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Biomedical subjects

S E Jones

Publications and source records attributed to S E Jones.

At least 109 records · Page 6Linked to original sources
PubMed1994

Substitution of the amino acid at position 102 with polar and aromatic residues influences substrate specificity of lactate dehydrogenase.

The Gln residue at amino acid position 102 of Bacillus stearothermophilus lactate dehydrogenase was replaced with Ser, Thr, Tyr, or Phe to investigate the effect on substrate recognition. The Q102S and Q102T mutant enzymes were found to have a broader range of substrate specificity (measured by kcat/Km) than the wild-type enzyme. However, it is evident that either Ser or Thr at position 102 are of a size able to accommodate a wide variety of substrates in the active site and substrate specificity appears to rely largely on size discrimination in these mutants. The Q102F and Q102Y mutant enzymes have low catalytic efficiency and do not show this relaxed substrate specificity. However, their activities are restored by the presence of an aromatic substrate. All of the enzymes have a very low catalytic efficiency with branched chain aliphatic substrates.

Amino Acid Sequence↗
PubMed1994

Neutralization escape mutants of type A influenza virus are readily selected by antisera from mice immunized with whole virus: a possible mechanism for antigenic drift.

It is not fully understood how antigenic drift of the haemagglutinin of type A influenza virus in man occurs in the presence of the expected polyclonal antibody response to the five antigenic sites, A to E. Here we show that 12% (11/92) of sera from mice which had mounted a secondary immune response to inactivated influenza virus were able to select escape mutants. No escape mutant was selected with serum from nonimmunized mice (0/65). Selection required only a single passage, and escape mutants were identified by their reaction with monoclonal antibodies (MAbs); all but one had altered reactivity at site A. Most of the site A escape mutants (7/10) were conventional in character and did not react in haemagglutination-inhibition (HI) or neutralization assays with the identifying MAb. The HA genes of three of these were part sequenced and had a predicted single amino acid substitution (Gly-144-->Glu) in site A. The other escape mutants (3/10) had a small (2-fold) reduction in HI and neutralization to the site A MAb, but no amino acid substitution in site A. The final mutant was a conventional site B escape mutant. To model antisera which selected escape mutants, we constructed 'pseudo-immune sera' using mixtures of two neutralizing MAbs in which the first MAb was held at a constant high concentration (1000 HIU/ml). Escape mutants could be selected to the first MAb when the titre of the second MAb was reduced to a low but still inhibiting concentration (1 to 3 HIU/ml). Mixtures of three MAbs also selected escape mutants with similar facility provided that the second and third MAbs were reduced to a similar low concentration. Thus it is possible that the ability of an antiserum to select escape mutants is due to the neutralizing antibody response being biased to an epitope/cross-reacting epitopes within a single antigenic site. However, when escape mutants were reacted in HI assay with their selecting antiserum, the maximum difference from the titre with wt virus was 75%. The findings of this study may be relevant to the understanding of antigenic drift in type A human influenza virus, and to immune-driven antigenic variation in other virus infections.

Animals↗
PubMed1994

Assessment of liposomal transfection of ocular tissues in vivo.

A possible route to the treatment of inherited retinal degenerations such as retinitis pigmentosa (RP) is the application of somatic gene therapy by the transfer and expression of corrective functional genes in ocular tissue. Cationic liposomes are established vehicles for the delivery and expression of exogenous genes in mammalian cells both in vitro and in vivo1. We report here a preliminary assessment of liposome-mediated transfer of a plasmid carrying the reporter gene lacZ (encoding the enzyme beta-galactosidase) into tissues of the adult rabbit eye.

Animals↗
PubMed1993

Phase II evaluation of carboplatin and VP-16 for patients with metastatic breast cancer and only one prior chemotherapy regimen.

UNLABELLED: BACKGROUND. New salvage chemotherapy is needed for metastatic breast cancer. Cisplatin and VP-16 have activity but considerable toxicity. METHODS: This study determines the response rate, response duration, and toxicity of a combination chemotherapy regimen of the better-tolerated carboplatin plus VP-16 in a group of patients with metastatic breast cancer and only one prior exposure to cytotoxic chemotherapy. RESULTS: Twenty-three patients received an average of 2.8 courses of treatment before a lack of response or progression of disease was noticed. Four patients had evidence of rapidly progressive disease or early death and received only one course. No complete responses occurred, but three patients (13%) experienced partial responses. Mean response duration was 5 months. Metastatic disease which responded included lung, lymph node, and chest wall sites. Toxicity was mainly myelosuppression with 57% of patients having grade 3-4 neutropenia or thrombocytopenia. Two patients (8%) had significant infection with neutropenia requiring hospitalization but no toxic deaths occurred. CONCLUSIONS: Carboplatin and VP-16 at this dose and schedule was a reasonably well-tolerated regimen with only modest activity in metastatic breast cancer as second-line cytotoxic chemotherapy.

Adult↗
PubMed1993

Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy.

BACKGROUND: Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure. PURPOSE: This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin). METHODS: We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy. RESULTS: The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group. CONCLUSIONS: We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer.

Adult↗
PubMed1993

Efficacy of oral ondansetron in the prevention of emesis in outpatients receiving cyclophosphamide-based chemotherapy. The Ondansetron Study Group.

OBJECTIVE: To evaluate the efficacy and safety of oral ondansetron (Zofran) as an antiemetic in patients receiving cyclophosphamide-based chemotherapy. DESIGN: A multicenter, randomized, double-blind, stratified, placebo-controlled trial conducted between March 1989 and January 1990. SETTING: Twenty-seven oncology centers including university hospitals, community cancer centers, and private medical oncology practices. PATIENTS: A total of 349 chemotherapy-naive patients having their first cycle of cyclophosphamide (> or = 450 mg/m2)-based chemotherapy. Patients also received methotrexate (> or = 30 mg/m2) or doxorubicin (> or = 35 mg/m2). All patients were evaluated for safety and 318 (91%) were evaluated for efficacy. INTERVENTIONS: Patients were randomly assigned to one of four treatment groups: placebo, 1 mg, 4 mg, or 8 mg of ondansetron. Assigned study medication was taken three times per day for 3 consecutive days. MEASUREMENTS: Time and number of emetic episodes as well as degree of nausea were recorded by patients for each of the 3 study days. RESULTS: Compared with placebo, all three doses of ondansetron were superior (P < 0.001) in preventing vomiting and controlling nausea. A complete response (no emetic episodes) was observed in 19%, 57%, 65%, and 66% of patients in the placebo, 1-mg, 4-mg, and 8-mg ondansetron groups, respectively. For patients who received higher-dose cyclophosphamide and doxorubicin, a dose-related trend in antiemetic efficacy of ondansetron was observed. Mild headache and constipation were the most frequently reported adverse events. No extrapyramidal reactions were observed. CONCLUSION: Oral ondansetron is a safe and effective antiemetic that is more efficacious than placebo for patients receiving cyclophosphamide-based chemotherapy.

Administration, Oral↗
PubMed1993

Clinical recognition and management of depression in node negative breast cancer patients treated with tamoxifen.

Depression is not an uncommon complaint of women with breast cancer and is usually assumed to be related to the cancer diagnosis itself or its treatment. As part of a prospective clinical trial of adjuvant therapy of node negative breast cancer, 301 patients treated and assessed by one oncologist (SEJ) were serially questioned for symptoms of depression in the first 6-12 months after completing initial treatment (surgery, radiation therapy, and/or chemotherapy). Two hundred and fifty-seven patients were evaluable for assessment of depression; 155 were receiving tamoxifen and 102 were not. Twenty-six patients had symptoms of depression including 23 (15%) treated with tamoxifen compared to 3 (3%) in the group not placed on tamoxifen (p < 0.005). Of the 23 patients with depression in the tamoxifen group, symptoms were temporally related to the initiation of therapy and occurred generally in the first 2 months of treatment. Eight patients had mild symptoms not requiring a dose reduction, 8 had significant depression requiring a dose reduction to relieve symptoms, and 7 required discontinuation of tamoxifen. We conclude that clinical depression as a side effect of tamoxifen therapy may be more common than previously believed and should be further rigorously investigated to confirm or deny our clinical impressions.

Adult↗
PubMed1993

Expression of mRNA for interleukin 6 by cells infiltrating epiretinal membranes in proliferative vitreoretinopathy.

We have investigated the expression of mRNA for interleukin 6 (IL-6) in cells infiltrating 12 epiretinal membranes, and the presence of biologically active IL-6 in vitreous humour available from five corresponding eyes. The results showed that nine of the 12 membranes (75%) contained cells expressing mRNA for this cytokine. Although in two of the specimens pigmented cells were identified as some of the cells expressing mRNA for IL-6, we did not identify the nature of IL-6 mRNA-producing cells infiltrating the membranes. Interestingly, two vitreous samples from eyes whose membranes did not contain cells with mRNA for IL-6 exhibited significant concentrations of IL-6 (315 and 28 micrograms/ml). Parallel study of mRNA for IL-6 in PVR biopsies and of IL-6 levels in corresponding vitreous may indicate how cytokine-mediated pathways of inflammation are involved in the pathogenesis of epiretinal membrane formation.

Base Sequence↗
PubMed1993

The effects of age on immune responses in the antigen-instilled dog lung. Antibody responses in the lung and lymphoid tissues following primary and secondary antigen instillation.

To evaluate the effects of age on immunity induced by lung immunization, 11 aged (12-17 years; median age = 14) and 12 young (2-5 years) male Beagle dogs were instilled with 10 mg of keyhole limpet hemocyanin (KLH) in the right cardiac lung lobe and 10(10) sheep red blood cells (SRBC) in the left cardiac lung lobe. Five aged and six young dogs were sacrificed at day 9 after primary antigen instillation. The remainder were given challenge antigen instillations of KLH and SRBC at day 21 and sacrificed 7 days later. Serum, bronchoalveolar lavage fluid and lung tissue from immunized and control lobes, tracheobronchial, mesenteric and popliteal lymph nodes, spleen, and blood were taken at sacrifice. Anti-KLH IgA, IgG and IgM antibody production by cells in lung tissue and lavage fluid from the KLH-exposed lobe was lower at primary immunization and challenge in aged than young dogs. Lavage fluid IgA and IgG levels from the KLH exposed lobe at primary immunization and challenge were lower in aged versus young dogs, while IgM levels were lower only after primary immunization. Localized lung immune memory responses were also markedly lower in aged dogs when compared with young dogs. Anti-SRBC responses were similar to the anti-KLH responses. Our data show that systemic immune responses are significantly lower in aged dogs following primary antigen instillation, but not after antigen challenge in the lung. This was not the case for localized lung immune responses, which were significantly lower in aged dogs even following antigen challenge. The data also show that antibody production by lavage cells is a good index of interstitial lung cell antibody production.

Aging↗
PubMed1993

Abnormal distribution of retinal clusterin in retinitis pigmentosa.

Increased expression of clusterin mRNA is associated with neurodegenerative states, including retinas affected by retinitis pigmentosa (RP). We have investigated the distribution of immunoreactive clusterin in normal and RP-affected retinas. Reactivity at the inner limiting membrane, plexiform layers, and photoreceptors in normal retina accords well with clusterin's postulated role as a membrane protective agent. In RP-affected retina the organized distribution is lost and overall reactivity appears decreased. The changes in this case may reflect increased turnover or removal of clusterin, perhaps via interaction with components of the immune system.

Adult↗
PubMed1993

Comparison of clusterin gene expression in normal and dystrophic human retinas.

To gain insight into the mechanisms underlying altered clusterin expression in retinal degeneration, the cellular distribution of clusterin mRNA in normal and in retinitis pigmentosa-affected retinas was compared using in situ hybridization. In contrast to the normal retina, where clusterin mRNA is localized in the inner nuclear and ganglion cell layers, a clustered distribution is observed throughout the dystrophic retina. The results indicate an expression of clusterin gene in normal retinal neurons and suggest that its altered regulation in neurodegeneration is not purely a glial cell phenomenon.

Adult↗
PubMed1993

Long-term antibody production after lung immunization and challenge: role of lung and lymphoid tissues.

After localized lung immunization and challenge, antigen-specific antibody continues to be produced in the immunized lung lobes of dogs for years after the last antigen exposure. Lavage fluid from immunized lung lobes contains significantly more antigen-specific antibody than lavage fluid from control lung lobes, and only cells from lung lobes exposed to antigen produce antibody. Although cells lavaged from the lung produce antibody, it is possible that cells in the lung interstitium or lymphoid tissues may be more important in long-term antibody production after lung immunization and challenge. The goal of this study was to compare the levels of antibody production by cells from dogs 2 yr after pulmonary immunization and challenge. Cells were evaluated from lung lavage, lung tissue, tracheobronchial lymph nodes, and distant lymphoid tissues. The results showed that cells lavaged from lung lobes immunized and challenged with sheep red blood cells (SRBC) were producing anti-SRBC IgG antibody 2 yr after the last antigen challenge. However, cells obtained by mincing tissues from immunized lung lobes were producing significantly higher levels of antibody than lavage cells. In contrast, lavage or tissue cells obtained from the control lobes did not produce detectable antibody. Only a low level of anti-SRBC IgG was produced by cells from the tracheobronchial lymph nodes, and minimal antibody was produced by cells from blood, spleen, or mesenteric and popliteal lymph nodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Analysis of differentially expressed genes in retinitis pigmentosa retinas. Altered expression of clusterin mRNA.

The molecular and cellular processes underlying photoreceptor degeneration in retinitis pigmentosa (RP) are unknown. We have investigated gene expression in diseased retinas using differential hybridization screening of a retinal cDNA library with probes derived from normal and RP retinal RNA. Most differential clones detected corresponded to transcripts absent from the dystrophic state, including e.g. opsin. However, one clone was noticeably increased in RP in comparison with the control: partial sequencing showed it encoded clusterin. Increased expression of clusterin has been identified in several cases of tissues undergoing apoptosis (programmed cell death), and our finding suggests that the degenerative changes in advanced RP may represent another example of apoptosis, possibly with common causative mechanisms.

Adult↗
PubMed1992

A phase II study of piritrexim in patients with advanced squamous head and neck cancer.

Piritrexim (PTX) is a newly developed lipid-soluble folate antagonist that crosses the cell membrane by a simple, rapid, carrier-independent diffusion process. A Phase II study was conducted to evaluate the activity of PTX in 34 patients with previously chemotherapy-naive squamous cell cancer of the head and neck area (SCCHN). Among them, 30 patients had received previous radiation therapy and/or surgery. Of 33 patients who could be examined, 3 had a complete response (CR), 6 had a partial response (PR), 11 had no change, and 13 had disease progression. The overall response rate (CR + PR) was 27% (9 of 33; 95% confidence interval, 13% to 46%). The response duration ranged from 36 to 360 + days (median, 162) and was similar to the best studies reported with methotrexate. The three most severe side effects (Grades 3 and 4 by World Health Organization criteria) were leukopenia, thrombocytopenia, and mucositis. These occurred in 41%, 26%, and 15% of the 34 patients, respectively. This study established PTX as an agent with some activity in SCCHN. The use of PTX in combination chemotherapeutic regimens needs to be explored.

Adult↗
PubMed1992

Using decision analysis to calculate the optimum treatment for microinvasive cervical cancer.

Decision theory was used to calculate the optimum treatment of microscopic squamous cervical cancer using probabilities obtained from an exhaustive literature review and a range of plausible value estimates. This showed that if there is no vascular involvement, survival is maximised by conservative treatment if tumour invasion is less than 3 mm while treatment by radical surgery results in maximal survival rates if the tumour invasion is over 3 mm. Radical surgery also maximises survival for smaller lesions where lymph channel involvement is present, especially if a surgical mortality at the lower end of the reported range is assumed. Refinement of our analysis to include an assessment of patient values showed that these conclusions are still valid regardless of the patient's relative preference for death from surgery or death from cancer. However, the wish to preserve fertility sharply reduces the overall net benefit of surgery. Conservative treatment becomes the preferred option for all microinvasive lesions even for patients who are prepared to trade-off a small (e.g. 2%) risk of death in order to retain their fertility.

Adult↗