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Biomedical subjects

D Harris

Publications and source records attributed to D Harris.

At least 145 records · Page 8Linked to original sources
PubMed1994

Interaction of liposome-associated all-trans-retinoic acid with squamous carcinoma cells.

Because of their antiproliferative and differentiation-inducing properties, retinoids have been used clinically as therapeutic and chemopreventive agents against squamous-cell carcinomas (SCC). As is the case for many therapeutic agents, however, the administration of retinoids is associated with toxic effects. Because encapsulation of certain drugs in lipid vesicles (liposomes) has been shown to result in reduced toxic effects, we studied the in vitro interaction of liposome-encapsulated all-trans-retinoic acid (L-ATRA) with a SCC line (MDA 886Ln) and its multicellular tumor spheroid (MTS) model. Various L-ATRA formulations were tested for incorporation of retinoic acid, toxic effects against human red blood cells, uptake and retention by tumor cells, and antiproliferative effects against SCC. Of the different formulations tested, L-ATRA containing diphosphatidyl palmitoylcholine (DPPC) and stearylamine (SA; 9:1, w/w) showed optimal drug incorporation, high stability, and minimal toxicity toward red blood cells and was highly efficacious in delivering ATRA and, thus, in inhibiting the growth of MDA 886Ln and its MTS model. DPPC: SA L-ATRA inhibited the expression of the enzyme keratinocyte transglutaminase in epidermal cells as effectively as did the free drug. These results suggest that liposomes can serve as an effective carrier system for the delivery of retinoids to SCC.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1994

Anti-idiotype and recombinant antigen in immunotherapy of colorectal cancer.

The CO17-1A/GA733 antigen (Ag), bound by monoclonal antibodies (MAb) CO17-1A and GA733 that define two different epitopes on the Ag, has proven a useful target in passive and active immunotherapy of colorectal carcinoma (CRC). Previous studies suggest that the antitumor effects demonstrated in MAb-treated patients may be mediated by idiotypic cascades. In approaches to active immunotherapy against the Ag, polyclonal goat and monoclonal rat anti-idiotypic antibodies (Ab2) directed against MAb CO17-1A or GA733 (Ab1) were administered as alum precipitates to 54 patients with CRC (stage Dukes' B, C, and D). The majority of the patients treated with the various Ab2 preparations developed anti-anti-idiotypic antibodies (Ab3) that specifically bound to the CO17-1A or GA733 epitope and shared idiotopes with the corresponding Ab1. Approximately 30% of the patients tested developed specific cellular immunity, i.e., Ag-specific T-cells mediating delayed-type hypersensitivity (DTH) reaction in vivo or proliferating on stimulation with the Ag in vitro. The humoral and cellular immune responses may underlie the clinical responses observed in some of the treated patients. Recently, the CO17-1A/GA733 Ag has been molecularly cloned and expressed in baculo-, adeno-, and vaccinia viruses. In preclinical studies, these recombinant Ag preparations elicited specific humoral immunity (cytotoxic antibodies) and cellular immunity (DTH-reactive and proliferative T-cells), similar to the native Ag. Antibody titers elicited in experimental animals by recombinant Ag were significantly higher than those elicited by Ab2, presumably because Ag expresses numerous epitopes, whereas Ab2 mimics a single epitope. Recombinant CO17-1A/GA733 Ag has potential as a vaccine for CRC patients.

Animals↗
PubMed1994

Variations in the management and outcome of non-small cell lung cancer in Ontario.

Prospectively gathered information in the Ontario Cancer Foundation's computerized clinical database was analysed to provide a description of the management of 12,399 patients with unresected non-small cell lung cancer (NSCLC) registered at seven regional cancer centres in Ontario between 1982 and 1991. Overall, 44% received initial thoracic radiotherapy, 19% received initial radiotherapy to metastatic sites, and 36% received no immediate radiotherapy. Of those who received thoracic radiation 41% received doses > or = 40 Gy and 59% received doses < 40 Gy. Among the seven centres, the proportion of patients receiving initial thoracic radiotherapy ranged from 41% to 56% (p < 0.001), and the proportion of those receiving doses > or = 40 Gy ranged from 30% to 68% (p < 0.001). Between 1982 and 1991, the overall proportion of patients who received initial thoracic radiotherapy decreased from 48% to 38%, the proportion of those receiving high dose treatment decreased from 55% to 28%, and the mean number of fractions given to the chest decreased from 17 to 10. Only 10% received chemotherapy at any time, and that proportion ranged from 3% to 21% (p < 0.001) among the seven centres. Between 1982 and 1991 the proportion of patients receiving chemotherapy decreased significantly from 15% to 8% (p < 0.001) across the Cancer Foundation as a whole. These wide variations in management policies were not associated with any significant differences in survival, which was similar at all seven centres, and remained constant between 1982 and 1991.

Adenocarcinoma↗
PubMed1994

Utah Growth Study: growth standards and the prevalence of growth hormone deficiency.

Serial measurements of elementary-school children were conducted for 2 consecutive years to assess height and growth velocity and to determine the prevalence of growth hormone deficiency (GHD) in American children. Trained volunteers measured 114,881 children the first year; 79,495 growth rates were calculated after the second measurements. The height and growth velocity curves generated were very similar to the currently used charts. We examined 555 children with short stature (< 3rd percentile) and poor growth rates (< 5 cm/yr). Five percent had an endocrine disorder. The presence of GHD (peak level, < 10 ng/dl with two provocative tests) was found in 16 previously unrecognized children; 17 children from this school population were already known to have GHD. Boys outnumbered girls 2.7:1 (p = 0.006). Six girls with Turner syndrome also were identified. We conclude that (1) the growth curves generated in the 1960s and 1970s are valid for children of the 1990s; (2) most children growing < 5 cm/yr (a commonly used threshold rate) will not have an endocrine disorder; (3) many children (48% in this study) with GHD and others with Turner syndrome may currently be unrecognized and untreated; (4) GHD appears to be more common in boys; and (5) the prevalence of GHD in the United States is at least 1:3480.

Child↗
PubMed1994

Immunomodulatory activity of monoclonal anti-idiotypic antibody to anti-colorectal carcinoma antibody CO17-1A in animals and patients.

Monoclonal anti-idiotypic antibody (Ab2) VF2 was derived from rats immunized with anti-colorectal carcinoma (anti-CRC) monoclonal antibody (Ab1) CO17-1A. In rabbits the Ab2 induced anti anti-idiotypic antibodies (Ab3) that shared idiotopes with the Ab1, bound to the same epitope on CRC cells as Ab1, and bound to the isolated CO17-1A antigen. Monoclonal Ab2 VF2 was superior to the previously described polyclonal goat Ab2 against Ab1 CO17-1A in its capacity to elicit humoral immunity in animals. Ab2 VF2 also induced a specific delayed-type hypersensitivity (DTH) response to challenge with irradiated CO17-1A antigen-positive human CRC cells in mice. Of nine CRC patients immunized with aluminum hydroxide-precipitated Ab2 VF2, six developed antibodies that bound to Ab2, but only three patients developed Ab3 that bound to idiotypic determinants on Ab2. However, the Ab3 did not bind to CO17-1A antigen-positive CRC cells. In contrast, in a previously described trial with polyclonal goat Ab2 to Ab1 CO17-1A, most of the patients developed anti-CRC antibodies. Four of the nine patients immunized with Ab2 VF2 developed DTH responses to intradermal challenge with the Ab2, and in one patient DTH was both Ab2- and antigen-specific. Peripheral blood mononu-clear cells of the four DTH-reactive patients did not proliferate in response to in vitro stimulation with either Ab2 or antigen. These studies demonstrate that the immunomodulatory activity of monoclonal Ab2 VF2 in animals is only in part predictive of its activity in patients.

Animals↗
PubMed1994

Comparative effects of calcipotriol (MC903) solution and placebo (vehicle of MC903) in the treatment of psoriasis of the scalp.

The efficacy and safety of calcipotriol solution in the treatment of scalp psoriasis was compared with placebo (vehicle solution), in a multicentre double-blind, randomized, parallel-group study of 49 adult patients. Calcipotriol solution (50 micrograms/ml), or placebo, was applied twice daily over a 4-week period. At the end of the study period 60% of patients on calcipotriol showed clearance or marked improvement of their psoriasis compared with 17% on placebo. Overall assessment of treatment response showed that calcipotriol was superior to placebo in both investigator (P < 0.001; 95% confidence interval for difference 19.0-67.6) and patient (P < 0.001; 95% confidence interval for difference 18.3-68.0) assessments. Total sign score for psoriasis (i.e. the sum of the scores for redness, thickness and scaliness) decreased by 48.9% in the calcipotriol group, and by 18.6% in the placebo group (P = 0.005). Calcipotriol was significantly superior to placebo in reducing redness, thickness, scaliness and extent of psoriasis, and in the patients' assessment in reducing scalp flaking and itching. No statistically significant changes in blood biochemistry were detected during the study, and the solution was generally well tolerated.

Adult↗
PubMed1994

Stelazine-induced pigmentation.

A case of a West Indian patient is reported who developed abnormal blue-grey pigmentation on exposed areas of skin following treatment with low dose stelazine. Oculocutaneous melanosis is a well-recognized side-effect of prolonged phenothiazine treatment. In this condition the areas of skin exposed to sunlight develop a violaceous, blue-grey or slate-grey colour in more severe cases. These characteristic changes are rarely seen now. We describe the case of a patient who developed pigmentation while taking a low dose of stelazine for 5 years.

Adult↗
PubMed1994

Magnitude-estimation scaling: an effective method for the measurement of the quality of filtered speech.

17 subjects provided magnitude estimations in the form of quality judgments of a filtered speech stimulus which was a nonsense sentence containing all of the consonants of English from Fairbanks. It was presented to subjects at 8 high-pass and 8 low-pass filtering conditions. Consistent magnitude estimations to the filtered stimulus were similar for both conditions. Also, for both conditions, subjects' numerical responses consistently increased in value as stimulus quality was judged to be poorer.

Adult↗
PubMed1994

Lingual vibrotactile magnitude-estimation scaling using a limited set of suprathreshold stimulus intensities.

The purpose of the present study was to assess feasibility of lingual vibrotactile suprathreshold testing with a limited number of intensities. 25 subjects ranging in age from 18 to 26 years (M = 19 yr.) participated. Two magnitude-estimation scaling tasks were presented to each subject with 1 wk. between tasks. One magnitude-estimation task involved eight suprathreshold intensities and the other involved four. Statistical analyses showed that there was no difference in subjects' responses to the two scaling efforts. In pure research endeavors it might make sense to continue to obtain as many magnitude-scaling data points as possible, but practical prudence may dictate a limited set of suprathreshold intensities for efficiency and subjects' comfort.

Adolescent↗
PubMed1994

Persistence of self-renewing leukemia cell progenitors during remission in children with B-precursor acute lymphoblastic leukemia.

No effective therapy is available for the majority of the 30-40% of children with acute lymphoblastic leukemia (ALL) who relapse. Since the morphologically undetectable, or occult, leukemia cells that persist during remission originate from the clone present at diagnosis, may also have both the capability to sustain the disease and to give rise to relapse, we are evaluating a method of identifying them. We have combined, for the first time, an ALL blast colony assay (BCA) and the polymerase chain reaction (PCR) to isolate residual leukemia cells in remission bone marrow aspirate specimens from eight patients with B-precursor ALL during early continuation therapy. We found colony-forming leukemia cells with in vitro self-renewal capability that survived chemotherapy for 15 months after diagnosis in all sequential specimens from these patients. To verify the leukemic nature of these cells their DNA was amplified by PCR and the product directly sequenced. In every case, the VHDJH sequence observed at diagnosis was found. None of the patients relapsed during this early phase of their treatment, consistent with the observation that patients with B-precursor ALL experience recurrence late in their course. Since it is possible that some of these persistent leukemia cells belong to the leukemia progenitor cell population that sustains the disease, the study of them could provide the means to determine the mechanisms of relapse.

Adolescent↗
PubMed1993

Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines.

Because human lymphotoxin (LT) was originally isolated from a lymphoblastoid cell line, we investigated the role of this molecule in three newly established Epstein-Barr virus (EBV)-infected human B cell lines. These lines were derived from acute lymphoblastic leukemia (Z-6), myelodysplastic syndrome (Z-43), and acute myelogenous leukemia (Z-55) patients who had a prior EBV infection. Each lymphoblastoid cell line had a karyotype that was different from that of the original parent leukemic cells, and all expressed B cell, but not T cell or myeloid surface markers. In all three lines, rearranged immunoglobulin heavy chain joining region (JH) bands were found, and the presence of EBV DNA was confirmed by Southern blotting. Z-6, Z-43, and Z-55 cell lines constitutively produced 192, 48, and 78 U/ml LT, respectively, as assessed by a cytotoxicity assay and antibody neutralization. Levels of tumor necrosis factor (TNF) were undetectable. Scatchard analysis revealed that all the cell lines expressed high-affinity TNF/LT receptors with receptor densities of 4197, 1258, and 1209 sites/cell on Z-6, Z-43, and Z-55, respectively. Furthermore, labeled TNF binding could be reversed by both unlabeled TNF, as well as by LT. Studies with p60 and p80 receptor-specific antibodies revealed that the three lines expressed primarily the p80 form of the TNF receptor. When studied in a clonogenic assay, exogenous LT stimulated proliferation of all three cell lines in a dose-dependent fashion at concentrations ranging from 25 to 500 U/ml. Similar results were obtained with [3H]TdR incorporation. Monoclonal anti-LT neutralizing antibodies at concentrations of 25-500 U/ml inhibited cellular multiplication in a dose-dependent manner. It is interesting that in spite of a common receptor, TNF (1,000 U/ml) had no direct effect on Z-55 cell growth, whereas it partially reversed the stimulatory effect of exogenous LT. In addition, TNF inhibited Z-6 and Z-43 cell proliferation, and its suppressive effect was reversed by exogenous LT. Both p80 and p60 forms of soluble TNF receptors suppressed the lymphoblastoid cell line proliferation and their inhibitory effect was partially reversed by LT. Our data suggest that (a) LT is an autocrine growth factor for EBV-transformed lymphoblastoid B cell lines; and (b) anti-LT antibodies, soluble TNF/LT receptors, and TNF itself can suppress the growth of lymphoblastoid cells, probably by modulating or competing with LT.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1993

Identification, classification, and analysis of beta-bulges in proteins.

A beta-bulge is a region of irregularity in a beta-sheet involving two beta-strands. It usually involves two or more residues in the bulged strand opposite to a single residue on the adjacent strand. These irregularities in beta-sheets were identified and classified automatically, extending the definition of beta-bulges given by Richardson et al. (Richardson, J.S., Getzoff, E.D., & Richardson, D.C., 1978, Proc. Natl. Acad. Sci. USA 75, 2574-2578). A set of 182 protein chains (170 proteins) was used, and a total of 362 bulges were extracted. Five types of beta-bulges were found: classic, G1, wide, bent, and special. Their characteristic amino acid preferences were found for most classes of bulges. Basically, bulges occur frequently in proteins; on average there are more than two bulges per protein. In general, beta-bulges produce two main changes in the structure of a beta-sheet: (1) disrupt the normal alternation of side-chain direction; (2) accentuate the twist of the sheet, altering the direction of the surrounding strands.

Amino Acid Sequence↗