PubMed Health⌕ Search

Biomedical subjects

S Minkin

Publications and source records attributed to S Minkin.

At least 19 recordsLinked to original sources
PubMed2005

A pilot randomised controlled trial to reduce colorectal cancer risk markers associated with B-vitamin deficiency, insulin resistance and colonic inflammation.

Colorectal cancer risk is associated with biochemical markers for B-vitamin deficiency, insulin resistance and colonic inflammation, suggesting that these three conditions are each involved in colon carcinogenesis. We expected that dietary supplements of folic acid, n-3 fatty acids and calcium would reduce the markers and thus possibly cancer risk. We therefore randomised 98 participants, with previous colonic polyps or intramucosal carcinomas, to a combined treatment of supplementary folic acid, fish oil and calcium carbonate, or placebos for 28 days. Blood and faecal samples were obtained prior to and at the conclusion of the intervention and analysed for plasma folate, homocysteine, insulin, free fatty acids, triglycerides and faecal calprotectin. In addition, plasma vitamin B12, thiamin, glucose and C-reactive protein were assessed. Our supplemental strategy modestly affected some of the biomarkers associated with folate metabolism and insulin resistance, but had no effect on those associated with colonic inflammation. This pilot study demonstrates the feasibility and practicality of clinical trials aimed at reducing diet-related biochemical risk markers for colon cancer. We suggest that long-term intervention studies with tumour-related end points should be undertaken when the intervention agents used are found effective in short-term biochemical risk marker trials.

Adenoma↗
PubMed2003

Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature.

Animal experiments and human ecological studies suggest that dietary fat intake is associated with a risk of breast cancer, but individual-based studies have given contradictory results. We have carried out a meta-analysis of this association to include all papers published up to July 2003. Case-control and cohort studies that examined the association of dietary fat, or fat-containing foods, with risk of breast cancer were identified. A total of 45 risk estimates for total fat intake were obtained. Descriptive data from each study were extracted with an estimate of relative risk and its associated 95% confidence interval (CI), and were analysed using the random effects model of DerSimonian and Laird. The summary relative risk, comparing the highest and lowest levels of intake of total fat, was 1.13 (95% CI: 1.03-1.25). Cohort studies (N=14) had a summary relative risk of 1.11 (95% CI: 0.99-1.25) and case-control studies (N=31) had a relative risk of 1.14 (95% CI 0.99-1.32). Significant summary relative risks were also found for saturated fat (RR, 1.19; 95% CI: 1.06-1.35) and meat intake (RR, 1.17; 95% CI 1.06-1.29). Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer. Case-control and cohort studies gave similar results.

Breast Neoplasms↗
PubMed2003

Quantitative PCR identifies a minimal deleted region of 120 kb extending from the Philadelphia chromosome ABL translocation breakpoint in chronic myeloid leukemia with poor outcome.

Fluorescence in situ hybridization (FISH) analysis has shown previously that 10-15% of chronic myeloid leukemias (CML) have hemizygous deletions of variable sizes affecting regions that flank the ABL and BCR translocation breakpoints on the derivative chromosome 9, and these patients have a poor outcome. FISH studies using large commercial genomic probes have previously suggested that haploinsufficiency of sequences flanking either ABL or BCR modify the disease process of CML and lead to an unfavorable prognosis. In this present study, real-time quantitative PCR (Q-PCR) analysis was used to identify and map much smaller hemizygous microdeletions in a subset of CML patients that were not deleted using large genomic FISH probes. Microdeletions were identified by Q-PCR in 25 of 71 patients selected based on less favorable outcome (chronic phase duration of less than 96 months and a survival time of less than 84 months). In contrast, no microdeletion was detected in any of 18 CML samples selected from a group with a more favorable outcome. Detailed mapping of the 25 Q-PCR microdeletions showed that the minimal deleted region extended approximately 120 kb from the 5' end of the ABL gene in the centromeric direction on the derivative chromosome 9, and the region 3' to BCR on chromosome 22 was excluded. Of the four ESTs and/or genes that map to the 120 kb region, the putative tumor suppressor PRDM12 is the strongest candidate gene. The potential role for each sequence in modifying the clinical behavior of CML is presented.

Chromosome Breakage↗
PubMed2003

The detection of change in mammographic density.

Mammographic density is associated with risk of breast cancer, and factors that change density may also change risk. There has, however, been little research into how change in serial mammograms is best detected. The purpose of the work described here was to examine the effects of different reading conditions on the detection of change in mammographic features. Mammograms were selected from women who had participated in a randomized controlled trial of screening for breast cancer. We selected two age-matched groups of subjects, one had undergone menopause after entry (n = 202) and another who had not (n = 202). Serial mammograms from these subjects were then measured four times using a computer-assisted method under different conditions: (a) films were randomized; (b) subjects were randomized (i.e., pairs of films from individuals were read one after the other), but the order of films was random and unknown to the reader; (c) subjects were randomized, and the order of films was sequential and known to the reader; and (d) subjects were randomized, and the order of films was random and unknown to the reader, but both films in each pair were read simultaneously on separate computer screens. The mean effect of the menopause on change in the mammographic measures of total, dense and nondense areas, percent density, and the associated variances were then compared. With one exception, all of the randomization and viewing methods confirmed a change in all mammographic measures at menopause and produced very similar overall results, suggesting that mammographic density is a robust measure. Compared with randomization of all films, the method in which subjects were randomized and paired films read one after the other in random and unknown order was associated with a slightly smaller mean difference and achieved a substantial reduction in variability, suggesting that it is the most sensitive method of randomization and viewing for the detection of change.

Breast↗
PubMed2002

The association of breast mitogens with mammographic densities.

Radiologically dense breast tissue (mammographic density) is strongly associated with risk of breast cancer, but the biological basis for this association is unknown. In this study we have examined the association of circulating levels of hormones and growth factors with mammographic density. A total of 382 subjects, 193 premenopausal and 189 postmenopausal, without previous breast cancer or current hormone use, were selected in each of five categories of breast density from mammography units. Risk factor information, anthropometric measures, and blood samples were obtained, and oestradiol, progesterone, sex hormone binding globulin, growth hormone, insulin-like growth factor-I and its principal binding protein, and prolactin measured. Mammograms were digitised and measured using a computer-assisted method. After adjustment for other risk factors, we found in premenopausal women that serum insulin-like growth factor-I levels, and in postmenopausal women, serum levels of prolactin, were both significantly and positively associated with per cent density. Total oestradiol and progesterone levels were unrelated to per cent density in both groups. In postmenopausal women, free oestradiol (negatively), and sex hormone binding globulin (positively), were significantly related to per cent density. These data show an association between blood levels of breast mitogens and mammographic density, and suggest a biological basis for the associated risk of breast cancer.

Adult↗
PubMed2001

Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis.

BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia(+) (Ph(+)) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5' region of ABL and the 3' region of the BCR genes on the 9q(+) chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph(+) CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3' regions of the CBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated with MLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior. (Blood. 2001;97:3581-3588)

Adolescent↗
PubMed2001

Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention.

Differences in the parenchymal pattern of the breast on mammography reflect differences in the amounts of stromal, epithelial, and fat tissue present in the breast. Stroma and epithelium are radiologically dense, whereas fat is lucent. Extensive areas of mammographically dense breast tissue are strongly associated with an increased risk of breast cancer. A variety of interventions, including gonadotropin-releasing hormone inhibitor, tamoxifen, stopping hormone replacement therapy (HRT), and adopting a low-fat, high-carbohydrate diet, all influence the tissue composition of the breast and reduce mammographic densities. Of the interventions examined to date, only tamoxifen has been shown to reduce the incidence of breast cancer, at least in the short term. Conversely, HRT, which increases density, also increases risk of breast cancer. These results suggest that mammographic density may be a short-term marker of the effect on the breast of potential preventive interventions for breast cancer.

Antineoplastic Agents, Hormonal↗
PubMed1999

A comparison in individual murine tumors of techniques for measuring oxygen levels.

PURPOSE: To investigate the relationship between different techniques for measuring oxygen levels in a murine tumor model. METHODS AND MATERIALS: Using the murine fibrosarcoma line KHT-C, five techniques of measuring oxygen levels-the Eppendorf pO2 Histograph, EF5 binding, the comet assay, a paired survival assay, and an in vivo growth delay assay-were assessed. In these experiments, three or more techniques were applied in different combinations to measure the oxygen levels in individual tumors. RESULTS: Statistically significant correlations were observed between the hypoxic proportions calculated from the paired survival assay with those from EF5 binding. The comet assay was found to have a statistically significant correlation with the paired survival analysis and the growth delay analysis. No statistically significant correlation was found between the Eppendorf pO2 Histograph measurements and those from the other techniques, although there were weak correlations with the paired survival assay and EF5 binding. For technical reasons, a comparison was not made between EF5 binding and the growth delay assay. CONCLUSIONS: The correlations found between EF5 binding and the comet assay with the radiobiological assays suggest that these techniques have potential for predicting outcome following radiation treatment. The lack of correlation seen between the pO2 Histograph data and the radiobiological assays is in contrast to results from early clinical trials.

Animals↗
PubMed1999

Likelihood-based experimental design for estimation of ED50.

In selecting the best dosage choice for the estimation of ED50, it is natural to try to minimize the length of the confidence intervals. In this presentation, the dose allocation that minimizes the length of the likelihood-based confidence intervals is presented and compared with alternative allocations that have been proposed based on the length of different types of confidence intervals, such as those based on the asymptotic variance or on Fieller's Theorem. Effective strategies to deal with the parameter dependence of these allocations are explored. A series of experiments to evaluate the effect of small doses per fraction on the radiation tolerance of the rat cervical spinal cord provide the motivation and an illustration for the proposed procedures.

Animals↗
PubMed1999

The use of needle biopsies for radiobiological assessment of oxygen levels in KHT-C tumors.

Hypoxia affects the sensitivity of cells to radiation. Hence there is considerable interest in the development and assessment of techniques for measuring oxygen levels. In the work described here, we explore the use of tumor needle biopsies (fine needle aspirates) in an assay that is standard in the field of radiation biology: the paired survival assay. We found that needle biopsies are a feasible option for estimating cell survival when conducting this assay, and that the variability in cell survival between tumors was greater than that between different biopsies from the same tumor. Using this technique, we then compared measurements of tumor hypoxia using the paired survival assay and the growth delay assay in the same individual tumors. We found a significant correlation between these two techniques.

Animals↗
PubMed1998

Aberrant crypt focus promotion and glucose intolerance: correlation in the rat across diets differing in fat, n-3 fatty acids and energy.

McKeown-Eyssen (Cancer Epidemiol. Biomarkers Prevent., 3, 687-695, 1994) and Giovannucci (Cancer Causes Control, 6, 164-179, 1995), noting the striking similarity in lifestyle risk factors for colorectal cancer and insulin resistance, proposed that the hyperinsulinemia, glycemia and hypertriglyceridemia associated with insulin resistance promotes colon cancer. To compare the effect of diet on colon cancer promotion and insulin resistance in the F344 rat, we assessed the effect of fat, n-3 fatty acids and energy in pairwise comparisons on average size of aberrant crypt foci (ACF) and on glucose intolerance in the same animals in a single experiment. Diets high in fat and energy increased and diets with increased n-3 fatty acids and calorie restriction decreased both ACF growth and glucose intolerance compared with control diets. The measures of promotion of colon cancer and insulin resistance were strongly correlated (n = 98, r = 0.67, P < 0.001). In addition, both were highly correlated with daily energy intake (r = 0.62 and 0.66) and were also correlated with basal (post-prandial) insulin, glucose and triglycerides (r = 0.31-0.53, P < 0.01). We concluded that ACF growth and glucose intolerance are correlated for a wide range of diets and that increased circulating energy (glucose and triglycerides) may lead to both colon cancer promotion and insulin resistance.

Animals↗
PubMed1997

Regional variation in nonmedical factors affecting family physicians' decisions about referral for consultation.

OBJECTIVE: To determine whether there is regional variation in environmental (non-medical) factors affecting referral decisions of family physicians (FPs). DESIGN: Cross-sectional interview survey. SETTING: Nova Scotia. PARTICIPANTS: A random sample of 125 FPs grouped into 1 of 5 functionally defined geographic regions of Nova Scotia (25 in each group). Groupings were based on access to general hospital beds through active staff hospital appointments or to specialist consultants in the community, or both. Participants were personally interviewed on site. No physician refused an interview. In 9 cases the physician indicated that he or she did not fit the profile of the assigned group; the physician was excluded from the study and the next doctor on the list was substituted. OUTCOME MEASURES: The questionnaire was designed to test several hypotheses about factors known to potentially influence decisions about referral. Geographic differences in factors affecting referral and in decisions about 5 hypothetical cases were assessed with the use of significance tests for proportions that were sensitive to specific orders across groups. RESULTS: Three factors affecting referral showed unequivocal variation across the 5 groups. Access to hospital facilities and remoteness from specialist care, leading to local styles of practice or treatment policies, and the FP's relationship with specialist consultants appeared to be important nonmedical factors affecting referral decisions. For similar case scenarios the physicians living in rural areas would refer only half as often overall as those living in urban areas with tertiary care hospitals; for some cases, such as a severe asthma attack, the difference was more than 7-fold. CONCLUSIONS: Significant differences in nonmedical factors affecting referral, and in referral decisions about hypothetical cases, were found between the groups of FPs. Differences in access to resources, creating local styles of practice, appeared to explain most of the variation. The results may account for previously observed differences in actual rates of referral for these particular groups.

Adult↗
PubMed1996

A role for paclitaxel in the combination chemotherapy of acute myeloblastic leukaemia: preclinical cell culture studies.

Paclitaxel dose responses in culture have been investigated alone and in association with cytosine arabinoside (ARA-C) and all-trans retinoic acid (ATRA), with the objective of identifying a role for paclitaxel in the treatment of acute myeloblastic leukaemia (AML). Initial studies were done to determine if paclitaxel dose responses of AML blast cell precursors were altered by regulatory compounds known to modify the dose responses of ARA-C. In contrast to ARA-C, paclitaxel dose responses were independent of cell culture method, the growth factors G-CSF and GM-CSF, and the ligands all-trans retinoic acid (ATRA) and hydrocortisone. Most blast cell populations were sensitive to paclitaxel; compared with normal marrow progenitors the dose responses were markedly heterogenous with some more, and others less, sensitive. Remission marrow progenitor paclitaxel responses resembled those of AML blasts in heterogeneity. The cell culture model tested the effect of pacliataxel and ATRA on the ARA-C dose responses of OCI/ AML-5; paclitaxel exposure was either before or after ARA-C to test for an effect of schedule; ATRA was added to the MEC cultures after paclitaxel and ARA-C. Repeat experiments were done to test three dose levels each of paclitaxel and ATRA. When paclitaxel was given after ARA-C, synergism was found for all but one of the dose combinations tested; only three examples of synergy were seen when paclitaxel preceded ARA-C. The studies justify trials combining ARA-C, paclitaxel and ATRA using a schedule suggested by the cell culture findings.

Adult↗
PubMed1996

DELISA: sensitive nonisotopic assay for GAD65 autoantibodies, a key risk-assessment marker for insulin-dependent diabetes mellitus.

Nonisotopic assays for the measurement of autoantibodies to 65-kDa glutamic acid decarboxylase (GAD65) have not previously achieved performance equivalent to radiobinding assays (RBA). We have developed a modified ELISA protocol, DELISA, for measuring autoantibodies to GAD65 in serum. The method overcomes the problems of poor sensitivity and specificity associated with conventional ELISAs. Serum containing GAD65 autoantibodies is incubated with biotinylated GAD65 (bGAD65). Sufficient soluble Protein A-dextran conjugate is added to bind the immunoglobulins in the sample, including GAD65 autoantibodies to which GAD65 is bound. After incubation, the mixture is transferred to a streptavidin-p4ated microtiter well, which binds free bGAD65 but not bGAD65 bound to autoantibodies. Streptavidin-bound bGAD65 is detected by means of a peroxidase-GAS65MAb conjugate. The method appears to have comparable sensitivity and specificity to those of RBAs. Reaction of the antibodies with soluble antigen to increase the binding rate and the use of high serum concentrations and very low antigen concentrations to increase sensitivity are critical elements of the method.

Autoantibodies↗
PubMed1996

Response of the blast stem cells of acute myeloblastic leukemia to G-CSF, GM-CSF, or the ligand for C-KIT, alone or in combination.

Growth factors are commonly included in protocols for the treatment of acute myeloblastic leukemia (AML). Because the response of blast stem cells in culture to growth factors might influence the contribution of factor to clinical outcome, we studied 42 patients with AML or severe myelodysplasia. Peripheral blood blast cells were cultured in a clonogenic assay at three cell concentrations and with the following combinations of growth factors: no added growth factor (NF), G-CSF, GM-CSF, Kit ligand (KL), G-CSF + KL, GM-CSF + KL, and G-CSF + GM-CSF + KL. The slope of the line relating cell number plated to colony formation was calculated by least squares. The slopes were used to form three equally sized groups of patients. Marked heterogeneity was found in response of the blast populations to factor. A few general conclusions emerged: (1) autonomous blast populations are very rare; (2) although usually a population responds better to one of the growth factors than to others, seldom is the response exclusively to one factor; (3) when more than one factor is included in the cultures, synergism is usually seen. Significant associations were seen between successful remission induction for low slope values in cultures with NF or KL alone. For remission, but not survival, associations were found with intermediate values of slope in cultures with G-CSF + KL and GM-CSF + KL. We conclude that measurements of growth factor response are feasible and yield clinically useful data.

Adult↗
PubMed1995

Sensitivities of AML blast stem cells to idarubicin and daunorubicin: a comparison with normal hematopoietic progenitors.

The objective of this study was to determine whether or not cell culture studies could contribute to the correct choice between idarubicin (IDA) and daunorubicin (DNR) for combination with ara-C in remission induction therapy of AML. Two growth factor-sensitive AML cell lines and the peripheral blood blast cells from 10 patients with AML were studied in culture for sensitivity to IDA and DNR under four culture conditions; cells were grown either in methylcellulose or suspension culture in the presence of G-CSF or GM-CSF. Normal bone marrow cells were cultured in methylcellulose in the presence of IDA or DNR under conditions suitable for the detection of BFU-E and CFU-C. Dose-response curves for AML blast cells were characterized by an initial shoulder and then an exponential decrease in survival. Marked patient-to-patient variation was observed for both portions of the survival curves. IDA was significantly more toxic to blast cells than DNR, especially for more sensitive cell populations. Consistent differences in drug sensitivity in the four culture conditions were not observed. BFU-E and CFU-C dose-response curves of normal marrow progenitors resembled those of AML blast cells but in contrast fell within a narrow range. The culture studies support the clinical finding in AML of modest superiority of IDA over DNR. The heterogeneity in sensitivity of AML blasts in culture suggests an opportunity to individualize treatment. Preclinical studies may help in developing such a therapeutic approach.

Aged↗
PubMed1994

Expression of the Kit and KitA receptor isoforms in human acute myelogenous leukemia.

Genetic and biologic evidence suggests that the Kit receptor tyrosine kinase is important in early events in hematopoietic stem cell differentiation. Two naturally occurring isoforms of the Kit receptor, termed Kit and KitA, were originally described in mouse cells and, subsequently, in human cells. These isoforms differ by the presence (KitA) or absence (Kit) of four amino acids (Gly-Asn-Asn-Lys) that lie immediately outside the transmembrane domain. RNase protection was used to measure the levels of Kit and KitA mRNA in normal bone marrow and the blast cells from individuals with acute myelogenous leukemia (AML). Although both isoforms were present in all the AML samples tested, there was considerable heterogeneity in the relative levels of the two transcripts, with Kit to KitA RNA ratios varying from as low as 1.3 to as high as 12. In contrast, the ratio of Kit to KitA transcripts in normal bone marrow was tightly clustered between 4.4 and 5.5. Because alterations in the relative levels of expression of Kit and KitA may affect the ability of a cell to respond to the Kit ligand, Steel factor, we examined the Kit/KitA RNA ratio in AML patients that differed with respect to a number of diagnostic, prognostic, and biologic parameters. The relative levels of Kit to KitA RNA was independent of French-American-British subtype, response to therapy, and primary and secondary plating efficiencies in vitro. Thus, these data suggest that the relative levels of the two isoforms of the Kit receptor in AML are not associated with any obvious biologic or clinical parameters and, therefore, may reflect naturally occurring changes in splicing mechanisms as stem cells differentiate.

Amino Acid Sequence↗