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Biomedical subjects

L Mills

Publications and source records attributed to L Mills.

17 recordsLinked to original sources
PubMed1992

Initial trial of bispecific antibody-mediated immunotherapy of CD15-bearing tumors: cytotoxicity of human tumor cells using a bispecific antibody comprised of anti-CD15 (MoAb PM81) and anti-CD64/Fc gamma RI (MoAb 32).

The high-affinity receptor for IgG, Fc gamma RI, expressed on monocytes and interferon-gamma (IFN-gamma)-stimulated neutrophils, is a trigger molecule for cell-mediated cytotoxicity. We have prepared murine monoclonal antibodies (MoAb 22 and MoAb 32) that bind to Fc gamma RI outside the ligand binding site and thus bind to and trigger cytotoxicity that is not competed by other immunoglobulins. Because of these properties, it seemed that these MoAbs would be very useful for the development of bispecific antibodies (BsAb) for targeting normal cellular immune defense mechanisms as a new form of immunotherapy for treatment of cancer. BsAbs incorporate into a single molecule the binding specifities of two different antibodies, and, thus, can be used to target myeloid cells to tumors, ensure activation of cellular cytotoxic mechanisms, and target cell lysis and/or phagocytosis. BsAbs were prepared using anti-Fc gamma RI MoAb and an anti-myeloid cell MoAb, PM81, reactive with the CD15 antigen, for studies of antibody-dependent cellular cytotoxicity. Conjugates were made by cross-linking sulfhydryl groups of Fab fragments of MoAb 32 or 22 (both IgG1) and sulfhydryl groups added to intact PM81 (an IgM) using N-succinimdyl-acetyl-S-thioacetate (SATA). The resulting product was purified by high-performance size-exclusion chromatography. The ability of the BsAbs to mediate attachment of human monocytes to tumor target cells was confirmed in a microtiter well assay of binding of MTT-labeled U937 cells (a human Fc gamma RI-bearing cell line) to SKBR-3 (PM81-reactive breast carcinoma) target cells. The ability of the BsAbs to mediate killing of HL-60 promyelocytic leukemia cells was studied using a 6-hour Chromium-51 release assay. Effector cells were monocytes obtained by cytopheresis and cultured for 18 hours with IFN-gamma. Monocytes alone caused minimal killing (5-20%), monocytes plus BsAb caused moderate killing (20-50%), and monocytes plus BsAb plus human serum resulted in maximal killing (50-80%). Experiments were performed to test the ability of the BsAb to purge bone marrow of small numbers of leukemia cells using bone marrow mononuclear phagocytes treated for 18 hours with IFN-gamma prior to adding target cells. Without the addition of human serum as a source of complement, a 90% depletion of clonogenic HL-60 cells could be demonstrated. With human complement, up to 95% depletion was seen. Thus, this BsAb possessed the ability to lyse tumor cell targets by two different mechanisms, complement and cell-mediated lysis.(ABSTRACT TRUNCATED AT 400 WORDS)

Antibodies, Monoclonal↗
PubMed1992

Transactivation of the major capsid protein gene of herpes simplex virus type 1 requires a cellular transcription factor.

The purpose of this investigation was to identify and characterize the regulatory elements involved in the transcriptional activation of the beta gamma (leaky-late or gamma 1) genes of herpes simplex virus type 1 (HSV-1) by using the major capsid protein (VP5 or ICP5) gene as model. Gel mobility shift assays with nuclear extracts from uninfected and infected HeLa cells enabled us to identify two major protein-DNA complexes involving the VP5 promoter. The mobilities of these two complexes remained unaltered, and no unique complexes were observed when infected cell nuclear extracts were used. DNase I and orthophenanthroline-Cu+ footprint analyses revealed that the two complexes involve a single binding site, GGCCATCTTGAA, located between -64 and -75 bp relative to the VP5 cap site. To determine the function of this leaky-late binding site (LBS) in VP5 gene activation, we tested the effect of mutations in this region by using transient expression of a cis-linked chloramphenicol acetyltransferase gene. Deletion of the above sequence resulted in a seven- to eightfold reduction in the level of transactivation of the chloramphenicol acetyltransferase gene by superinfection with HSV-1 or by cotransfection of HSV-1 immediate-early genes. From these results, we conclude that the LBS sequence and a cellular factor(s) are involved in the transactivation of the VP5 gene. A search of published gene sequences revealed that sequences related to the LBS exist in a number of other HSV-1, cytomegalovirus, retrovirus, and cellular promoters. Sequence homologies of binding sites and results of unpublished competition binding studies suggest that this leaky-late binding factor may be related to, or the same as, a ubiquitous cellular transcriptional factor called YY1 or common factor-1 (also known as NF-E1, delta, and UCRBP).

Base Sequence↗
PubMed1992

The sensitivity of auditory brainstem response testing in small acoustic neuromas.

Auditory brainstem response (ABR) testing is a reliable and sensitive test for retrocochlear pathology in neurotologic diagnosis. Several investigators have reported the sensitivity of ABR testing as 95% or greater. Fifty-one consecutive patients with surgically confirmed acoustic neuromas were examined. Forty patients had sufficient hearing preoperatively for assessment with ABR. In addition, all had been evaluated with gadolinium-enhanced magnetic resonance imaging and conventional electronystagmography. Overall, 34 of 40 patients (85%) had abnormal ABRs. One of 25 patients with extracanalicular tumors had a normal ABR for a false-negative rate of 4%; however, 5 of 15 patients with intracanalicular tumors had normal ABRs for a false-negative rate of 33%. Tumor size and nerve of origin were important factors affecting the ABR sensitivity. The ABR was less sensitive in detecting intracanalicular tumors than in detecting extracanalicular tumors.

Audiometry, Pure-Tone↗
PubMed1991

Botulinum A toxin for the treatment of adult-onset spasmodic torticollis.

Thirty-five patients with adult-onset idiopathic torticollis were treated by local injections of botulinum A toxin into dystonic cervical muscles. Substantial improvement with respect to reduction and elimination of pain was found in 81 percent, improvement in posture deformity and involuntary spasms in 70 percent, increased range of motion of the neck in 78 percent, reduction in visible sternocleidomastoid hypertrophy in 86 percent, and improvement in tremor in 65 percent. The syndrome was divided into four subtypes based on pattern of dystonic muscle groups involved in the dystonia, head and shoulder posture, and sternocleidomastoid muscle hypertrophy. Injection strategy based on this subdivision is described.

Adult↗
PubMed1989

Utility of flow cytometric reticulocyte quantification as a predictor of engraftment in autologous bone marrow transplantation.

Flow cytometric reticulocyte quantification with thiazole orange (TO) was used to study erythropoiesis in 20 patients following autologous bone marrow transplantation for the treatment of acute myelogenous leukemia. Flow cytometric reticulocyte analysis provided not only the reticulocyte percentage and absolute reticulocyte count but a quantitative reticulocyte maturity index (RMI) proportional to the amount of RNA in the reticulocytes. The RMI values, but not the reticulocyte percentage or absolute counts, correlated temporally with the rise in the absolute neutrophil counts in the posttransplantation period. In the majority of patients (12/20), the RMI value was the earliest indicator of bone marrow engraftment. The findings of this study demonstrate an important clinical utility of TO reticulocyte analysis by flow cytometry and indicate the diagnostic importance of the RMI measurement in the evaluation of erythropoietic activity in bone marrow transplant patients.

Adolescent↗
PubMed1986

Rat insulin-like growth factor II gene. A single gene with two promoters expressing a multitranscript family.

We have characterized the single-copy rat gene encoding the protein precursor of insulin-like growth factor II (pre-pro-rIGF-II) that is located downstream from and in the same transcriptional orientation as the homologous insulin II gene (5'-insulin-IGF-II-3'). This gene consists of at least three coding exons and utilizes two promoters that generate alternate 5' non-coding exons. Multiple transcripts from both promoters appear primarily in fetal or neonatal tissues (in all of the developmental stages and tissues that we have examined), but they are extremely rare or undetectable in adult tissues, with the exception of the brain and the spinal cord. These transcripts, which exhibit characteristic developmental profiles in various tissues, differ both in the presence of one of the alternate 5' non-coding exons and in the length of their fourth exon. The possible occurrence of differential splicing or differential polyadenylation (or both) in this region is discussed.

Animals↗
PubMed1979

Hemodynamic evaluation of the Carpentier-Edwards bioprosthesis in the aortic position.

The Carpentier-Edwards bioprosthesis is a glutaraldehyde-fixed porcine xenograft with a fully flexible thin-walled stent. Cardiac catheterization studies were performed in 17 patients to evaluate use of this valve in the aortic position. Hemodynamic studies established a mean peak gradient across the prosthesis of 19 mm Hg (range 5 to 65). The mean effective orifice area was calculated to be 1.6 cm2 (range 0.8 to 3.3). All patients demonstrated an improvement in functional class after operation. Mean left ventricular ejection fraction increased from 51 +/- 16 to 68 +/- 9 percent (P less than 0.004) in eight patients operated on for aortic stenosis, but was not significantly changed in patients operated on for aortic insufficiency. Hemodynamic comparison of the Carpentier-Edwards bioprosthesis with the standard Hancock xenograft showed similar effective orifice areas for the 23 and 25 mm diameter valves. In two patients studied the 21 mm Carpentier valve demonstrated a greater effective orifice area than that previously reported for the standard Hancock xenograft. The Carpentier-Edwards bioprosthesis affords both clinical and hemodynamic improvement when used in the aortic position and may allow improved effective orifice area when used in the smaller aortic root.

Adult↗
PubMed1979

Dissecting aortic aneurysm involving a right-sided aortic arch.

In this case, the first reported instance of aortic dissection involving a right-sided arch, an anomalous fourth arch vessel, the left subclavian artery, arose from a congenital aortic diverticulum. This report emphasizes the need for precise anatomic definition with aortography to permit appropriate therapy when congenital anomalies of the aortic arch are complicated by dissecting hematoma.

Aortic Dissection↗
PubMed1979

Stimulation by a hydroxythiazolobenzimidazole of enhanced formation of antibodies to sheep erythrocytes in vitro and in vivo.

A hydroxythiazolobenzimidazole, a low molecular weight compound, was found to have an immunoenhancing effect on both the in vivo and in vitro antibody response of mouse spleen cells to an optimum immunizing dose of sheep red blood cells. At noncytotoxic concentrations the optimum range of 25 to 50 micrograms per 5 x 19(6) spleen cells was most effective in vitro. Concentrations greater than 100 micrograms per culture were toxic in vitro and reduced cell viability as well as antibody responsiveness. The compound enhanced to an even greater degree the antibody response of spleen cell cultures immunized with suboptimum doses of SRBC. The background PFC response, in the absence of SRBC, also was stimulated by the benzimidazole. These immunoenhancing responses were not related to mitogenic effects, since increased thymidine uptake did not occur when normal mouse spleen cells were incubated with graded doses of the compound. Therefore, the immunostimulatory properties of the compound, both in vivo and in vitro, were not due to mitogenic stimulation of lymphoid cells.

Animals↗
PubMed1977

Relationship between antigenic stimulation and increased splenic peroxidase levels during the immune response.

Immunization of mice with either soluble or particulate antigens induced a marked increase in peroxidase activity of spleen cell homogenates. Animals immunized with sheep erythrocytes showed maximum splenic peroxidase activity at 2 days. By the 4th day after immunization, when the hemolytic antibody plaque-forming cell response was maximal, peroxidase activity returned to normal levels. Increased splenic peroxidase activity also occurred in mice immunized with rabbit erythrocytes, as well as with rabbit serum or bovine serum albumin. No change in splenic peroxidase activity occurred in mice injected with syngeneic mouse erythrocytes or serum. Both glass-adherent spleen cell populations, morphologically consisting of 90 to 95% macrophages, as well as nonadherent cells, consisting of more than 90% lymphocytes by the same criteria, showed peroxidase activity. Immunization of mice with sheep erythrocytes resulted in an intracellular redistribution of the peroxidase activity among several distinct subcellular fractions prepared by differential centrifugation. Maximum redistribution occurred with granule-associated enzyme activity. A possible relationship between peroxidase activity with functional activity of lymphocytes and macrophages during humor immune responses seemed likely.

Animals↗