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Biomedical subjects

J H Kearsley

Publications and source records attributed to J H Kearsley.

At least 19 recordsLinked to original sources
PubMed2002

ATM induction insufficiency in a radiosensitive breast-cancer patient.

The ataxia telangiectasia (A-T) gene (ATM) is a dominant breast cancer gene with tumour suppressor activity. ATM also regulates cellular sensitivity to ionising radiation (IR) presumably through its role as a facilitator of DNA repair. In normal cells and tissues the ATM protein is rapidly induced by IR to threshold/maximum levels. The kinase function of the ATM protein is also rapidly activated in response to IR. The fact that women carriers of ATM mutations can have an increased risk of developing breast cancer and that many sporadic breast tumours have reduced levels of the ATM protein broadens the scope of ATM's tumour suppressor within the breast. This report describes the downregulation of ATM protein levels in a radiosensitive breast cancer patient. Postinduction ATM levels were up to tenfold lower in the patient's fresh tissues compared to normal controls. These results might indicate a much broader role for ATM anomalies in breast cancer aetiology.

Ataxia Telangiectasia↗
PubMed2001

Rapid radiation-induction of ATM protein levels in situ.

Ataxia-telangiectasia (A-T) is characterised by hypersensitivity to ionising radiation (IR), immunodeficiency, neurodegeneration and predisposition to malignancy. Mutations in the A-T gene (ATM) often result in reduced levels of ATM protein and/or compromise ATM function. IR induced DNA damage is known to rapidly upregulate ATM kinase activity/phosphorylation events in the control of cell cycle progression and other processes. Variable expression of ATM levels in different tissues and its upregulation during cellular proliferation indicate that the level of ATM is also regulated by mechanisms other than gene mutation. Here, we report on the IR induction of ATM protein levels within a number of different cell types and tissues. Induction had begun within 5 min and peaked within 2 h of exposure to 2 Gy of IR, suggesting a rapid post-translational mechanism. Low basal levels of ATM protein were more responsive to IR induction compared to high ATM levels in the same cell type. Irradiation of fresh skin biopsies led to an average three-fold increase in ATM levels while immunohistochemical analyses indicated "low expressing" cells within the basal layer with ten-fold increases in ATM levels following IR. ATM "high expressing" lymphoblastoid cell lines (LCLs) which were initially resistant to the radiation-induction of ATM levels also became responsive to IR after ATM antisense expression was used to reduce the basal levels of the protein. These results demonstrate that ATM is present in variable amounts in different tissue/cell types and where basal levels are low ATM levels can be rapidly induced by IR to saturable levels specific for different cell types. ATM radiation-induction is a sensitive and rapid radioprotective response that complements the IR mediated activation of ATM.

Ataxia Telangiectasia Mutated Proteins↗
PubMed1999

nm23 protein expression and p53 immunoreactivity in cutaneous fibrohistiocytic tumors.

Recent data indicate that reduced expression of the 17-kD protein encoded by the nm23 gene may be important in the pathogenesis of several types of human tumors. Immunohistochemistry was performed using a murine monoclonal antibody, NCL-nm23 (Novocastra, 1:150 dilution) to investigate nm23 protein immunoreactivity in a group of locally aggressive cutaneous fibrohistiocytic tumors; dermatofibrosarcoma protuberans (DFSP) (n = 14) and atypical fibroxanthoma (AFX) (n = 7). Cases of dermatofibroma (DF) (n = 17) formed the benign control group. Comparison with p53 protein immunoreactivity in the same cases studied previously was made. Strong immunohistological expression of the nm23 protein was seen in most of the cases of DF (n = 15; 88%) in the form of strong cytoplasmic immunolabelling without nuclear staining. However, strong nm23 immunoreactivity was observed in only a minority of the cases of DFSP (n = 5; 36%) and AFX (n = 2; 29%). Statistically significant differences in nm23 immunoreactivity were found between DFSP and DF (p = 0.008, chi 2 test with continuity correction) and between AFX and DF (p = 0.015; chi 2 test with continuity correction). No significant difference was seen between DFSP and AFX (p = 0.87, chi 2 test with continuity correction). There was inverse correlation between nm23 and p53 immunoreactivity (r = 0.331; r2 = 0.109; p = 0.046; simple regression analysis). In summary, nm23 protein immunoreactivity is reduced in DFSP and AFX but not in dermatofibroma suggesting that reduced expression of the protein may be important in influencing the behavior of fibrohistiocytic tumors, although this is not well characterised. nm23 protein expression is also found to be inversely related to p53 immunohistological expression in these tumors.

Antigens, Neoplasm↗
PubMed1999

Malignant phyllodes tumours of the breast display increased stromal p53 protein expression.

AIMS: To determine the variation in p53 protein expression in phyllodes tumours and fibroadenomas of the breast. METHODS AND RESULTS: Fifteen phyllodes tumours (six malignant, nine benign) and 20 fibroadenomas were examined for p53 expression by immunohistochemistry. Five of the six malignant phyllodes tumours showed moderate or strong p53 positivity at sites of peri-epithelial stromal condensation and atypia. All 20 fibroadenomas, nine benign phyllodes tumours and one malignant phyllodes tumour showed either negativity or focal weak nuclear positivity of scattered stromal cells. CONCLUSIONS: Increased p53 immunoreactivity is present in malignant phyllodes tumours in contrast to benign phyllodes tumours and fibroadenomas. Malignant phyllodes tumours display a distinctive pattern of p53 immunostaining which may be of diagnostic value. These findings suggest that p53 protein may be important in the progression of benign to malignant phyllodes tumours.

Adult↗
PubMed1999

ATM protein synthesis patterns in sporadic breast cancer.

AIMS: The gene mutated in ataxia-telangiectasia (A-T), designated ATM (for "A-T mutated"), is believed to be associated with an increased risk of developing breast cancer. Most patients with A-T have null mutations of the ATM gene that appear to give rise to a truncated nonfunctional ATM protein. Therefore, the increased risk of breast cancer reported in A-T heterozygotes appears to be the result of haplo-insufficiency of ATM in breast tissues. This study aimed to determine whether reduced synthesis of ATM was also an important factor in sporadic breast cancer. METHODS: Paraffin wax embedded tissues from patients with breast invasive ductal carcinoma (IDC) (n = 42), patients with ductal carcinoma in situ (DCIS) (n = 17), and others with lymph node metastases (n = 14) were studied. A streptavidin-biotin-peroxidase system was used to stain tissue sections for the ATM protein using the ATM-4BA and CT-1 polyclonal and monoclonal antibodies, respectively. The protein truncation test was used to screen for mutations in the ATM gene in those patients who had greatly reduced ATM protein immunoreactivity in the primary carcinoma (n = 3). RESULTS: Most metastatic breast carcinomas in lymph nodes (71%) had greatly reduced or absent ATM protein synthesis, which was significant when compared with that observed in non-metastatic invasive breast carcinomas (p = 0.029; chi 2 test). Although not significant (p = 0.045; chi 2 test), some sporadic breast carcinomas (14 of 42) also had reduced or absent ATM protein immunoreactivity. The protein truncation test did not reveal any gross ATM gene abnormality in the cases tested, indicating that the patients were not A-T heterozygotes, who are predisposed to breast cancer. CONCLUSIONS: A reduction in immunohistochemically detectable ATM protein in sporadic breast carcinoma implicates ATM in the progression of the disease.

Adult↗
PubMed1998

Absence of ATM truncations in patients with severe acute radiation reactions.

PURPOSE: Severe acute toxicity limits the effective use of radiotherapy in patients who are radiosensitive, and it is not usually possible to identify these radiohypersensitive (R-H) individuals before treatment commences. Five such R-H patients were detected over a 3-year period. We undertook this study to determine whether the severe acute radiohypersensitivity of these five individuals showed any correlation with cellular and molecular parameters known to be abnormal in radiosensitivity-related syndromes such as ataxia-telangiectasia (A-T). METHODS AND MATERIALS: Lymphoblastoid cells were isolated from fresh blood from the 5 R-H individuals who had previously demonstrated clinical R-H at least 9 months prior to sampling. Lymphoblastoid cell lines (LCLs) were established to determine the extent of postradiation chromosomal aberrations, cell cycle delay, cell proliferation, and tumor suppressor p53 protein stabilization. The polymerase chain reaction (PCR) and protein truncation (PTT) assays were used to test for the possibility of mutations in the gene mutated in A-T, termed ATM. RESULTS: LCLs derived from R-H subjects retained a significantly higher degree of radiation-induced chromosomal aberrations when compared to normal control LCLs. p53 stabilization by ionizing radiation appeared normal in all but one R-H subject. There was no evidence of A-T gene truncation mutations in any of the R-H subjects tested. CONCLUSIONS: All R-H subjects in this study had their cellular radiosensitivity confirmed by the chromosomal aberration assay. Delayed p53 stabilization at 4 hours postirradiation in one R-H subject suggested that different etiologies may apply in the radiohypersensitivity investigated in this study.

Adult↗
PubMed1998

Heterogeneity in Klippel-Feil syndrome: a new classification.

BACKGROUND: Klippel-Feil syndrome (KFS) is characterised by congenital vertebral fusion of the cervical spine and a wide spectrum of associated anomalies. KFS has often been considered a sporadic syndrome. However, since the publication of the original KFS classification early this century, a number of KFS families have indicated heterogeneity complicated by a broad range of variable expression. OBJECTIVE: The two major objectives of this study were (1) to identify differences and similarities in the postnatal appearance, morphology, position and inheritance of vertebral fusions within and between KFS families and (2) to establish a new KFS classification focussed on KFS aetiology. MATERIALS AND METHODS: Vertebral fusions were assessed via spinal radiography. Chromosomal karyotypes were performed using routine cytogenetics. RESULTS: The medical histories of three KFS families are presented. The postnatal time, position and appearance of vertebral fusions, associated anomalies and mode of inheritance were different for the three KFS families. Four classes of KFS are described in a comprehensive classification table that allays much of the uncertainty arising from KFS heterogeneity and variable expression. CONCLUSION: We have described four different KFS classes (KF1-4) within a comprehensive classification that addresses KFS genetic heterogeneity. The position of vertebral fusions in the cervical spine and their incidence within affected families are delineating features of KFS.

Adult↗
PubMed1998

Delayed presentation of primary testicular seminoma.

A case is reported here of delayed presentation of primary testicular seminoma, 9 years after initial presentation with retroperitoneal disease. The diagnostic difficulty associated with primary extragonadal germ cell tumour is emphasized.

Adult↗
PubMed1998

Clinical radiohypersensitivity screening using radiation-induced chromosomal aberrations.

Severe acute toxicity to radiotherapy (radiohypersensitivity) can limit the effective use of radiotherapy and it is not usually possible to identify such individuals before treatment commences. Five patients with acute radiohypersensitivity (RH) were detected over a 3-year period. All five RH subjects demonstrated a significantly higher degree of radiation-induced chromosomal aberrations (ICA) in fresh blood lymphocytes when compared to normal controls. Results indicate the feasibility of using the ICA assay in conjunction with other tests to screen for radiosensitivity.

Case-Control Studies↗
PubMed1998

Quality-of-life assessment during palliative radiotherapy.

A total of 164 consecutive patients with a range of biopsy-proven locally advanced or metastatic cancers were interviewed to assess quality of life using the Rotterdam Symptom Check List (RSCL) at three longitudinal time intervals during a course of palliative radiotherapy. Of the 164 patients, 120 were able to complete all 3 questionnaires. Paired t-tests were used to assess the significance of changes in the patients' mean scores over time. Of the 33 symptoms assessed in the RSCL, changes in the degree of symptomatology were highly consistent with changes expected in clinical practice, as a result of either disease progression or side effects of treatment. It is concluded that the RSCL provides a practical assessment of various symptoms in patients receiving palliative radiotherapy, and that the changes in symptom profile over time are relevant to clinical practice. The RSCL has never been previously used in the assessment of palliative radiotherapy, and the present study validates this instrument.

Adult↗
PubMed1998

Liver metastases from transitional cell carcinoma are lipiodol avid.

A case of transitional cell carcinoma of the bladder with symptomatic liver metastases is presented. When conventional chemotherapy failed, a lipiodol CT scan demonstrated avid uptake by the tumours, which has implications for targeted cancer therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1998

Upregulation of ATM in sclerosing adenosis of the breast.

The gene mutated in ataxia telangiectasia (ATM) has an established tumour suppressor role in breast cancer. ATM appears to be expressed in most normal cells, including breast epithelium, where it has been postulated to have a nuclear role in cell cycle regulation following DNA damage. However, ATM is not upregulated after DNA damage. In this study, we demonstrate an absence of immunohistologically detectable levels of ATM in the normally quiescent myoepithelial cells that line normal breast ducts. This contrasts dramatically with the significant expression of ATM in the proliferative myoepithelium of sclerosing adenosis (n = 7). This upregulation of ATM suggests that ATM expression is coupled to the proliferative status of the myoepithelium. Our results also indicate that there are factors other than ATM gene mutations that can dramatically influence ATM expression in the breast and that these factors should be considered for their possible implications in carcinogenesis.

Actins↗
PubMed1997

Production and verification of an anti-ovine IgE monoclonal antibody.

Recombinant mouse/sheep IgE was used in the production of an anti-IgE monoclonal using conventional hybridoma techniques. The specificity of hybridomas secreting anti sheep IgE monoclonal antibodies was verified using a number of assays including competitive ELISAs, ability to induce mediator release from mast cells, and IgE binding using western blotting. Immunohistochemical staining demonstrated the binding of putative anti-IgE monoclonals to the sheep mast cell surface. The isotype of the antibody was IgG1:K.

Animals↗
PubMed1996

An open multicentre study of tropisetron for cisplatin-induced nausea and vomiting.

OBJECTIVES: (i) To assess the efficacy and tolerability of tropisetron when used for acute and delayed cisplatin-induced emesis. (ii) To investigate whether dexamethasone added to tropisetron improves the control of emesis for patients who do not achieve a complete response to tropisetron alone. (iii) To assess sex of the patient and alcohol intake as prognostic factors for nausea and vomiting. DESIGN: A prospective open label phase II trial over one or two cycles of chemotherapy. Data collection was based on observed response and patients' self-reporting. SETTING: Twenty Australian tertiary care hospitals in 1994. PATIENTS: 102 male and female patients from 18 to 75 years with histologically confirmed malignancy receiving their first chemotherapy containing > or = 50 mg/m2 cisplatin. INTERVENTION: In Cycle 1 tropisetron 5 mg was given intravenously before chemotherapy on Day 1, then 5 mg orally before breakfast on Days 2 to 6. In Cycle 2, dexamethasone 20 mg intravenously on Day 1, then 8 mg orally on Days 2 to 6 could be added to tropisetron if a complete antiemetic response had not been achieved in Cycle 1. MAIN OUTCOME MEASURES: Number of vomiting episodes and severity of nausea for 6 days after chemotherapy; severity of side effects; patient satisfaction with chemotherapy treatment; oestradiol levels in women; and past alcohol consumption in men and women. RESULTS: (i) The complete response rate (CR) for acute emesis in Cycle 1 was 64% (95% confidence interval [CI], 54%-72%), with 84% (95% CI, 76%-90%) having < or = 2 vomits. The CR for delayed emesis was 24% (95% CI, 17%-32%). The CR for acute nausea was 56% (95% CI, 47%-66%), with 97% (95% CI, 91%-99%) having < or = 2 nausea episodes. The CR for delayed nausea was 21% (95% CI, 14%-30%). Seventy-one patients received Cycle 2. The main side effects were headache (20 patients) and constipation (16 patients). The control of acute emesis was rated as "good" or "very good" by 68% of investigators; 85% rated the tolerability of treatment as "good" or "very good". Treatment was rated as "very satisfactory" or "satisfactory" by 52% of patients. (ii) The CR for acute emesis with dexamethasone added was 78% (95% CI, 64%-88%). (iii) Women with lower oestradiol levels had better control of emesis, although this difference was not statistically significant. Chronic alcohol intake and binge drinking were strongly associated with a complete acute antiemetic response. CONCLUSIONS: Tropisetron was effective for acute cisplatin-induced emesis; adding dexamethasone enhanced this response. Both single and combined therapy had less effect on delayed emesis. The impact of alcohol on control of emesis is a chronic rather than acute phenomenon which requires prospective testing.

Adolescent↗
PubMed1996

Patterned expression in familial Klippel-Feil syndrome.

Klippel-Feil syndrome (KFS) is characterised by congenital fusion of vertebrae within the rostral spine. The first KFS gene (SGM1) locus identified on chromosome 8 segregates with vertebral fusions and associated vocal impairment within the KF2-01 family (Clarke et al., '94, '95). Here, we describe the unique pattern of variable phenotypic expression within the KF2-01 family. The pattern of anomalies revealed a cumulative, rostrocaudal graded sequence of skipped vertebral fusions. This fusion pattern presents striking similarities with the mutant phenotype and gene expression profile of the Drosophila segment polarity gene engrailed.

Adolescent↗