cell ovarian neoplasms, OC 133 bound only to serous tumors. In developing monoclonal reagents, cell lines may provide a useful source of antigen, but promising antibodies should be screened for reactivity with sections of normal and malignant human tissues.

Animals↗
PubMed1983

Novel approach to construction of human "myeloma analogues" for production of human monoclonal antibodies.

The production of human monoclonal antibodies has been impeded by the lack of human myeloma cell lines which grow easily, fuse efficiently, clone readily, and continuously secrete large amounts of antibody. A cell line, HM 2.0, was constructed by fusing a HAT-sensitive, nonsecreting, human myeloma cell line, LSM 1.2, with cells from a patient with plasma cell leukemia. In marked contrast to LSM 1.2, which could not support the secretion of immunoglobulin, fusion of HM 2.0 with cells from spleen or peripheral blood routinely resulted in the secretion of antibody to pneumococcal polysaccharides and tetanus toxoid. The fusion efficiency of HM 2.0, as measured by growth of colonies, was greater than 1 per 1.2 X 10(3) peripheral blood mononuclear cells and the number of hybrids secreting specific antibody was greater than 1 per 1.1 X 10(5) mononuclear cells from immunized individuals. This is an improvement over our previously described human "myeloma analogue" LSM 2.7, derived by fusion of a HAT-sensitive, nonsecreting human myeloma cell line, LSM 1.1, with cells from a normal donor, as well as all previously described human lymphoblastoid and myeloma cell lines. These results demonstrate that somatic cell hybridization can be used to modify an existing cell line in such a manner as to yield a "new" cell line with the attributes necessary for the production of human monoclonal antibodies.

Antibodies, Bacterial↗
PubMed1983

Distribution and modulation of a human leukemia-associated antigen (CALLA).

CALLA is a 100,000-dalton surface glycoprotein expressed by malignant cells of patients with clinically important subtypes of acute leukemia. Incubation of human leukemic cells expressing CALLA with specific monoclonal antibody (J5) at 37 degrees C causes rapid and selective internalization and degradation of this antigen (antigenic modulation). In these studies we show that CALLA-specific monoclonal antibodies also identify a cell surface glycoprotein having a m. w. of approximately 100,000 on 2 to 6% of nonmyeloid nucleated cells of normal adult bone marrow, on normal fibroblasts in tissue culture, and on cells of several nonhematopoietic human tumor cell lines. J5 antibody similarly modulates the surface expression of CALLA on nonleukemic cell populations, although the extent of modulation at a given concentration of antibody varied considerably. Modulation was almost complete for CALLA on cells of normal bone marrow, but was highly variable for cells of nonhematopoietic cell lines, possibly reflecting variability in antibody access to surface antigen. Using fluoresceinated or iodinated J5 antibody to modulate expression of CALLA on cells of leukemic cell lines, we show that antibody-antigen complexes undergo a temperature-dependent redistribution on the cell surface during modulation to form microaggregates. Antibody as well as antigen is then internalized. Studies of [35S]methionine-labeled cells indicate that synthesis of CALLA continues despite modulation of its surface expression by specific antibody, implying that the presence of CALLA on the cell surface reflects a dynamic equilibrium between the processes of surface expression of newly synthesized glycoprotein and its spontaneous and antibody-mediated clearance. The implications of these observations for immunotherapy are discussed.

Antibodies, Monoclonal↗
PubMed1982

A new fluorescent dihydrofolate reductase probe for studies of methotrexate resistance.

A new fluorescent methotrexate analogue (PT430) was synthesized as a reported ligand for dihydrofolate reductase. The analogue was prepared by attachment of lysine in place of the glutamate side chain of methotrexate and conjugation to fluorescein isothiocyanate via the epsilon-amino group of lysine. Spectrophotometric enzyme inhibition assays showed PT430 to be about one-tenth as potent as methotrexate against either Lactobacillus casei or L1210 mouse leukemia enzyme; competitive radioligand binding assays using tritiated methotrexate gave similar results. In assays of L1210 cell proliferation in culture, on the other hand, PT430 was 100-fold less toxic than methotrexate. In dilute solution, the fluorescence intensity of PT430 was 5-fold lower than that of equimolar fluorescein and diminished with decreasing pH. On complexation with dihydrofolate reductase, however, fluorescence intensity was enhanced 3- to 5-fold depending on the pH. Measurement of fluorescence increase with added ligand provided data for the determination of the stoichiometric ratio, dissociation constant, and extent of fluorescence enhancement. Specificity of PT430 for methotrexate binding sites was indicated by the observation of decreased fluorescence uptake in PT430-treated L1210 cells in the presence of methotrexate. Fluorescence uptake occurred faster, and to a greater extent, in methotrexate-resistant dihydrofolate reductase overproducing L1210/R6 cells than in the methotrexate-sensitive parent line. Therefore, PT430 may be used as a flow cytometry probe to detect methotrexate resistance based on dihydrofolate reductase overproduction.

Animals↗
PubMed1982

An enzyme-linked immunosorbent assay (ELISA) for the detection of monoclonal antibodies to cell surface antigens on viable cells.

A rapid and inexpensive ELISA method is described which is suitable for the large scale screening of monoclonal antibodies to cell surface antigens. The use of acrylic plates and viable cells eliminates background and false positive reactions, and avoids modification of surface antigens caused by fixation. This facilitates easy and rapid detection of positives by visual inspection of the plates. The specificity and sensitivity of the methods is comparable to indirect immunofluorescence or radioimmunoassay. The advantages of this ELISA system when compared to these methods and to previously described ELISA systems utilizing fixed cells are discussed.

Animals↗