Biomedical subjects

Robert Clarke

Publications and source records attributed to Robert Clarke.

At least 19 recordsLinked to original sources

PubMed2026

Cross-Ancestry Proteogenomic Analyses Identified New Therapeutic Insights for Ischemic Heart Disease.

BACKGROUND: Most drugs target proteins, and proteome-wide genetic analyses in diverse populations could discover potential novel and repurposed targets for improved prevention and treatment of ischemic heart disease (IHD) beyond statin therapy. OBJECTIVES: The purposes of this study were to use cis-acting single nucleotide polymorphisms (cis-pQTLs) identified for plasma proteins in East Asians and Europeans to discover and validate potential drug targets for IHD. METHODS: We measured plasma levels of 9,520 (Olink/SomaScan: 2,923/7,297) proteins in a case-cohort study of IHD (1,976 incident cases and 2,001 subcohort controls) in statin-free individuals in the prospective China Kadoorie Biobank (CKB). Genome-wide association studies identified 2,895 (Olink/SomaScan: 1,301/1,594) cis-pQTLs for these proteins in CKB. Two-sample Mendelian randomization (MR) and colocalization analyses assessed associations of all available cis-pQTLs for these proteins with IHD in East Asians (n = 29,319 cases), with further replication in Europeans (n = 181,522 cases) and comparison with findings in previous MR studies. RESULTS: In CKB observational analyses, a total of 959 (Olink/SomaScan: 426/533) proteins were associated at false discovery rate-corrected P < 0.05 with IHD after adjusting for major IHD risk factors. Two-sample MR analyses provided genetic support for 54 unique (Olink/SomaScan: 36/28) proteins in IHD etiology. Colocalization analyses confirmed shared gene-protein-IHD associations (posterior probability of hypothesis 4 [PPH4] ≥0.8) for 15 unique (Olink/SomaScan: 10/10) proteins, including 8 lipid-related, 3 inflammation-related, 1 blood pressure-related, and 3 alcohol-related proteins in East Asians. In Europeans, MR analyses of 12 non-alcohol-related proteins showed directionally concordant results for 8 proteins, with 5 having strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8), including 4 lipid-related (proprotein convertase subtilisin/kexin type 9, LPA, APOE, cadherin-1) and 1 systolic blood pressure-related (fibroblast growth factor 5) protein. However, 4 proteins showed directionally discordant MR results, including 2 lipid-related (APOA5, SORT1) and 1 inflammation-related (transforming growth factor beta 1) proteins with strong colocalization evidence of shared gene-protein-IHD associations (PPH4 ≥0.8). Comparison with previous MR studies revealed little consistency across studies in the number and identity of target proteins for IHD beyond well-established lipid-related (low-density lipoprotein cholesterol, lipoprotein(a), and triglycerides) or inflammation-related (interleukin-6) protein targets. CONCLUSIONS: The findings support a role for lipid-driven chronic inflammation in IHD etiology, and treatment strategies simultaneously targeting multiple lipid and inflammation pathways should be prioritized for further research to improve drug treatment of IHD beyond statin therapy.

Aged↗

PubMed2025

Bayesian identification of differentially expressed isoforms using a novel joint model of RNA-seq data.

We develop a Bayesian approach, BayesIso, to identify differentially expressed isoforms from RNA-seq data. The approach features a novel joint model of the sample variability and the deferential state of isoforms. Specifically, the within-sample variability and the between-sample variability of each isoform are modeled by a Poisson-Lognormal model and a Gamma-Gamma model, respectively. Using a Bayesian framework, the differential state of each isoform and the model parameters are jointly estimated by a Markov Chain Monte Carlo (MCMC) method. Extensive studies using simulation and real data demonstrate that BayesIso can effectively detect isoforms of less differentially expressed and differential transcripts for genes with multiple isoforms. We applied the approach to breast cancer RNA-seq data and uncovered a unique set of isoforms that form key pathways associated with breast cancer recurrence. First, PI3K/AKT/mTOR signaling and PTEN signaling pathways are identified as being involved in breast cancer development. Further integrated with protein-protein interaction data, pathways of Jak-STAT, mTOR, MAPK and Wnt signaling are revealed in association with breast cancer recurrence. Finally, several pathways are activated in the early recurrence of breast cancer. In tumors that occur early, members of pathways of cellular metabolism and cell cycle (such as CD36 and TOP2A) are upregulated, while immune response genes such as NFATC1 are downregulated.

Humans↗

PubMed2003

Cadmium mimics the in vivo effects of estrogen in the uterus and mammary gland.

It has been suggested that environmental contaminants that mimic the effects of estrogen contribute to disruption of the reproductive systems of animals in the wild, and to the high incidence of hormone-related cancers and diseases in Western populations. Previous studies have shown that functionally, cadmium acts like steroidal estrogens in breast cancer cells as a result of its ability to form a high-affinity complex with the hormone binding domain of the estrogen receptor. The results of the present study show that cadmium also has potent estrogen-like activity in vivo. Exposure to cadmium increased uterine wet weight, promoted growth and development of the mammary glands and induced hormone-regulated genes in ovariectomized animals. In the uterus, the increase in wet weight was accompanied by proliferation of the endometrium and induction of progesterone receptor (PgR) and complement component C3. In the mammary gland, cadmium promoted an increase in the formation of side branches and alveolar buds and the induction of casein, whey acidic protein, PgR and C3. In utero exposure to the metal also mimicked the effects of estrogens. Female offspring experienced an earlier onset of puberty and an increase in the epithelial area and the number of terminal end buds in the mammary gland.

Animals↗

PubMed2003

Utility of TICS-M for the assessment of cognitive function in older adults.

BACKGROUND: Routine screening of high-risk elderly people for early cognitive impairment is constrained by the limitations of currently available cognitive function tests. The Telephone Interview of Cognitive Status is a novel instrument for assessment of cognitive function that can be administered in person or by telephone. OBJECTIVE: To evaluate the determinants and utility of TICS-M (13-item modified version) for assessment of cognitive function in healthy elderly people. METHODS: The utility of TICS-M was compared with more widely used MMSE and CAMCOG in a cross-sectional survey of 120 older (62 to 89 years) UK adults. RESULTS: The TICS-M cognitive test scores (27.97, SD 4.15) were normally distributed in contrast with those for MMSE and CAMCOG that had a negatively skewed distribution. TICS-M scores were inversely correlated with age (r = -0.21) and with the NART fullscale IQ (r = -0.35), but were independent of years of education in this cohort. TICS-M was highly correlated with MMSE (r = 0.57) and with CAMCOG (r = 0.62) scores. The time required to complete the test is comparable to MMSE and substantially less than CAMCOG. CONCLUSIONS: The normal distribution of TICS-M test scores suggest that this test is less constrained by the ceiling effect which limits the utility of MMSE and CAMCOG test scores in detecting early cognitive impairment. TICS-M is an appropriate instrument to assess cognitive function in both research and in clinical practice.

Aged↗

PubMed2003

Effect of vitamins and aspirin on markers of platelet activation, oxidative stress and homocysteine in people at high risk of dementia.

OBJECTIVES: To examine the association of cognitive impairment with platelet activation and reactive oxygen species and total homocysteine levels; and to assess the biochemical efficacy of treatment with aspirin and vitamin supplements in people at high risk of dementia. SUBJECTS: People with dementia or mild cognitive impairment. DESIGN AND INTERVENTION: In a 2 x 2 x 2 factorial design trial, 149 people at high-risk of dementia were randomized to receive either low-dose aspirin (81 mg) or placebo; and folic acid (2 mg) plus vitamin B12 (1 mg) or placebo; and vitamins E (500 mg) plus C (200 mg) or placebo. Participants were seen twice before and once after 12 weeks of treatment. MAIN OUTCOME MEASURES: At each visit, participants had their cognitive function assessed and had blood collected for homocysteine, folate and vitamin B12 determination and urine collected for markers of platelet activation (11-dehydro-thromboxane B2) and reactive oxygen species (8-epi-PGF2 alpha). RESULTS: Prior to treatment, cognitive function was inversely related with homocysteine and with urinary thromboxane and isoprostane, and these associations were independent of age. Aspirin was associated with a median reduction in 11-dehydrothromboxane B2 of 73% (P < 0.001). B-vitamins lowered plasma homocysteine concentration by 30% (P < 0.0001) and antioxidant vitamins lowered isoprostane excretion by 26% (P < 0.1). No effect of treatment on cognitive function was detected. CONCLUSIONS: Aspirin and B-vitamins were effective in reducing biochemical factors associated with cognitive impairment in people at risk of dementia. Large-scale trials are now required to assess the relevance of aspirin and B-vitamins for the maintenance of cognitive function in people at risk of dementia.

Aged↗

PubMed2003

Identification of a putative intestinal stem cell and early lineage marker; musashi-1.

There are few reliable markers for adult stem cells and none for those of the intestinal epithelium. Previously, indirect experimental approaches have predicted stem cell position and numbers. The Musashi-1 (Msi-1) gene encodes an RNA binding protein associated with asymmetric divisions in neural progenitor cells. Two-day-old, adult, and 4.5 h, 1-, 2-, 4- and 12-day post-irradiation samples of BDF1 mouse small intestine, together with some samples of mouse colon were stained with a rat monoclonal antibody to Musashi-1 (14 H-1). Min ( + / - ) mice with small intestinal adenomas of varying sizes were also analysed. Samples of human small and large bowel were also studied but the antibody staining was weak. Musashi-1 expression was observed using immunohistochemistry in neonatal, adult, and regenerating crypts with a staining pattern consistent with the predicted number and distribution of early lineage cells including the functional stem cells in these situations. Early dysplastic crypts and adenomas were also strongly Musashi-1 positive. In situ hybridization studies showed similar expression patterns for the Musashi mRNA and real-time quantitative RT-PCR showed dramatically more Msi-1 mRNA expression in Min tumours compared with adjacent normal tissue. These observations suggest that Musashi-1 is a marker of stem and early lineage progenitor cells in murine intestinal tissue.

Adult↗

PubMed2003

Homocysteine, renal function, and risk of cardiovascular disease.

BACKGROUND: Patients with renal impairment have markedly elevated homocysteine levels and are at particularly high risk of ischemic heart disease (IHD) and stroke, but the relevance of elevated homocysteine levels in this population is uncertain. METHODS: We examined the association with IHD from a meta-analysis of 30 population studies of differences in homocysteine concentrations (involving 5000 IHD and 1100 stroke events in apparently healthy individuals), and from a meta-analysis of 40 studies (involving 11,000 IHD events) of the association of methylene-tetrahydrofolate reductase (MTHFR) and homocysteine with IHD. We explored the association of renal function with homocysteine levels in a cross-sectional study of 1200 healthy elderly individuals. RESULTS: Among prospective studies, a 25% lower blood homocysteine level was associated with an 11% lower risk of IHD and about a 20% lower risk of stroke, after adjustment for known cardiovascular risk factors. Individuals who had the TT genotype for MTHFR compared with those with CC had 25% higher homocysteine levels and a 16% higher risk of IHD. Among individuals aged over 65 years, a 1% higher serum creatinine level was associated with about a 1% higher homocysteine concentration. CONCLUSIONS: The concordance of the IHD risks obtained in the studies of genetically determined differences in homocysteine and the population-based studies of homocysteine suggest that these associations are likely to be causal. Renal function is an important determinant of circulating homocysteine concentrations. Results of ongoing randomized trials of folic acid-based vitamins in patients with renal disease are required to clarify the relevance of lowering homocysteine for vascular disease.

Homocysteine↗

PubMed2003

Screening for vitamin B-12 and folate deficiency in older persons.

BACKGROUND: Vitamin B-12 deficiency is usually accompanied by elevated concentrations of serum total homocysteine (tHcy) and methylmalonic acid (MMA). Folate deficiency also results in elevated tHcy. Measurement of these metabolites can be used to screen for functional vitamin B-12 or folate deficiency. OBJECTIVE: We assessed the prevalence of vitamin B-12 and folate deficiency in a population-based study (n = 1562) of older persons living in Oxford City, United Kingdom. DESIGN: We postulated that, as vitamin B-12 or folate concentrations declined from adequate to impaired levels, tHcy (or MMA) concentrations would increase. Individuals were classified as being at high risk of vitamin B-12 deficiency if they had low vitamin B-12 (< 150 pmol/L) or borderline vitamin B-12 (150-200 pmol/L) accompanied by elevated MMA (> 0.35 micromol/L) or tHcy (> 15.0 micromol/L). Individuals were classified as being at high risk of folate deficiency if they had low folate (< 5 nmol/L) or borderline folate (5-7 nmol/L) accompanied by elevated tHcy (> 15 micromol/L). RESULTS: Cutoffs of 15.0 micro mol/L for tHcy and 0.35 micro mol/L for MMA identified persons with normal or elevated concentrations. Among persons aged 65-74 and >or= 75 y, respectively, approximately 10% and 20% were at high risk of vitamin B-12 deficiency. About 10% and 20%, respectively, were also at high risk of folate deficiency. About 10% of persons with vitamin B-12 deficiency also had folate deficiency. CONCLUSION: Use of tHcy or MMA among older persons with borderline vitamin concentrations may identify those at high risk of vitamin B-12 deficiency who should be considered for treatment.

Age Factors↗

PubMed2003

Folic acid and reduction of plasma homocysteine concentrations in older adults: a dose-response study.

BACKGROUND: Elevated homocysteine concentrations, a likely risk factor for cardiovascular disease, can be lowered effectively with folic acid. The minimum dose of folic acid required for maximal reduction of homocysteine concentrations is not yet known reliably. OBJECTIVE: We aimed to determine the lowest folic acid dose that decreases plasma homocysteine concentrations adequately in healthy older adults. DESIGN: A dose-response trial with a randomized, double-blind, parallel-group, placebo-controlled design was carried out among 316 Dutch men and women aged 50-75 y. Subjects received daily for 12 wk either a placebo or 1 of the 6 following folic acid doses: 50, 100, 200, 400, 600, or 800 micro g. The relative changes in plasma homocysteine concentration in response to increasing doses of folic acid were used to calculate the dose-response curve. An adequate dose of folic acid was defined as the dose that induced >or= 90% of the maximal reduction in homocysteine concentration. RESULTS: The relative decrease in plasma homocysteine concentration was associated exponentially with increasing doses of folic acid. From the dose-response curve, the adequate daily dose of folic acid was estimated to be 392 micro g, which decreased plasma homocysteine concentrations 22%. CONCLUSION: In older adults, daily supplementation with folic acid effectively lowers plasma homocysteine concentrations, and a daily dose of approximately 400 micro g is the minimum dose required for adequate homocysteine reduction.

Aged↗

PubMed2003

Regression dilution bias in blood total and high-density lipoprotein cholesterol and blood pressure in the Glostrup and Framingham prospective studies.

BACKGROUND: In epidemiological studies, within-person variability in measured values of a risk factor may underestimate the association between prolonged or 'usual' levels of a risk factor with risk of disease - 'regression dilution'. The importance of regression dilution for high-density lipoprotein (HDL)-cholesterol and the extent to which this may differ from that for total cholesterol is not known. The aim of this study was to assess the magnitude of regression dilution bias for HDL-cholesterol, total cholesterol and blood pressure after varying intervals of follow-up in two prospective cohort studies. METHODS: Regression dilution ratios were estimated for each risk factor using the correlations between baseline and re-survey values in the Glostrup Population Studies and the NHLBI Framingham Heart Study after various time intervals. The regression dilution ratios in each cohort after a fixed interval between measurements were compared. RESULTS: The regression dilution ratios after 10 years were 0.51 and 0.56 for systolic blood pressure in Glostrup and Framingham, respectively; 0.52 and 0.54 for diastolic blood pressure; and 0.68 and 0.63 for total cholesterol. In both studies, the regression dilution ratios for these risk factors became more extreme with increasing intervals between measurements. The regression dilution ratio for HDL-cholesterol after 10 years in Glostrup was 0.72, which suggests that the importance of regression dilution for HDL-cholesterol was similar to that for total cholesterol. CONCLUSION: Failure to correct for increasing regression dilution with longer follow-up may account for some of the discrepant results obtained for the importance of these risk factors in epidemiological studies at varying intervals of follow-up.

Adult↗

PubMed2003

Estrogen withdrawal-induced NF-kappaB activity and bcl-3 expression in breast cancer cells: roles in growth and hormone independence.

About one-third of breast cancers express a functional estrogen (beta-estradiol [E2]) receptor (ER) and are initially dependent on E2 for growth and survival but eventually progress to hormone independence. We show here that ER(+), E2-independent MCF-7/LCC1 cells derived from E2-dependent MCF-7 cells contain elevated basal NF-kappaB activity and elevated expression of the transcriptional coactivator Bcl-3 compared with the parental MCF-7 line. LCC1 NF-kappaB activity consists primarily of p50 dimers, although low levels of a p65/p50 complex are also present. The ER(-) breast cancer cell lines harbor abundant levels of both NF-kappaB complexes. In contrast, nuclear extracts from MCF-7 cells contain a significantly lower level of p50 and p65 than do LCC1 cells. Estrogen withdrawal increases both NF-kappaB DNA binding activity and expression of Bcl-3 in MCF-7 and LCC1 cells in vitro and in vivo. Tumors derived from MCF-7 cells ectopically expressing Bcl-3 remain E2 dependent but display a markedly higher tumor establishment and growth rate compared to controls. Expression of a stable form of IkappaBalpha in LCC1 cells severely reduced nuclear expression of p65 and the p65/p50 DNA binding heterodimer. Whereas LCC1 tumors in nude mice were stable or grew, LCC1(IkappaBalpha) tumors regressed after E2 withdrawal. Thus, both p50/Bcl-3- and p65/p50-associated NF-kappaB activities are activated early in progression and serve differential roles in growth and hormone independence, respectively. We propose that E2 withdrawal may initiate selection for hormone independence in breast cancer cells by activation of NF-kappaB and Bcl-3, which could then supplant E2 by providing both survival and growth signals.

Animals↗

PubMed2002

Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.

BACKGROUND: The age-specific relevance of blood pressure to cause-specific mortality is best assessed by collaborative meta-analysis of individual participant data from the separate prospective studies. METHODS: Information was obtained on each of one million adults with no previous vascular disease recorded at baseline in 61 prospective observational studies of blood pressure and mortality. During 12.7 million person-years at risk, there were about 56000 vascular deaths (12000 stroke, 34000 ischaemic heart disease [IHD], 10000 other vascular) and 66000 other deaths at ages 40-89 years. Meta-analyses, involving "time-dependent" correction for regression dilution, related mortality during each decade of age at death to the estimated usual blood pressure at the start of that decade. FINDINGS: Within each decade of age at death, the proportional difference in the risk of vascular death associated with a given absolute difference in usual blood pressure is about the same down to at least 115 mm Hg usual systolic blood pressure (SBP) and 75 mm Hg usual diastolic blood pressure (DBP), below which there is little evidence. At ages 40-69 years, each difference of 20 mm Hg usual SBP (or, approximately equivalently, 10 mm Hg usual DBP) is associated with more than a twofold difference in the stroke death rate, and with twofold differences in the death rates from IHD and from other vascular causes. All of these proportional differences in vascular mortality are about half as extreme at ages 80-89 years as at ages 40-49 years, but the annual absolute differences in risk are greater in old age. The age-specific associations are similar for men and women, and for cerebral haemorrhage and cerebral ischaemia. For predicting vascular mortality from a single blood pressure measurement, the average of SBP and DBP is slightly more informative than either alone, and pulse pressure is much less informative. INTERPRETATION: Throughout middle and old age, usual blood pressure is strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold down to at least 115/75 mm Hg.

Adult↗

PubMed2002

Block principal component analysis with application to gene microarray data classification.

We propose a block principal component analysis method for extracting information from a database with a large number of variables and a relatively small number of subjects, such as a microarray gene expression database. This new procedure has the advantage of computational simplicity, and theory and numerical results demonstrate it to be as efficient as the ordinary principal component analysis when used for dimension reduction, variable selection and data visualization and classification. The method is illustrated with the well-known National Cancer Institute database of 60 human cancer cell lines data (NCI60) of gene microarray expressions, in the context of classification of cancer cell lines.

DNA, Neoplasm↗

PubMed2002

Association of interferon regulatory factor-1, nucleophosmin, nuclear factor-kappaB, and cyclic AMP response element binding with acquired resistance to Faslodex (ICI 182,780).

To identify genes associated with survival from antiestrogens, both serial analysis of geneexpression and gene expression microarrays were used to explore the transcriptomes of antiestrogen-responsive (MCF7/LCC1) and -resistant variants(MCF7/LCC9) of the MCF-7 human breast cancer cell line. Structure of the gene microarray expression data was visualized at the top level using a novel algorithm that derives the first three principal components,fitted to the antiestrogen-resistant and -responsive gene expression data, from Fisher's information matrix. The differential regulation of several candidate genes was confirmed. Functional studies of the basal expression and endocrine regulation of transcriptional activation of implicated transcription factors were studied using promoter-reporter assays. The putative tumor suppressor interferon regulatory factor-1 is down-regulated in resistant cells, whereas its nucleolar phosphoprotein inhibitor nucleophosmin is up-regulated. Resistant cells also up-regulate the transcriptional activation of cyclic AMP response element (CRE) binding and nuclear factor kappaB (NFkappaB) while down-regulating epidermal growth factor receptor protein expression. Inhibition of NFkappaB activity by ICI 182,780 is lost in resistant cells, but CRE activity is not regulated by ICI 182,780 in either responsive or resistant cells. Parthenolide, a potent and specific inhibitor of NFkappaB, inhibits the anchorage-dependent proliferation of antiestrogen-resistant but not antiestrogen-responsive cells. This observation implies a greater reliance on their increased NFkappaB signaling for proliferation in cells that have survived prolonged exposure to ICI 182,780. These data from serial analysis of gene expression and gene microarray studies implicate changes in a novel signaling pathway, involving interferon regulatory factor-1, nucleophosmin, NFkappaB, and CRE binding in cell survival after antiestrogen exposure. Cells can up-regulate some estrogen-responsive genes while concurrently losing the ability of antiestrogens to regulate their expression. Signaling pathways that are not regulated by estrogens also can be up-regulated. Thus, some breast cancer cells may survive antiestrogen treatment by bypassing specific growth inhibitory signals induced by antagonist-occupied estrogen receptors.

Animals↗

PubMed2002

Functionally active estrogen receptor isoform profiles in the breast tumors of African American women are different from the profiles in breast tumors of Caucasian women.

BACKGROUND: Several cancer surveys have shown that African-American women (AAW) develop highly aggressive breast tumors and experience about three times higher mortality rates compared with other populations. Generally, breast tumors in AAW are poorly differentiated or undifferentiated and exhibit increased frequency of nuclear atypia, higher mitotic activity, higher S-phase fraction, and tumor necrosis. The molecular factors responsible for these tumor characteristics are mostly unknown. METHODS: To explore whether the aggressive tumor biology observed in AAW is related to distinct alterations in estrogen receptor (ER) isoforms, the relative expression levels of four functionally active ER isoform mRNAs, ERalpha wild type, ERbeta wild type, ERalpha exon 3delta, and ERalpha exon 5delta, were measured by reverse transcriptase-polymerase chain reaction analysis in 18 immunohistochemically ERalpha positive tumors and in 6 ERalpha negative tumors and their matched normal tissues. RESULTS: In the tumors of AAW, the protective ERbeta isoform was decreased significantly compared with matched normal tissues (paired t test; n = 24 patients; P = 0.0018). In addition, both the constitutively active ERalpha exon 5delta and the dominant negative ERalpha exon 3delta mRNA levels were elevated in tumor tissues compared with matched normal tissues (paired t tests; n = 24 patients; P = 0.0002 and P = 0.024, respectively). CONCLUSIONS: The data presented here show for the first time that functionally active ER isoform profiles in the breast tumors of AAW are different from those in Caucasian women. The tumors in AAW are characterized by decreased levels of the protective ERbeta isoform and elevated levels of the constitutively active ERalpha exon 5delta isoform. Variations in estrogen-mediated signaling because of the alterations in these two ER isoforms may account in part for differences in tumor biology between AAW and Caucasian women.

Black People↗

PubMed2002

C-7 analogues of progesterone as potent inhibitors of the P-glycoprotein efflux pump.

The P-glycoprotein product (Pgp) of the MDR1 gene has been implicated in the multiple drug resistance phenotype expressed by many cancers. Functioning as an efflux pump, P-glycoprotein prevents the accumulation of high intracellular concentrations of substrates. We have taken a rational approach to designing inhibitors of P-glycoprotein function, selecting a natural substrate (progesterone) as our lead compound. We hypothesized that progesterone, substituted at C-7 with an aromatic moiety(s), would exhibit reduced Pgp affinity, significantly increased antiPgp activity, and reduced affinity for progesterone receptors (PGR). We synthesized 7 alpha-[4'-(aminophenyl)thio]pregna-4-ene-3,20-dione (2), which comprises a C-7 alpha thiol bridge linking an aminophenyl moiety to progesterone, from pregna-4,6-diene-3,20-dione (1). The subsequent addition reaction of 2 with the appropriate isocyanate produced an initial series of compounds (3-6). Compounds 3-5 (respectively, -CH(2)CH(2)Cl; -CH(2)CH(3); and -CH(CH(3))C(6)H(5)) exhibit a significantly increased ability to inhibit P-glycoprotein. Potency for restoring doxorubicin accumulation in MDR1-transduced human breast cancer cells is increased up to 60-fold as compared with progesterone. Compound 5 has greater potency than verapamil and is equipotent with cyclosporin A, for inhibiting P-glycoprotein function. Furthermore, 5 does not bind to PGR, implying a potential reduction in in vivo toxicity. These data identify C-7-substituted progesterone analogues and 5, in particular, as rationally designed antiPgp compounds worthy of further evaluation/development.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

Homocysteine, silent brain infarcts, and white matter lesions: The Rotterdam Scan Study.

Silent brain infarcts and white matter lesions are frequently seen on magnetic resonance imaging in healthy elderly people and both are associated with an increased risk of stroke and dementia. Plasma total homocysteine may be a potentially modifiable risk factor for stroke and dementia. We examined whether elevated total homocysteine levels are associated with silent brain infarcts and white matter lesions. The Rotterdam Scan Study is a population-based study of 1,077 people aged 60 to 90 years who had cerebral magnetic resonance imaging. The cross-sectional relation of total homocysteine with silent infarcts and white matter lesions was analyzed with adjustment for cardiovascular risk factors. The mean plasma total homocysteine level was 11.5 micromol/l (standard deviation 4.1). The risk of silent brain infarcts increased with increasing total homocysteine levels (odds ratio 1.24/standard deviation increase, 95% confidence interval 1.06-1.45). The severity of periventricular white matter lesions and extent of subcortical white matter lesions were also significantly associated with total homocysteine levels, even after excluding those with silent brain infarcts. The overall risk of having either a silent brain infarct or severe white matter lesions was strongly associated with total homocysteine levels (odds ratio 1.35/standard deviation increase, 95% confidence interval 1.16-1.58). We concluded that total homocysteine levels are associated with silent brain infarcts and white matter lesions independent of each other and of other cardiovascular risk factors.

Aged↗

PubMed2002

Do estrogens always increase breast cancer risk?

The etiology of breast cancer is closely linked to the female hormone estrogen, with high life-time exposure being suggested to increase breast cancer risk [Nature 303 (1983) 767]. However, there appears to be a disparity between studies attempting to establish an association between high estrogen levels and breast cancer risk. This disparity becomes smaller by taking into consideration a timing factor, and we propose that estrogens can increase, decrease, or have no effect on breast cancer risk, depending on the timing of estrogen exposure. We further propose that the timing of estrogenic exposures may play at least as important a role in affecting breast cancer risk as life-time exposure.

Breast Neoplasms↗