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Biomedical subjects

Michael E Jones

Publications and source records attributed to Michael E Jones.

10 recordsLinked to original sources
PubMed2025

Beyond BRCA deficiency: Clinical and molecular predictors of survival in patients with BRCA-deficient tubo-ovarian high-grade serous carcinoma.

BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤3 years, n=42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n=1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.

Journal Article↗
PubMed2005

Tamoxifen treatment for breast cancer and risk of endometrial cancer: a case-control study.

BACKGROUND: Tamoxifen treatment of breast cancer is associated with an increased risk of endometrial cancer, but tamoxifen-related risks of endometrial cancer are unclear in premenopausal women, in long-term users of tamoxifen, and in women for whom several years have passed since ending treatment. We conducted a case-control study in Britain to investigate these risks. METHODS: We compared treatment information on 813 case patients who had endometrial cancer after their diagnosis for breast cancer and 1067 control patients who had breast cancer but not subsequent endometrial cancer. We assessed risk by conditional logistic regression analysis. All statistical tests were two-sided. RESULTS: Overall, tamoxifen treatment, compared with no treatment, was associated with an increased risk of endometrial cancer (odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.8 to 3.0). Risk increased statistically significantly (P(trend)<.001) with duration of treatment (for > or =5 years of treatment compared with no treatment, OR = 3.6, 95% CI = 2.6 to 4.8). As an indication of background levels of treatment, 16% of control patients received 5 years or more of treatment. Risk of endometrial cancer adjusted for treatment duration did not diminish in follow-up to at least 5 years after the last treatment ended. Risk of endometrial cancer was not associated with the daily dose of tamoxifen and was comparable in pre- and postmenopausal women. Ever treatment with tamoxifen was associated with a much greater risk of Mullerian and mesodermal mixed endometrial tumors (OR = 13.5, 95% CI = 4.1 to 44.5) than of adenocarcinoma (OR = 2.1, 95% CI = 1.6 to 2.7) or clear cell and papillary serous tumors (OR = 3.1, 95% CI = 0.8 to 17.9). CONCLUSIONS: There is an increasing risk of endometrial cancer associated with longer tamoxifen treatment, extending well beyond 5 years. The increased risk of endometrial cancer associated with tamoxifen treatment should be considered clinically for both premenopausal and postmenopausal women during treatment and for at least 5 years after the last treatment.

Aged↗
PubMed2005

Psychosocial and socioeconomic risk factors for premature death in young people with type 1 diabetes.

OBJECTIVE: Mortality from acute diabetes-related events is greatly raised in young adults with type 1 diabetes. Psychosocial and socioeconomic risk factors are examined for deaths from acute events separately from deaths due to other causes. RESEARCH DESIGN AND METHODS: This study had a nested case-control design. The cases were patients from the Diabetes UK cohort who died before age 40 years. Deaths were categorized as acute events or chronic conditions related to diabetes. Where possible, two matched control subjects were selected for each case. Data relating to psychosocial and socioeconomic factors and variables related to diabetes complications were extracted from the case notes. Risks of death were estimated by calculation of odds ratios (ORs). RESULTS: Case notes were obtained for 98 case and 137 control subjects. Fifty-one deaths were attributed to acute causes, 34 to chronic conditions related to diabetes, and the remaining 13 were unrelated to diabetes. Living alone (OR 4.4), past drug abuse (5.7), and previous psychiatric referral (4.6) were all significantly associated with death from acute events but not death from chronic conditions. There was no association between deaths from acute events and nephropathy, hypertension, neuropathy, or retinopathy, although all of these were associated with deaths from chronic conditions. CONCLUSIONS: The results indicate that psychosocial factors are powerful risk factors for mortality from acute events in patients with type 1 diabetes, although not for mortality from chronic conditions. The data enable the identification of a high-risk group suitable for targeting with preventive measures to reduce acute event mortality.

Adolescent↗
PubMed2003

Mortality of hepatitis B surface antigen-positive blood donors in England and Wales.

BACKGROUND: Large population-based cohort studies in areas of high hepatitis B virus (HBV) prevalence have provided the evidence establishing hepatitis B surface antigen (HBsAg) carriage as a risk factor for hepatocellular carcinoma (HCC) and liver disease. Fewer studies have examined this in Western countries, where both HBV infection and carriage are less common and transmission patterns differ. This is the only prospective population-based study to examine this relationship in Europe. METHODS: In all, 2681 male and 977 female blood donors in England and Wales, found to be HBsAg positive during routine blood-donation screening, were followed up from recruitment in 1970-1982 to December 1999 and their cause-specific mortality was analysed. This was compared with that of the general population of England and Wales. RESULTS: During a mean of 22 years of follow-up, 17.4% of the 420 deaths were due to HCC or liver disease. There were 20 deaths from HCC in male HBsAg carriers, representing a significantly high standardized mortality ratio (SMR) compared to the male population of England and Wales of 26 (SMR = 26.26; 95% CI: 16.04- 40.54). The HCC incidence rate in males was 33.5 per 100 000 person years and 4.4 per 100 000 person years in females. Men had 8.5 (SMR = 8.50; 95% CI: 6.25- 11.31) and women had 3.9 times the risk of death from liver disease (SMR = 3.89; 95% CI: 1.26-9.09). The risk of circulatory disease deaths was reduced in both males and females. There was a significant increased risk of non-Hodgkins lymphoma that was not apparent in the first decade of follow-up. The increased risk of HCC and liver disease in men fell with follow-up. CONCLUSION: Hepatitis B surface antigen carriage is a significant risk factor in England and Wales for both liver disease and HCC mortality. However, this risk has declined with duration of follow-up. This could be due to natural reversion to HBsAg negativity or as a result of treatment and avoidance of other risk factors. The increased risk of non-Hodgkins lymphoma seen in longer follow-up is likely to be related to HIV infection acquired subsequent to recruitment.

Adolescent↗
PubMed2003

Mortality after radiological investigation with radioactive Thorotrast: a follow-up study of up to fifty years in Portugal.

Cerebral angiography using a radioactive radiological contrast medium, Thorotrast, was pioneered by Moniz in Portugal in the 1920s. Thorotrast is retained by the reticuloendothelial system, with a biological half-life of several hundred years, so that such patients suffer lifetime exposure to internal radiation. We studied mortality in Portuguese patients who were administered Thorotrast during the period 1928-1959 and in a comparison group of patients who received nonradioactive contrast agents. There were 1096 systemically exposed, 1014 unexposed, and, unique to the Portuguese study, 240 locally exposed Thorotrast patients who were successfully traced and followed up to the end of 1996. Mortality was significantly raised among systemically exposed Thorotrast patients relative to those unexposed for all causes [relative risk (RR) = 2.63], all neoplasms (RR = 6.72), liver cancer (RR = 42.4), chronic liver disease (RR = 5.12), other non-neoplastic diseases of the digestive system (RR = 4.87), neoplastic (RR = 21.9) and non-neoplastic hematological disorders (RR = 6.00), and non-neoplastic diseases of the respiratory system (RR = 4.31). Risks for most of these conditions increased significantly with time since first administration of the contrast medium and with cumulative alpha-particle radiation dose. Mortality was also significantly raised for non-neoplastic disorders of the nervous system (RR = 12.7) and ill-defined conditions (RR = 3.74), but these associations are likely to reflect the initial diagnosis, not Thorotrast exposure, because risks declined significantly with time and/or dose. There were no significant excess deaths from oropharyngeal or nasal cancers, or from any other cause, among patients exposed to Thorotrast locally for visualization of the perinasal sinuses, and no clear trend in risk with time since exposure. This study shows an association between systemic, but not local, exposure to Thorotrast and mortality from liver cancer, chronic liver disease, and neoplastic and non-neoplastic hematological disorders, with risks for these conditions remaining high for over 40 years after administration. Liver conditions, but not hematological disorders, showed a strong and consistent gradient with cumulative alpha-particle radiation dose.

Adolescent↗
PubMed2002

Quiet direct simulation of Eulerian fluids.

The direct simulation Monte Carlo method of modeling fluids requires sampling one or more random variables every time step for each particle. In this paper a "quiet Monte Carlo" technique is proposed that eliminates the random sampling and the noise it produces by deterministically generating a small number of computational particles. The technique is applied to particle equations of motion appropriate for modeling an Eulerian fluid. Results indicate that strong one- and two-dimensional shocks with large dynamic ranges are accurately represented with only a few particles per cell.

Journal Article↗
PubMed2002

Implications of the simultaneous occurrence of hepatic glycolysis from glucose and gluconeogenesis from glycerol.

Glycolysis from [6-(3)H]glucose and gluconeogenesis from [U-(14)C]glycerol were examined in isolated hepatocytes from fasted rats. A 5 mm bolus of glycerol inhibited phosphorylation of 40 mm glucose by 50% and glycolysis by more than 60%, and caused cellular ATP depletion and glycerol 3-phosphate accumulation. Gluconeogenesis from 5 mm glycerol was unaffected by the presence of 40 mm glucose. When nonsaturating concentrations of glycerol (< 200 microm) were maintained in the medium by infusion of glycerol, cellular ATP concentrations remained normal. The rate of uptake of infused glycerol was unaffected by 40 mm glucose, but carbohydrate synthesis from glycerol was inhibited 25%, a corresponding amount of glycerol being diverted to glycolytic products, whereas 10 mm glucose had no inhibitory effect on conversion of infused glycerol into carbohydrate. Glycerol infusion depressed glycolysis from 10 mm and 40 mm glucose by 15 and 25%, respectively; however, the overall rates of glycolysis were unchanged because of a concomitant increase in glycolysis from the infused glycerol. These studies show that exposure of hepatocytes to glucose and low quasi-steady-state concentrations of glycerol result in the simultaneous occurrence, at substantial rates, of glycolysis from glucose and gluconeogenesis from the added glycerol. We interpret our results as demonstrating that, in hepatocytes from normal rats, segments of the pathways of glycolysis from glucose and gluconeogenesis from glycerol are compartmentalized and that this segregation prevents substantial cross-over of phosphorylated intermediates from one pathway to the other. The competition between glucose and glycerol implies that glycolysis and phosphorylation of glycerol take place in the same cells, and that the occurrence of simultaneous glycolysis and gluconeogenesis may indicate channelling within the cytoplasm of individual hepatocytes.

Animals↗
PubMed2002

Stochastic processes in the causation of rheumatic disease.

OBJECTIVE: Rheumatic disorders arise in certain individuals depending on the interaction of genetic and environmental factors, the contribution for each varying with the specific rheumatic disorder. However, a third variable, i.e., random or stochastic processes, may be important, but this has been poorly studied. We examined 3 rheumatic disorders to determine whether a simple stochastic process might be consistent with the incidence data. METHODS: A questionnaire and clinical survey of patients with ankylosing spondylitis, rheumatoid arthritis, and systemic sclerosis was performed to determine age at onset of first symptom. Population data were obtained from the Australian Bureau of Statistics. Computer modeling of the equation dN/dt = kP0 tr-1exp(-ktr/r) was performed, where dN/dt is the age-specific incidence rate, P0 is the proportion of population at risk, t is the age at onset, k is a constant, and r is the number of random events that must occur before the disease manifests. RESULTS: Analysis of the age-specific incidence for each of these 3 rheumatic disorders was consistent with the stochastic model, where r varied from 4 to 9. CONCLUSION: An examination of the age-specific incidence suggests that only a small number of random events need to occur in a predisposed population to allow the emergence of the rheumatic disorder. These random events might be environmental (e.g., infections or exposure to toxins) or due to acquired genetic changes (e.g., somatic mutations involving pivotal immune or growth/repair genes).

Adolescent↗