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Biomedical subjects

J Bishop

Publications and source records attributed to J Bishop.

At least 73 records · Page 4Linked to original sources
PubMed1996

Aneuploid epididymal sperm detected in chromosomally normal and Robertsonian translocation-bearing mice using a new three-chromosome FISH method.

We present a new method to detect epididymal sperm aneuploidy (ESA) in mice using simultaneous fluorescence in situ hybridization (FISH) with DNA probes specific for mouse chromosomes X, Y and 8. The method was applied to Robertsonian (Rb) translocation (8.14) heterozygotes and homozygotes as well as the chromosomally normal B6C3F1. The sex ratios of sperm did not differ from the expected 1:1 and the hybridization efficiencies were approximately 99.7% for over 60 000 sperm analyzed. Mice heterozygous for Rb (8.14) produced about tenfold higher rates of sperm with chromosome 8 hyperhaploidy than did Rb (8.14) homozygotes or chromosomally normal mice, while frequencies of sperm with hyperhaploidies for chromosomes X and Y were unaffected in all three lines of mice. Hyperhaploid frequencies obtained with the ESA method were consistent with those of the previous testicular FISH method and were validated by published data obtained by conventional cytogenetic analyses (meiotic metaphase II and first cleavage). Thus, the mouse three-chromosome ESA assay together with the previously developed aneuploidy assay for human sperm constitute a promising pair of interspecific biomarkers for comparative studies of the genetic and physiologic mechanisms of the induction and persistence of aneuploidy in male germ cells.

Aneuploidy↗
PubMed1996

Abnormal colonic accumulation of fluorine-18-FDG in pseudomembranous colitis.

A 51-yr-old man with a history of pancreatic carcinoma was studied with [18F]fluorodeoxyglucose ([18F]FDG) and PET as part of staging for residual disease after chemotherapy. The PET study was performed during a clostridium difficile-associated diarrheal illness. Striking [18F]FDG uptake was demonstrated in the wall of the colon over its entire length. Clostridium difficile associated diarrhea and mechanisms of [18F]FDG uptake in normal and abnormal tissues are briefly reviewed and a mechanism for FDG uptake in this patient is postulated.

Colon↗
PubMed1995

Decision logic for retreatment of asymptomatic lung cancer recurrence based on positron emission tomography findings.

PURPOSE: The purpose of the study was to determine if Positron emission tomography (PET) 2-[F-18] fluoro-2-deoxy-D-glucose (FDG) imaging could detect subclinical local lung cancer recurrence and whether retreatment of such recurrence was feasible and beneficial. METHODS AND MATERIALS: Twenty patients with biopsy proven lung cancer were studied with Positron emission tomography for the purpose of detecting subclinical lung cancer recurrence over a period of 4.25 years. All patients were treated with external radiation as part or all of their therapy. Twenty patients had baseline PET and computed tomography (CT) studies for comparison with later studies. Surviving patients had a total of 40 sequential PET scans and 35 CT scans. The follow-up interval ranged from 5 to 40 months posttreatment. The differential uptake ratio (DUR) was determined for regions of interest of increased FDG uptake. RESULTS: The median DUR value of the 20 baseline PET studies was 5.59. The DUR value of greater than 3 was empirically selected as being positive for tumor detection. On baseline studies, PET had a 100% correlation with the CT findings in regard to detection of the site of primary tumor involvement. Four of 20 patients showed areas of discordance in the mediastinal and hilar areas on initial PET and CT studies. Seven of 17 patients showed discordant posttreatment PET-CT findings. Two false positive PET studies were due to radiation pneumonitis and one to macrophage glycolysis in tumor necrosis. For detection of asymptomatic tumor recurrence, analysis of sequential PET and CT studies, biopsy results, and the patient's clinical course suggested that PET had a sensitivity of 100%, specificity of 89.3%, and accuracy of 92.5%. Computerized Tomography was found to have a sensitivity of 67%, specificity of 85%, and accuracy of 82% for detection of such early-stage recurrence. Five patients went on to have retreatment with external irradiation based upon the PET evidence. Four retreated patients had biopsies that corroborated the positive PET findings, and one patient was retreated on the basis of the qualitative appearance of the posttreatment PET study. Two of the five retreated patients remain alive without evidence of tumor to 34 months following initial therapy. CONCLUSION: Positron emission tomography scanning appears to be effective in detecting and following the progression of recurrent lung cancer. Retreatment of patients with asymptomatic recurrent tumor has resulted in absent or decreased FDG activity. Monitoring of patients with PET may provide prolonged survival in patients who otherwise would fail treatment because of local tumor recurrence.

Adenocarcinoma↗
PubMed1995

The immunogenicity of MUC1 peptides and fusion protein.

Mucin 1 (MUC1) is highly expressed in breast cancer, has an ubiquitous distribution and, due to altered glycosylation, peptides within the VNTR are exposed. These peptides are the target for anti-MUC1 antibodies, which give a differential reaction on cancer compared with normal tissue. The amino acids, APDTR or adjacent amino acids, are highly immunogenic in mice for antibody production (after immunisation with either breast cancer cells, human milk fat globule (HMFG) or the VNTR peptide). In addition, human studies show that this region of the MUC1 VNTR functions as target epitopes for cytotoxic T cells. We have performed preclinical and clinical studies to examine the immune responses to MUC1 in mice and humans: (a) MUC1+ 3T3 or P815+ 3T3 cells in syngeneic mice are rejected, with the generation of both cytotoxic T lymphocyte (CTL) and DTH responses and a weak antibody response and a weak antibody responses; this type of immunity gives rise to total resistance to re-challenge with high doses of these tumors; (b) immunisation with peptides (VNTR x 2), a fusion protein (VNTR x 5), or HMFG leads to no CTLs, DTH, good antibody production and weak tumour protection (to 10(6) cells, but not 5 x 10(6) cells) (possibly a TH2 type response); (c) immunisation with mannan-fusion protein (MFP) gives rise to good protection (resistance to 50 x 10(6) cells), CTL and DTH responses and weak antibody responses (possibly a TH1 type response, similar in magnitude to that obtained after tumor rejection); (d) established tumors can be rapidly rejected by delayed treatment of MFP; (e) the CTL responses are MHC restricted (in contrast to the human studies); (f) APDTR appears not to be the T cell reactive epitope in mice. On the basis of these findings, two clinical trials are in progress: (a) VNTR x 2 (diphtheria toxoid) which gives rise to some T cell proliferation, DTH and antibody responses in some patients and (b) an MFP trial. The ability to alter the immune response towards cellular immunity with mannan or to humoral immunity with peptides, allows the immune response to be selectively manipulated.

Animals↗
PubMed1995

A phase III study of accelerated radiotherapy with and without carboplatin in nonsmall cell lung cancer: an interim toxicity analysis of the first 100 patients.

PURPOSE: In 1989 we initiated a multicenter randomized trial to determine if accelerated radiotherapy with or without concurrent carboplatin improves local control and survival in patients with limited nonsmall cell lung cancer. This interim analysis was performed on the first 100 patients to determine whether the toxicity of the four treatment arms is acceptable. METHODS AND MATERIALS: One hundred patients with limited nonsmall cell lung cancer have been randomized to receive one of four treatments: arm I, radiotherapy 60 Gray (Gy) in 30 fractions in 6 weeks; arm II, accelerated radiotherapy 60 Gy in 30 fractions in 3 weeks; arm III, radiotherapy as in arm I plus carboplatin 350 mg/m2 during weeks 1 and 5 of radiotherapy; arm IV, radiotherapy as in arm II plus carboplatin 350 mg/m2 during week 1. Survival was measured for the group as a whole and treatment-related toxicities in the four arms were compared. RESULTS: The estimated median survival for all 100 patients was 17.1 months with 33% estimated survival at 2 years. The major toxicities were hematologic and esophageal. Patients receiving carboplatin had more neutropenia (p < 0.0001) and thrombocytopenia (p = 0.002) than patients receiving radiotherapy alone, and this was most marked in patients on arm III. Both carboplatin and accelerated radiotherapy separately caused more severe esophagitis when compared to conventional radiotherapy alone (p = 0.011 and p = 0.0017, respectively). Esophagitis was more prolonged in patients having accelerated radiotherapy (p < 0.0001, median duration 3.2 months compared with 1.4 months for patients receiving conventional fractionation). Six patients (23%) treated on arm II have required dilatation of esophageal stricture, one dying with a laryngo-esophageal fistula. CONCLUSION: In patients receiving radiotherapy for unresectable lung cancer, overall treatment time can be halved and carboplatin administered concurrently with increased but acceptable esophageal and hematologic toxicity.

Adult↗
PubMed1995

Aneuploidy in late-step spermatids of mice detected by two-chromosome fluorescence in situ hybridization.

A multicolor procedure employing fluorescence in situ hybridization is described for detecting chromosomal domains and germinal aneuploidy in late-step spermatids in mice using DNA probes specific for repetitive sequences near the centromeres of chromosomes 8 and X. These probes were nick-translated with biotin- or digoxigenin-labeled nucleotides, and were detected with FITC or rhodamine. Probe and hybridization specificities were confirmed using metaphase chromosomes from spleen and bone marrow cells as well as from primary and secondary spermatocytes. Late-step spermatids, identified in testicular preparations by their hooked shape, yielded compact fluorescence domains in approximately 50% and > 99% of cells when hybridized with probes for chromosomes X and 8, respectively. In a survey of > 80,000 late-step spermatids from 8 healthy young adult C57BL/6 or B6C3F1 mice, approximately 3/10,000 spermatids had fluorescence phenotypes indicative of X-X or 8-8 hyperhaploidy. These frequencies are consistent with published frequencies of aneuploidy in meiotic metaphase II and first cleavage metaphases of the mouse, providing preliminary validation of sperm hybridization for the detection of aneuploidy. No significant animal or strain differences were observed. In addition, the hyperhaploidy frequencies for murine spermatids were indistinguishable for those for sperm from healthy men obtained by a similar hybridization procedure. These procedures for detecting aneuploid male gametes are examples of "bridging biomarkers" between human and animal studies. They have promising applications for investigations of the genetic, reproductive, and toxicological factors leading to abnormal reproductive outcomes of paternal origin.

Aneuploidy↗
PubMed1995

Shave excision of benign papular naevocytic naevi.

Patients frequently request removal of benign papular naevi for cosmetic or functional reasons. Shave excision plus electrocautery is probably the most widely used method of removal, but this method is said to result in retained hair or pigment if deeply pigmented or hairy naevi are treated. In a prospective study, 82 benign papular naevi of all types were treated by shave excision using hot-wire electrocautery for haemostasis. Details of the naevi were accurately recorded before treatment and reassessment of shave sites carried out at 6-8 months. At review, a scar was visible at only 63% (52/82) of shave sites and all of these were cosmetically acceptable. Only 27% (15/55) of the initially pigmented naevi retained pigment and only 24% (5/21) of the initially hairy naevi regrew hair. Shave excision and electrocautery of benign naevi, including hairy and deeply pigmented ones, produce excellent cosmetic results. The patient must be warned that there is a potential risk of a scar or pigment remaining after shave excision of any naevus and for hair regrowth after shave excision of hairy naevi.

Adolescent↗
PubMed1995

Estradiol enhances brain glucose uptake in ovariectomized rats.

This study was designed to investigate the effects of 17 beta-estradiol benzoate (E2B) on brain glucose uptake and transport across the blood-brain barrier (BBB). Both a time- and dose-response evaluation of the effect of E2B on glucose uptake in the central nervous system (CNS) were conducted. E2B, in doses ranging from 1 to 100 micrograms/kg body weight, was injected subcutaneously at 2 to 24 h prior to evaluation. The 4-h time point and 10 micrograms/kg dose of E2B produced the most widespread increases in glucose uptake. Six regions responded to E2B with elevated glucose uptake by as much as 120% when compared to oil-treated controls. We then evaluated the effects of E2B on transport of glucose across the BBB. E2B significantly increased the extraction of labeled sugar across the BBB by 40% without affecting extraction of the internal standard. Collectively, these studies indicate that physiological levels of estradiol (E2) may play an important role in modulating cerebral glucose homeostasis.

Animals↗
PubMed1995

Aneuploidies and micronuclei in the germ cells of male mice of advanced age.

The objective of this research was to determine whether the frequencies of chromosomally defective germ cells increased with age in male laboratory mice. Two types of chromosomal abnormalities were characterized: (1) testicular spermatid aneuploidy (TSA) as measured by a new method of multi-color fluorescence in situ hybridization (FISH) with DNA probes specific for mouse chromosomes X, Y and 8, and (2) spermatid micronucleus (SMN) analyses using anti-kinetochore antibodies. B6C3F1 mice (aged 22.5 to 30.5 months, heavier than controls but otherwise in good health) showed significant approximately 2.0 fold increases in the aneuploidy phenotypes X-X-8, Y-Y-8, 8-8-X and 8-8-Y with the greatest effects appearing in animals aged greater than 28 months. No age effect was observed, however, in X-Y-8 hyperhaploidy. Major age-related increases were seen in Y-Y-8 and X-X-8 hyperhaploidies suggesting that advanced paternal age is associated primarily with meiosis II rather than meiosis I disjunction errors. A approximately 5 fold increase was also found in the frequency of micronucleated spermatids in aged mice when compared with young controls. All micronuclei detected in the aged animals lacked kinetochore labeling, suggesting that they either did not contain intact chromosomes or the chromosomes lacked detectable kinetochores. The findings of the TSA and SMN assays are consistent with meiotic or premeiotic effects of advanced age on germ cell chromosomes, but there were differences in the age dependencies of aneuploidy and micronuclei. In summary, advanced paternal age may be a risk factor for chromosomal abnormalities (both aneuploidy and structural abnormalities) in male germ cells.

Aging↗
PubMed1995

A phase II trial of zeniplatin in metastatic melanoma.

A third-generation platinum analogue, zeniplatin, was administered at a dose of 145 mg/m2 intravenously over 60-90 minutes every 21 days as the initial chemotherapy to 21 patients with metastatic melanoma. Prehydration and mannitol diuresis was introduced after the first 7 patients. There were 17 males and 4 females. The median age was 52 (range: 29-81). ECOG performance status was 0 in 10 patients, 1 in 8 patients and 2 in 3 patients. Major disease sites were lymph nodes, skin, lung, liver, and bone. Patients received a median of 2 cycles (range: 1-7). Two patients achieved partial responses. One with nodal disease progressed after 166 days and the other with buccal mucosal disease after 142 days. A third patient showed partial regression of nodal disease but developed cerebral metastases. Gastrointestinal toxicity included WHO grade 3 vomiting in 8 patients and nausea in 2. Antiemetics were used, but ondansetron was not available. WHO grade 3 hematologic toxicities included neutropenia in 8 patients and anemia and thrombocytopenia in 1 patient. Thrombocytosis was seen in 35% of courses. Dosage reduction was required in 15% of courses and escalation in 5% of courses. Three patients developed phlebitis related to the infusion. One patient developed a reversible rise in serum creatinine, but, unlike other studies, no severe nephrotoxicity was reported. Zeniplatin demonstrated only modest activity in melanoma with significant gastrointestinal and hematologic toxicity.

Adult↗
PubMed1995

Australasian multicentre phase II study of paclitaxel (Taxol) in relapsed ovarian cancer.

BACKGROUND: Until recently there has been no effective therapy for patients with relapsed ovarian carcinoma following standard platinum based chemotherapy. Paclitaxel has recently been approved for clinical use in this malignancy. AIMS: To evaluate the objective response rate and toxicity of paclitaxel in patients with relapsed ovarian cancer. METHODS: Paclitaxel was given on an outpatient basis as a three hour infusion every 21 days for a maximum of ten cycles to 72 patients with advanced ovarian cancer previously treated with at least one platinum containing regimen. The starting dose was either 175 mg/m2 (patients with one or two prior chemotherapy regimens) or 135 mg/m2 (three previous regimens). Premedication was given because of the documented risk of hypersensitivity reactions to paclitaxel. RESULTS: The overall response rate was 22% (95% confidence interval [CI] 13% to 34%) in the 72 patients enrolled in the study: four patients had a complete response. Three patients (4%) ceased treatment due to hypersensitivity reactions. Other significant (WHO grade 3 or 4) toxicities included neutropenia (51%), myalgia (14%), neurological (3%), alopecia (93%) and nausea and vomiting (3%). The estimated median survival of all patients was 9.8 months (95% CI: 9.1-13.0 months) with 44% alive at one year (standard error [SE] 7%). CONCLUSIONS: This study confirms that paclitaxel given as a three hour infusion has significant activity and acceptable toxicity in advanced ovarian carcinoma previously treated with platinum regimens.

Adolescent↗
PubMed1995

The effects of gestation dating on the calculation of patient specific risks in Down's syndrome screening.

In Down's syndrome screening using biochemical markers, the marker concentrations are adjusted for the gestational age of the fetus, since they are known to change with gestational age. This adjustment is performed by referring to the population median of each marker for the appropriate gestational age group. The measurement of gestational age is subject to error, whatever method is used, and the population median used is actually the median of a mixture of distributions for different true gestational ages. We show how the proportions in this mixture can be estimated and how the true median corresponding to a given true gestational age can be estimated. For simplicity, we consider the case of using a single marker, namely maternal serum alpha-fetoprotein, and show that the usual estimation method has considerable bias. The effect of this mixture on the calculation of patient-specific risks is discussed and we show that detection rates can be improved by allowing for this error in the dating process. The overall detection rate is increased by about 1%. The increase in detection rate is age-dependent and for some maternal ages the increase is of the order of 5%. The comparative effects of different methods for dating are discussed.

Biomarkers↗
PubMed1994

Filgrastim in patients with chemotherapy-induced febrile neutropenia. A double-blind, placebo-controlled trial.

OBJECTIVE: To determine if filgrastim (recombinant human methionyl granulocyte colony-stimulating factor) used in addition to standard inpatient antibiotic therapy accelerated recovery from infection associated with chemotherapy-induced neutropenia. DESIGN: Randomized, double-blind, placebo-controlled trial. SETTING: Hematology and oncology wards of four teaching hospitals. PATIENTS: 218 patients with cancer who had fever (temperature > 38.2 degrees C) and neutropenia (neutrophil count < 1.0 x 10(9)/L) after chemotherapy. INTERVENTION: Patients were randomly assigned to receive filgrastim (12 micrograms/kg of body weight per day) (n = 109) or placebo (n = 107) beginning within 12 hours of empiric therapy with tobramycin and piperacillin. Patients received treatment and remained in the study until the neutrophil count was greater than 0.5 x 10(9)/L and until 4 days without fever (temperature < 37.5 degrees C) had elapsed. MEASUREMENTS: Days of neutropenia and fever and days in the study (hospitalization); time to resolution of fever and febrile neutropenia; and frequency of the use of alternative antibiotics. RESULTS: Compared with placebo, filgrastim reduced the median number of days of neutropenia (3.0 compared with 4.0 days of a neutrophil count of < 0.5 x 10(9)/L; P = 0.005) and the time to resolution of febrile neutropenia (5.0 compared with 6.0 days; P = 0.01) but not days of fever (3.0 days for both groups). The frequency of the use of alternative antibiotics was similar in the two groups (46% compared with 41%; P = 0.48). The median number of days patients were hospitalized while on study was the same (8.0 days; P = 0.09); however, filgrastim decreased the risk for prolonged hospitalization (> 11 days, 4th quartile) by half (relative risk, 2.1 [95% CI, 1.1 to 4.1]; P = 0.02). In exploratory subset analyses, filgrastim appeared to provide the greatest benefit in patients with documented infection and in patients presenting with neutrophil counts of less than 0.1 x 10(9)/L. CONCLUSIONS: Filgrastim treatment used with antibiotics at the onset of febrile neutropenia in patients with cancer who have received chemotherapy accelerated neutrophil recovery and shortened the duration of febrile neutropenia.

Adolescent↗
PubMed1994

Prognostic value of immunophenotyping in acute myeloid leukemia. Australian Leukaemia Study Group.

The diagnostic and prognostic value of immunophenotyping with 18 murine monoclonal antibodies (MoAbs) to a variety of leukocyte differentiation antigens was assessed in 168 adults aged 15 to 60 years with acute myeloid leukemia (AML). Patients were entered on the multicentre Australian Leukaemia Study Group M4 protocol, and were randomized to receive either standard or high-dose Ara-C together with daunorubicin and etoposide as induction chemotherapy, followed by standard consolidation and maintenance therapy. Diagnostic bone marrow aspirate (152 cases) or peripheral blood samples (16) were analyzed by indirect immunofluorescence and flow cytometry. MoAbs used were directed at myeloid (CD11b, CD13, CD14, CD15, CD33, CD41), lymphoid (CD2, CD3, CD7, CD9, CD10, CD19), or stem cell (HLA-DR, CD34, c-kit receptor) antigens, as well as the leukocyte integrins CD18 and CD49e, and the transferrin receptor CD71. Of the myeloid markers, CD13 and CD33 were the most useful diagnostically (71% and 79% of cases positive, respectively), with CD11b, CD14, and CD15 less commonly positive. A minority of cases expressed lymphoid antigens, either T cell (CD2 16%, CD3 7%, CD7 28%) or B cell (CD10 2%, CD19 7%). CD34 was detected on 42% and c-kit receptor on 48%. When patients were analyzed for response to treatment, CD2, CD9, and CD14 were significantly associated with complete remission rate: cases expressing these antigens had a poorer response than negative cases. In univariate analysis, CD11b+ cases had shorter periods of remission (relative risk of relapse, 2.33; P = .003) and shorter survival (relative death rate, 1.91; P = .006). In multivariate analysis, adjusting for other prognostic factors, CD9 and CD11b were significantly predictive of shorter survival. No other marker had a significant predictive effect. We conclude that myeloid MoAbs are useful in confirming the diagnosis of AML, but their prognostic value may be limited to CD11b. Lymphoid antigen expression is a consistent phenomenon in a minority of cases of AML, but appears to have little clinical significance.

Acute Disease↗
PubMed1994

Estradiol treatment increases viability of glioma and neuroblastoma cells in vitro.

The present study provides evidence that 17-beta-estradiol (E2) exerts cytoprotective effects on both glial and neuronal cell lines. In C6 rat glioma cells, the addition of E2 to serum free media enhances live cell number by 40% at 24 h and 75% at 96 h when compared to serum free media conditions. E2 treatment of C6 cells in serum free medium did not increase thymidine uptake at any sampling time, indicating that the observed effect of E2 on C6 cell number was not due to a mitogenic effect of the steroid hormone. The addition of E2 to SK-N-SH cells in serum free media maintained both total and live cell number at a level comparable to the fetal bovine serum (FBS) treated cells at both 24 and 48 h. At 96 h after treatment with E2, total and live cell numbers were diminished relative to the 48-h sample and the 96-h FBS group, but were still more than twice the number observed in serum free media. Associated with the reduced effects of E2 at 96 h was an increase in the ratio of dead to total cells, although it remained about 50% less than the serum free group. Through 48 h, E2 exposure did not increase thymidine uptake in SK-N-SH cells, indicating that the effect of E2 on SK-N-SH cells was cytoprotective rather than mitogenic. Collectively, these data support a cytoprotective action of E2 on neuronal or glial cell types in vitro.

Animals↗