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Biomedical subjects

J E Harris

Publications and source records attributed to J E Harris.

At least 127 records · Page 7Linked to original sources
PubMed1987

Modification of the effects of cytotoxic chemotherapy on the immune responses of cancer patients with a nonsteroidal, antiinflammatory drug, piroxicam. A pilot study of the Eastern Cooperative Oncology Group.

We have attempted to modify the manner in which chemotherapy influences immune function in lung cancer patients by adding the nonsteroidal, antiinflammatory drug (NSAID) piroxicam to a cytotoxic drug treatment regimen. Eighteen previously untreated patients with lung cancer received cytotoxic chemotherapy with mitomycin-C (10 mg/m2), vinblastine (6 mg/m2), and cis-platinum (40 mg/m2) (MVP) on day 1 of a 21-day treatment cycle; 12/18 patients also received piroxicam (20 mg/day) beginning 10 days prior to MVP and persisting throughout the 21-day treatment cycle. In vitro tests included (a) phytohemagglutinin (PHA) responsiveness in the presence of indomethacin or interleukin-2 (IL-2), (b) natural killer cell (NK) function, and (c) PHA-induced IL-2 synthesis. In the 6 patients treated with MVP alone, depressed PHA reactivity was found pretherapy, which was augmented by indomethacin, but not by IL-2; this was associated with impaired production of IL-2. By days 7-14, PHA reactivity, IL-2 responsiveness, and IL-2 production rebounded to normal. By days 14-21, PHA reactivity had declined once again in association with increased indomethacin-regulation and impaired IL-2 responsiveness and production. In the 12 patients who received MVP plus piroxicam, PHA and IL-2 assays improved by days 7-14 and indomethacin-regulation was normal; moreover, this improvement persisted throughout the 21-day treatment cycle. Immunological rebound persisted through as many as 3 consecutive 21-day MVP plus piroxicam treatment cycles in patients who were continuously monitored. In contrast to these results, piroxicam did not alter the way chemotherapy affected NK function. These results demonstrate that the immunomodulatory effects of cytotoxic chemotherapy can be modified or ameliorated by adding an NSAID to the cytotoxic drug treatment regimen; for certain functions, such as mitogen-stimulated blastogenesis or IL-2 production, sustained immunological rebound without immunosuppression can be achieved by this maneuver.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1987

Modulation of immune function in cancer patients.

This paper will focus on three aspects of work which we have conducted in our laboratory over the past several years. Firstly, it will present results of studies in which we have found a selective inhibition of suppressor cell function in solid tumor cancer patients treated with cytotoxic drugs. Secondly, it will show that this selective inhibition results in an augmentation of other forms of immune reactivity and, in particular, an enhanced interleukin-2 production and response to this. Finally, it will demonstrate how we have made use of that information to intervene pharmacologically to modulate the immunosuppression which usually follows the use of cytotoxic drugs in solid tumor cancer patients.

Antineoplastic Agents↗
PubMed1987

High-dose lymphoblastoid interferon in advanced renal cell carcinoma: an Eastern Cooperative Oncology Group Study.

This report describes a phase II Eastern Cooperative Oncology Group (ECOG) study of high-dose lymphoblastoid interferon (IFN alpha-n1) in 39 patients with measurable, advanced renal cell carcinoma. The original treatment plan was 30 X 10(6) units/m2 (30 mU) of IFN alpha-n1 im daily X 10 days; treatments were repeated every 21 days. This dose and schedule proved intolerable, with none of seven patients able to complete greater than 10 days of therapy because of fever, lassitude, hepatic dysfunction, and myelosuppression. Patients were subsequently treated with the following regimen: 3 mU/m2 on Day 1; 5 mU/m2 on Day 2; 10 mU/m2 on Day 3; and 20 mU/m2 on Days 4-10. Thirty-three new patients received this regimen and two patients received this schedule after having received 30 mU/m2. Using this second regimen, 30% of the patients were able to complete two cycles of treatment without dose reduction or interruption. Five patients (13%) had partial response (ECOG criteria) of measurable tumor. Median time to response was 140 days. Responses were documented in lung metastases in four patients and in a pelvic soft tissue mass in the fifth. Response rates and survival times are similar to those seen in prior ECOG phase II trials in advanced renal cell carcinoma. Eight of 39 patients are still alive greater than 2 years after beginning therapy. Only two of these patients had had an objective response, however. Such prolonged survival is more frequent than has been seen in previous ECOG studies. The relative contribution of patient selection and interferon therapy to this survival is uncertain.

Aged↗
PubMed1986

Abnormal monocyte function in patients with Kaposi's sarcoma.

Monocyte-mediated functions were evaluated in the peripheral blood mononuclear cells (PBMC) of 11 previously untreated patients with Kaposi's sarcoma in association with the acquired immune deficiency syndrome (KS/AIDS). All patients had lymphadenopathy, an abnormal OKT.4/OKT.8 ratio, and a good performance status; none had clinically apparent infections at the time of testing. Monocyte functional assessments included immunoregulatory activity in phytohemagglutinin-stimulated (PHA) lymphoblastogenesis assays, natural killer (NK) assays, Interleukin 2 (IL2) production assays and, quantitation of opsonized zymosan-induced chemiluminescence responses. A group of seven hemophilia patients who had been receiving concentrated blood products and who presented with evidence of an abnormal OKT.4/OKT.8 ratio were also investigated as controls. As a group, the patients with KS/AIDS had a significantly depressed response to PHA compared with normal control subjects and patients with hemophilia; this was significantly elevated by indomethacin or by the removal of glass adherent cells. PBMC from KS/AIDS patients also had an impaired ability to produce IL2 in PHA-stimulated cultures which was enhanced by the addition of indomethacin. NK function was also suppressed in both groups of patients, but could not be augmented by the removal of glass adherent monocytes. Chemiluminescence responses to opsonized zymosan were variable, but found to be significantly different from normal in the majority of patients studied. These results demonstrate that monocyte function can be abnormal in patients with KS/AIDS and might contribute to some of the immunologic impairment seen in these patients.

Acquired Immunodeficiency Syndrome↗
PubMed1986

Effect of chemotherapy on NK function in the peripheral blood of cancer patients.

The effects of cytotoxic chemotherapy on NK cell function and on glass adherent cell regulation of NK cell function was evaluated in the peripheral blood mononuclear cells of 20 previously untreated solid tumor patients. Most of the patients studied had lung cancer and received one of four combination chemotherapy treatment regimens. In addition, one patient with colon carcinoma and one patient with melanoma were studied, each of whom received treatment with a single agent. The results demonstrated that chemotherapy exerted a differential influence on NK activity which correlated with the pretreatment NK level of function in the individual patient. In patients with depressed NK levels prior to treatment, chemotherapy augmented NK function; in patients with normal levels prior to treatment, chemotherapy depressed NK function. The effects observed appeared to be associated with the capacity of chemotherapy to influence glass adherent cell regulation of NK activity. There was no apparent correlation between the effects of chemotherapy on numbers of NK effector cells, Leu11+ cells, or latex-ingesting cells. Also, there was no correlation between the effects seen and the type of drug treatment that was administered; rather, this was dependent on the pretreatment NK level of function which in turn was associated with glass adherent cell regulation of NK function.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1986

Modulation of lymphocyte responsiveness to phytohemagglutinin by micromolecular fibrinogen degradation products.

The ability of fibrinogen degradation products (FDP) to influence the regulatory function of adherent cells from peripheral blood mononuclear cells (PBMC) was evaluated. FDP were prepared by digestion of fibrin clots with plasmin. These FDP were incubated overnight with glass-adherent cells following which these treated and untreated cells were cocultivated with fresh autologous responder PBMC in the presence of the T-cell mitogen, phytohemagglutinin (PHA). Lipid metabolism of FDP-treated monocytes was evaluated in cells that had been prelabeled with [3H]arachidonic acid (AA) prior to their overnight incubation with FDP; supernatants were analyzed for conversion of AA to cyclooxygenase and lipoxygenase products by thin-layer chromatography. Treatment of glass-adherent cells with the FDP digests converted these monocytes into suppressor cells. The suppression exerted by these cells in the PHA assay was dose dependent. The suppression exerted by FDP-pretreated monocytes was reversed by treating the PHA-stimulated cocultures with indomethacin and was associated with increased cyclooxygenase activity. These studies demonstrated that FDP can alter T-cell immune function through the induction of monocyte suppressor cells; the means by which that occurs is associated with stimulation of lipid metabolism and secretion of eicosanoids with immunoregulatory capacity.

Arachidonic Acids↗
PubMed1986

Ontogeny of gut-associated lymphoid tissue (GALT) in the dogfish Scyliorhinus canicula L.

Cartilaginous fish occupy a fundamental position in vertebrate phylogeny and it is likely that this group has retained some of the ancestral immune mechanisms. The ontogeny of GALT has received little attention in elasmobranchs and this study correlates this development with morphological differentiation, development of other lymphoid organs, exposure to seawater and transition from yolk dependence to exogenous food as a source of nutrient. GALT was first represented by individual lymphocyte-like and macrophage-like cells in the lamina propria. In later stages accumulations and intraepithelial leucocytes were recorded prior to hatching. The size of accumulations and the number of lymphocyte and macrophage-like cells infiltrating the lamina propria and epithelium increased in fish as they became dependent upon an exogenous diet. Although GALT developed after the thymus and lymphoid-like tissue in the kidney and at approximately the same time as the epigonal, Leydig and spleen, the source of cells populating the gut is unknown. Plasma cells and granulocytes were not observed in the developing fish until 6 months post-hatch after which the fish had a similar GALT distribution and content to the adult fish.

Animals↗
PubMed1986

Subjective memory assessment and test performance in elderly adults.

The everyday memory of a group of elderly adults was assessed using techniques developed for use with younger head-injured people (Sunderland et al., 1983). The participants completed a memory questionnaire and a daily checklist; their spouses gave their assessment using a separate questionnaire. These subjective methods showed only moderate agreement, and the questionnaire had low test-retest reliability. It appears that these methods of subjective memory assessment have little validity when used with normal elderly adults. Two positive findings did emerge: As in previous studies, a story recall test was the strongest predictor of reported memory performance; and despite a universal belief among elderly adults that their memory had deteriorated with age, very few of them felt that they were at all handicapped by forgetfulness in everyday life.

Aged↗
PubMed1986

dam methylation in the archaebacteria.

The DNA of certain species of halophilic and methanogenic archaebacteria is dam methylated, as shown by restriction endonuclease sensitivities. The Dam+ phenotype appears to be confined to particular taxonomic groupings defined by DNA:rRNA hybridization or 16S RNA oligonucleotide cataloguing.

Archaea↗
PubMed1986

Properties of in vitro recombinant derivatives of pJV1, a multi-copy plasmid from Streptomyces phaeochromogenes.

The 10.8 kb plasmid pJV1, isolated from Streptomyces phaeochromogenes, has a high copy number (about 150) and a broad host range among Streptomyces spp. Several pJV1 derivatives carrying the thiostrepton resistance gene (tsr) of S. azureus were made. One derivative, pWOR191, was shown to promote its own transfer and to mobilize chromosomal markers in S. lividans. Another derivative, pWOR109, was non-transmissible. Deletion in vitro of a segment of pWOR109 gave pWOR120 (5.6 kb), which has single BamHI and Bg/II sites shown to be capable of accepting 'foreign' DNA such as a previously cloned S. antibioticus DNA fragment encoding tyrosinase, giving vectors (pWOR125, pWOR126) with properties resembling the well-established multicopy vector pIJ702. Shuttle vectors capable of functioning in both S. lividans and Escherichia coli were also constructed. The region of pJV1 essential for replication and maintenance was localized to a 2.5 kb segment. Stable maintenance of pWOR109 and pWOR120 was observed in the presence of derivatives of pIJ101, the progenitor of pIJ702.

Chromosomes, Bacterial↗
PubMed1986

Modulation of cellular immune responses in mice with disseminated histoplasmosis by recombinant interleukin-2.

Depression of the cellular immune responses in mice with disseminated histoplasmosis is associated with deficient production of interleukin-2 (IL-2) by splenocytes. Therefore, we examined whether a highly purified preparation of IL-2, recombinant human IL-2 (rIL-2), could modify the cellular immune responses in infected mice and whether this lymphokine could alter the severity of histoplasmosis in animals. Exogenous rIL-2, at concentrations of up to 1,000 U/ml, failed to augment the proliferative responses to concanavalin A by unfractionated splenocytes or splenic T cells from mice infected for 1 week. In addition, rIL-2 did not modulate the plaque-forming cell response to sheep erythrocytes by splenocytes from these same mice. However, at week 3, rIL-2 in concentrations ranging from 10 to 1,000 U/ml considerably augmented the proliferative response to concanavalin A and plaque-forming cell response to sheep erythrocytes by splenocytes from infected mice. Kinetics studies demonstrated that rIL-2 exerted maximal immunoregulatory activity when added on day 0 or 1 to cultures of splenocytes. In vivo administration of rIL-2, 200 to 20,000 U/day, for 10 days to normal and 3-week-infected mice did not alter the proliferative activity of splenocytes to concanavalin A; 200,000 U of rIL-2 per day actually depressed the proliferative responses of splenocytes from normal and infected mice. In vivo, rIL-2 did not modify delayed-type hypersensitivity responses to sheep erythrocytes or to histoplasmin by normal and infected mice. Moreover, treatment with rIL-2 in vivo did not reduce the number of Histoplasma CFU in spleens of mice. Thus, despite the immunoenhancing effect of rIL-2 in vitro, this lymphokine failed to exert similar effects in vivo.

Animals↗
PubMed1986

The mind-body problem from a medical perspective.

Classical philosophical ideas on the mind-body problem were interpreted in the light of contemporary theories. There are two mind-body theories that are suspect for a natural scientist, namely, parallelism and panpsychism. There are three further theories that are considered radical and not supported by current research: epiphenomenalism, central-state materialism and behaviorism. That leaves us with the two most prevalent theories, namely, interactionism and neural identity. The authors discuss the evidence for and against each theory.

Humans↗
PubMed1986

Tamoxifen versus placebo: double-blind adjuvant trial in elderly women with stage II breast cancer.

One hundred eighty-one elderly women with stage II breast cancer were prospectively randomized to receive tamoxifen or placebo for 24 months in a double-blind adjuvant trial conducted by the Eastern Cooperative Oncology Group. They were stratified prior to randomization on the basis of the number of positive axillary nodes and the estrogen receptor status of their primary tumor. One hundred seventy were considered eligible and analyzed in this trial. The median age was 71 years with a range from 65 to 84 years. Twenty-one percent of the patients were over the age of 75 and 33% were between 71 and 75 years. Estrogen receptor status was positive in 85% of the patients and unknown in another 12%. Progesterone receptor status was positive in 35%, negative in 16%, and unknown in 49%. With a median follow-up of 55 months, the overall percent disease free at 4 years is 73 for the tamoxifen arm and 52 for the placebo arm (P = .003). Significant benefit is seen following tamoxifen in the subsets with 4-10 positive axillary lymph nodes, those who were estrogen receptor positive, or progesterone receptor unknown, and those who had a tumor size less than 3 cm. Most other subsets benefited as well. There were more distant (29 vs. 13) and bone only (15 vs. 3) sites of first recurrence in the placebo arm, whereas locoregional recurrences were similar (8 each). The recorded toxicity was similar, except for more hot flashes observed among women in the tamoxifen arm.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1985

Three-dimensional architecture of the cell sheath and septa of Methanospirillum hungatei.

The methanogenic bacterium Methanospirillum hungatei exists as filaments which have a very unusual cell wall architecture, comprising a long cylindrical sheath within which there may be many individual cells arranged in a line. The sheath has a two-dimensional crystalline structure, and the cells are separated within the tube by septa which also have a crystalline structure. We have used computer image processing of tilted-view electron micrographs to analyze the structure in negative stains of both of these components in three dimensions. The repeating unit of the sheath consists of four approximately spherical domains ca. 2.5 nm in diameter arranged in a row. Based on observations of the type of lattice imperfections that occur, we suggest that each of the domains represents a separate polypeptide subunit and that the subunits are incorporated into the wall one by one. The septa are circular plates of remarkably constant size. They are normally found as double layers. They are hexagonally symmetrical and consist of trimerically associated subunits which interact about dimer axes to form an open network containing large pores ca. 15 nm in diameter.

Cell Division↗