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Biomedical subjects

T Ojasoo

Publications and source records attributed to T Ojasoo.

At least 19 recordsLinked to original sources
PubMed2000

Deaths from breast cancer: tackling multidimensionality and non-linearity by correspondence analysis.

AIM: We investigated the use of non-linear, multidimensional factor analysis for the study of observational data on death from breast cancer. These data were obtained in the context of a clinical practice and not in a clinical trial. We looked into the correlations between patient characteristics and time of death and/or disease-free interval. PATIENTS AND METHODS: We first analyzed the characteristics of a population of patients that had died from breast cancer (n = 295), then of a population including patients still alive 7 years after surgery (n = 344). We used correspondence analysis (CA) which is based on chi(2)-metrics, does not assume linear relationships, and provides graphic overviews. RESULTS: The CA mapped variables (clinical stage, histoprognostic grade, node status, receptor positivity) in a way that fits in well with available knowledge on their importance as prognostic factors. We observed, however, that death occurred during three main periods (1-3, 4-7, < OR = 8 years after surgery) defined by different mixes of variables as if the disease progressed by stage rather than continuously. The CA distinguished long-term survivors (>7 years) from patients who died 8-10 years after surgery. Long-term survivors tended to be node-negative; those who died at 8-10 years tended to be the youngest patients (under 40). CONCLUSIONS: Because correspondence analysis combines the advantages of multidimensional and non-linear methods, it is a valuable exploratory tool for describing multiple correlations within a population before attempting to establish statistical significance of selected variables by more classic methods.

Adult↗
PubMed1999

From the life-cycles of clinical evidence to the learning curve of clinical experience.

Treatments on offer to an individual with suspected disease are based on concepts which, like products, go through life-cycles (introduction, growth, maturity, decline). We argue that randomized controlled trials, meta-analyses, and guidelines have reached maturity and/or are already on the decline and note renewed interest in case reports and qualitative medicine. The latter emphasize individual rather than 'average' patients. Moreover, we point out that scientific evidence relates not only to variables that can be measured but also to categorical variables that are often neglected. An appropriate treatment strategy is probably one which is indicated by several methods based on different concepts rather than by a single standard method. The doctor's role is to use his critical judgement and experience to appraise evidence from formal trials and from analyses of observational data and to share his views with the patient.

Clinical Protocols↗
PubMed1999

Inhibition of chemiluminescence in human PMNs by monocyclic phenolic acids and flavonoids.

Flavonoids are metabolized in vivo to monocyclic phenolic acids. We investigated whether 18 phenolic acids of the benzoic, phenylacetic, phenylpropanoic or cinnamic series-known or potential metabolites of flavonoids-inhibit reactive oxygen species (ROS) released by human polymorphonuclear neutrophils (PMNs). Chemiluminescence was measured after PMN stimulation with three agents (N-fMetLeuPhe, phorbol myristate acetate (PMA), or opsonised zymosan) using two probes (lucigenin or luminol) with or without horseradish peroxidase (HRP) in order to derive specificity profiles for each test compound. The profiles of the phenolic acids and flavonoids were compared by a multivariate (correspondence) factor analysis. Overall, the phenolic acids were less specific than the flavonoids and, with a few exceptions, less potent. Phenolic acids had virtually no effect on the chemiluminescence related to O2- formation that is measured by lucigenin but inhibited luminol luminescence. Inhibition for all but two phenolic acids was sensitive to HRP and might be explained by a scavenger mechanism. Few structure-activity relationships emerged suggesting that simple properties such as radical scavenging and/or redox activity rather than overall structure might be the key determinants of chemiluminescence inhibition. Whatever the mechanism, however, we conclude that part of the in vivo pharmacological activity of flavonoids may readily be accounted for by phenolic acids.

Adult↗
PubMed1998

Study of the age and sex dependence of trace elements in hair by correspondence analysis.

The aim of the study was to examine the potential of multidimensional analysis, and in particular of correspondence analysis (CA), in bringing to light the influence of sex and age on trace element (TE) concentrations in hair from an unselected French population. Sixteen elements (S, Hg, Se, Zn, Pb, Cd, Ni, Co, Mn, Fe, Cr, Mg, Al, Ca, Cu, Ag) were assayed by inductively coupled argon plasma (ICAP) emission spectroscopy in the scalp hair of 135 men and 346 women. In spite of the high background noise, CA was able to reveal the differing patterns in males and females. For instance, in this population, higher relative levels of the essential elements, Ca, Mg, Zn, and Cu, but also of Ag, characterized women's hair, whereas higher relative levels of the heavy metals, Fe and Pb, were associated with men's hair. Al and Ag were unexplainedly high in the hair of the youngest members of the population. The Cu and Co of youth seemed to give way to a predominance of Zn in maturity. The hair of individuals in their forties tended to be richest in Ca and Mg, but these elements decreased with advancing age. Heavy metals (Hg, Pb, Fe) accumulated with age, whereas Se, Mn, and Cr seemed independent of age. CA is manifestly a very useful tool for revealing underlying dimensions in complex dynamic systems and unsuspected relationships among variables. Clearly, the significance of the high Al and Ag contents in the hair of certain members of the population, especially of the very young, needs to be investigated from both physiological and toxicological aspects.

Adolescent↗
PubMed1998

Correspondence analysis of protein kinase C (PKC) inhibition by bis-basic substituted benzamides.

We describe the synthesis of a novel series of bis-basic substituted benzamides and their relative potency in inhibiting rat brain protein kinase alpha (PKC alpha) activity. None of the compounds inhibited enzyme activity via the catalytic domain but several did via the regulatory domain at 1-5 microM concentrations. Inhibition was comparable to that of several di- and triphenylacrylonitriles and triphenylethylenes. According to a multivariate factor (correspondence) analysis of QSAR descriptors, hydrophobicity (log p) and hydration energy were the most discriminant descriptors, much more so than molecular mass, molar refractivity, polarizability, molecular volume and solvent-accessible surface. Inhibitory activity was correlated with high hydrophobicity and low hydration energy. The higher potency of GL9 (N,N'-oxalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide]) that differed from its congener (GL25) by the presence of an oxamide rather than succinamide moiety was tentatively explained by the greater negative charges associated with the carbonyl groups of its oxamide residue. The higher potency of GL22 (N,N'-tere-phthalyl-bis[(o-amino)[2-(diethylamino)ethyl]-benzamide ] in which an aromatic ring is inserted between two benzamide moieties in para, para' rather than ortho, ortho' positions as in GL23 might be due to a planar conformation facilitating membrane insertion. In conclusion, correspondence analysis is a neat way of highlighting similarities and differences in molecular properties (QSAR descriptors and potency). Therapeutic doses of many classes of drug might interfere with the regulatory domain of PKC alpha if, like our test-compounds, they have basic side-chain(s), high hydrophobicity, low hydration energy, a planar conformation and/or a highly charged reactive (oxamide) moiety.

Animals↗
PubMed1997

Cytotoxicity and antiestrogenicity of a novel series of basic diphenylethylenes.

On the premise that it is necessary to develop antiestrogens with a higher cytotoxic component in order to reduce the risks of the development of heterogeneous malignant cell populations in breast cancer, we studied a novel series of basic diphenylethylenes, for the most part devoid of estrogenic activity, with low antiestrogenicity but much enhanced cytotoxicity compared to the reference drug tamoxifen. The main structural features associated with cytotoxicity were E isomery, substituents of five to eight carbons on the ethylene bond, and dibasicity.

Antineoplastic Agents↗
PubMed1996

Taxonomy of nuclear receptors and SERPINS by multivariate analysis of amino-acid composition.

The global amino-acid composition of a protein, although a cruder variable than sequence, is nevertheless informative and has been correlated with protein structural class. In the present study, we have applied complementary multivariate methods based on chi 2-metrics (correspondence factor analysis (CFA), minimum spanning tree (MST), ascending hierarchical classification (AHC)) to the analysis of the amino-acid frequency patterns of the C-terminal domain of 39 members of the nuclear receptor superfamily. The correlations we observed among receptors by this simple approach were, with few exceptions, in line with published phylogenetic dendrograms derived by sequence alignment. Further multivariate analyses were performed on the receptor population combined with 26 serine protease inhibitors (SERPINS) in view of the analogies detected between these superfamilies by hydrophobic cluster analysis (HCA), which were at the origin of the choice of alpha 1-antitrypsin as a 3-dimensional (3D) model for the receptor hormone-binding domain. Both the MST and AHC identified two distinct protein populations which in the principal phi 1 phi 2 CFA plot showed virtually no overlap, thus suggesting that receptors and SERPINS have different overall folding patterns, although the lower-order phi 3 phi 4 plot did reveal some similarities, essentially in the use of hydrophobic amino acids, that might account for analogies in HCA patterns. Receptors had a preference for those amino acids that are more frequent in alpha-helices and SERPINS for those in beta-strands and also tended to use different amino acids in turns. We therefore propose that multivariate analysis of amino-acid composition may prove helpful in identifying proteins for subsequent HCA.

Amino Acids↗
PubMed1995

Correspondence factor analysis of steroid libraries.

The receptor binding of a library of 187 steroids to five steroid hormone receptors (estrogen, progestin, androgen, mineralocorticoid, and glucocorticoid) has been analyzed by correspondence factor analysis (CFA) in order to illustrate how the method could be used to derive structure-activity-relationships from much larger libraries. CFA is a cartographic multivariate technique that provides objective distribution maps of the data after reduction and filtering of redundant information and noise. The key to the analysis of very complex data tables is the formation of barycenters (steroids with one or more common structural fragments) that can be introduced into CFA analyses used as mathematical models. This is possible in CFA because the method uses X2-metrics and is based on the distributional equivalence of the rows and columns of the transformed data matrix. We have thus demonstrated, in purely objective statistical terms, the general conclusions on the specificity of various functional and other groups derived from prior analyses by expert intuition and reasoning. A finer analysis was made of a series of A-ring phenols showing the high degree of glucocorticoid receptor and progesterone receptor binding that can be generated by certain C-11-substitutions despite the presence of the phenolic A-ring characteristic of estrogen receptor-specific binding.

Databases, Factual↗
PubMed1994

Affiliations among steroid receptors as revealed by multivariate analysis of steroid binding data.

To illustrate the informative value of descriptive multivariate analysis in biochemical screening, we have analyzed several data matrices relating to the binding of steroids to the estrogen, progestin, androgen, glucocorticoid and mineralocorticoid receptors in different organs and species. We first compared dendrograms of steroid hormone receptors, that were obtained by an automatic hierarchical classification analysis of the binding data, to published phylogenetic trees of nuclear receptors based on amino-acid sequence analysis. The former classification describes the affiliations among the receptors as given by the binding specificity of a population of 187 steroids in a traditional cytosol binding assay (an indirect comparison of ligand binding sites); the latter describes the affiliations among the receptors as given by a comparison of selected primary sequences involved in ligand-dependent regulation of transactivation and dimerization. A similar hierarchical classification was also performed on the binding data of 62 steroids to myometrium cytosol from different species in order to show to what extent the progesterone-binding proteins in these species are affiliated. Hierarchical clustering methods classify each type of variable (receptor or steroid) independently. In order to be able to correlate both types of variable (receptors and steroids) on single-display graphs, it is necessary to resort to correspondence factorial analysis (CFA). CFA ranks the information content within the experimental system, highlighting major correlations and disclosing secondary correlations by eliminating redundant information and background noise. This multivariate method, applied to the analysis of published data, illustrated the particular specificity of estrogen binding in human vagina and raised the question of the nature of the binding protein in this tissue. Our examples are based on small data tables that can and have been analyzed de visu. However, it is certain that such descriptive multivariate techniques are indispensable for the analysis of large data banks not only to define structure-activity relationships but to estimate the degrees of affiliation among the biological variables being measured. Knowledge of such affiliations will help to organize available information in a context where the complexity of the biological systems under study is becoming increasingly apparent.

Animals↗
PubMed1993

Effects of flavonoids on the release of reactive oxygen species by stimulated human neutrophils. Multivariate analysis of structure-activity relationships (SAR).

In the present study we measured the inhibition by 34 compounds, either flavonoids or related substances, of the release of reactive oxygen species by human neutrophils after stimulation by three agents: the bacterial peptide N-fMetLeuPhe (FMLP), the protein kinase C activator phorbol myristate acetate (PMA) or opsonized zymosan (OZ), using two chemiluminescent probes, lucigenin or luminol in the presence or absence of horseradish peroxidase (HRP). The data matrix (34 x 7) was submitted to multivariate analysis: first, a correspondence factorial analysis to uncover levels of correlation among the biochemical parameters and the specificity of action of the test-compounds and second, a minimum spanning tree analysis that classified the chemical structures into a network describing both specificity and amplitude of the inhibition of the chemiluminescence response. The major conclusions of the analyses were: (a) opposition between inhibition of poly-morphonuclear leukocytes (PMNs) stimulated by FMLP and of PMNs stimulated by PMA or OZ implying that, for the molecules under study, there was a fundamental difference in the manner in which this inhibition occurred and, conversely, a difference in the nature of the stimulatory action of these activators. Molecules lacking hydroxyl groups on ring B, i.e. chrysin, chalcone, flavone and galangin, molecules glycosylated in position 7, i.e. hesperidin and naringin and ring B mono-hydroxylated molecules were, for the most part, at the origin of this dichotomy and might interfere with the membrane FMLP receptor; (b) a marked difference in chemiluminescence inhibition in the presence or absence of HRP that can be explained by the differential action of catechins compared to flavone and flavonol derivatives; (c) a similarity in biological profile between non-flavonoids such as chalcone and phloretin and low mean-activity flavonoids such as chrysin and galangin and between the non-flavonoid curcumin and the highly active flavonoid isorhamnetin; (d) a reaffirmation of the importance of ring A (C5,7) and ring B (C3',4') dihydroxylation, ring C (C3) hydroxylation, but also of the presence of a methoxy group on ring B in engendering high potency. This potency is generally decreased by C2-C3 saturation and by glycosylation. The most active molecules identified in this study provide valuable information for the selection of simpler molecules (e.g. metabolites accounting for the potency of orally administered flavonoids) for further structure-activity relationship (SAR) studies that could lead to the design of novel drugs or prodrugs.

Acridines↗
PubMed1993

Multivariate analysis of plasma hormones in patients with metastatic prostate cancer receiving combined LHRH-analog and antiandrogen therapy.

The following hormones, the plasma protein SHBG, and the tumor markers prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA) were assayed at 18 time-points over 1 month during a double-blind randomized study in 36 stage D2 cancer patients receiving either "buserelin+placebo" or "buserelin+nilutamide (Anandron)": LH, FSH, estradiol, testosterone, dihydrotestosterone, androstenedione, 5-androstene-3,17 beta-diol, dehydroepiandrosterone and its sulfate, cortisol, 17 alpha-hydroxyprogesterone, pregnenolone, 17 alpha-hydroxypregnenolone, and 3 alpha-androstanediol glucuronide. Multivariate analysis of the treatment values (over 10,000 assays) by two complementary methods, correspondence factorial analysis (CFA) and the minimum spanning tree (MST) method, identified those variables within the pathways of androgen metabolism that were correlated over time and, in a comparison of the two treatment groups, identified the enzyme targets of nilutamide action in humans. Whereas nilutamide tended to decrease androstenedione slightly, it affected no other variables including cortisol, except for pregnenolone, 17 alpha-OH-pregnenolone, and 17 alpha-OH-progesterone, which were increased. These increases are indicative of weak inhibition of C17,20 lyase by nilutamide, but, according to the multivariate analysis, are insufficient to account for the more marked and rapid fall in PAP and PSA noted on addition of nilutamide to buserelin that must therefore be explained by another mechanism such as androgen receptor blockade by nilutamide.

Aged↗
PubMed1993

Relative involvement of protein kinase C and of the estrogen receptor in the cytotoxic action of a population of triphenylethylenes on MCF7 cells as revealed by correspondence factorial (CF) analysis.

A multivariate statistical method, correspondence factorial (CF) analysis, was used to examine the correlations among the protein binding and cell proliferation effects of a series of 36 di- and triphenylethylenes (DPEs and TPEs). The analysis was applied to a study which measured their competition for estradiol binding to cytosol estrogen receptor (ER), their influence on protein kinase C (PKC) activity under different conditions of enzyme activation, their ability to promote the growth of a breast cancer cell line and to inhibit growth at high concentrations (cytotoxicity). The CF analysis revealed several levels of correlation. First, it distinguished those molecules within the population that stimulated rather than inhibited PKC activity. Second, it made apparent a strong correlation between cytotoxicity and inhibition of Ca++ and phosphatidylserine-dependent PKC activity, which was most marked when the enzyme had been activated by diacylglycerol indicating that PKC inhibition under physiological conditions might contribute to the overall cytotoxicity of these compounds. Third, a lower level of correlation was established between competition for ER binding and cytotoxicity. Taken together, the results suggest that MCF7 cells might be most sensitive to a cytotoxic effect of TPEs (via PKC and other targets) when they at the same time decrease estrogen-stimulated proliferation via an ER-mediated antiestrogenic effect.

Animals↗
PubMed1993

A multivariate approach to the description of patient populations. An example of the analysis of the hormone profiles of patients with advanced prostate cancer.

In view of the multifactorial nature of the endocrine dysfunctions that may develop during prostate cancer and the unsuitability of the most widely used statistical methods to study such dysfunction, we have in the present study examined the relationships among 17 biological variables in 26 patients with advanced prostate cancer by two complementary multivariate methods, correspondence factorial analysis (CFA) and a hierarchical automatic classification procedure. The 17 variables included 14 hormones, their precursors or metabolites [LH, FSH, estradiol (E2), testosterone, dihydrotestosterone (DHT), androstenedione (A), androstenediol (Ediol), dehydroepiandrosterone (DHA), DHA-sulphate (DS), cortisol (CORT), 17 alpha-hydroxyprogesterone (17-OH-PROG), pregnenolone (PREG), 17 alpha-hydroxypregnenolone (17-OH-PREG), and androstanediol glucuronide (ADG)], one plasma binding protein, namely, sex-hormone-binding protein (SHBG) and two tumour markers, prostatic acid phosphatase (PAP) and prostate-specific antigen (PSA). The originality of these multivariate methods is that they do not preselect a dependent variable nor perform two-by-two correlations as in stepwise multiple regression analysis but describe the patient population by extracting layers of correlations (from strong to weak) from amid confounding variables. Compared to principal component analysis which is based on covariance, CFA, based on the chi 2-metric, enables the licit representation of both tests and patients on the same factorial maps. From an examination of proximity among variables, it is possible to deduce which tests are related, which groups of patients have similar hormone profiles, and which tests vary most in which patients. The most discriminant factors in this particular population of patients were PSA and PAP levels, which were, however, not strongly correlated and were apparently selectively associated with certain hormones. PAP seemed the more pathological marker; PSA was somewhat anticorrelated to the adrenal androgen (DHA and DS) and PREG levels. The hormones with the lowest variance were A, Ediol and CORT reflecting their key roles in metabolism. A number of patients were hypogonadic. SHBG levels were not closely related to total T levels but anticorrelated with ADG suggesting that, in the patients concerned, SHBG decreases the bioavailable T fraction. There was no correlation between ADG and precursor hormones (PREG, DHA, DS) but a slight anticorrelation between these precursors and DHT. Therefore the source of ADG in these patients does not seem to be increased levels of precursor hormones nor of DHT but increased peripheral tissue metabolism of androgens. In future, descriptive multivariate analyses of large patient cohorts should help to define subpopulations with distinctive hormone profiles for prospective clinical studies.

Hormones↗
PubMed1992

Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation.

The response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.

Acrylonitrile↗