Collaboration Spotting for oral medicine.

AIM: The goal of the Collaboration Spotting project is to create an automatic system to collect information about publications and patents related to a given technology, to identify the key players involved, and to highlight collaborations and related technologies. The collected information can be visualized in a web browser as interactive graphical maps showing in an intuitive way the players and their collaborations (Sociogram) and the relations among the technologies (Technogram). We propose to use the system to study technologies related to oral medicine. METHODS: In order to create a sociogram, we create a logical filter based on a set of keywords related to the technology under study. This filter is used to extract a list of publications from the Web of Science™ database. The list is validated by an expert in the technology and sent to CERN where it is inserted in the Collaboration Spotting database. Here, an automatic software system uses the data to generate the final maps. RESULTS: We studied a set of recent technologies related to bone regeneration procedures of oro-maxillo-facial critical size defects, namely the use of porous hydroxyapatite (HA) as a bone substitute alone (bone graft) or as a tridimensional support (scaffold) for insemination and differentiation ex vivo of mesenchymal stem cells. We produced the sociograms for these technologies and the resulting maps are now accessible on-line. CONCLUSION: The Collaboration Spotting system allows the automatic creation of interactive maps to show the current and historical state of research on a specific technology. These maps are an ideal tool both for researchers who want to assess the state-of-the-art in a given technology, and for research organizations who want to evaluate their contribution to the technological development in a given field. We demonstrated that the system can be used in oral medicine as is produced the maps for an initial set of technologies in this field. We now plan to enlarge the set of mapped technologies in order to make the Collaboration Spotting system a useful reference tool for oral medicine research.

Collaboration spotting for dental science.

AIM: The goal of the Collaboration Spotting project is to create an automatic system to collect information about publications and patents related to a given technology, to identify the key players involved, and to highlight collaborations and related technologies. The collected information can be visualized in a web browser as interactive graphical maps showing in an intuitive way the players and their collaborations (Sociogram) and the relations among the technologies (Technogram). We propose to use the system to study technologies related to Dental Science. METHODS: In order to create a Sociogram, we create a logical filter based on a set of keywords related to the technology under study. This filter is used to extract a list of publications from the Web of Science™ database. The list is validated by an expert in the technology and sent to CERN where it is inserted in the Collaboration Spotting database. Here, an automatic software system uses the data to generate the final maps. RESULTS: We studied a set of recent technologies related to bone regeneration procedures of oro--maxillo--facial critical size defects, namely the use of Porous HydroxyApatite (HA) as a bone substitute alone (bone graft) or as a tridimensional support (scaffold) for insemination and differentiation ex--vivo of Mesenchymal Stem Cells. We produced the Sociograms for these technologies and the resulting maps are now accessible on--line. CONCLUSION: The Collaboration Spotting system allows the automatic creation of interactive maps to show the current and historical state of research on a specific technology. These maps are an ideal tool both for researchers who want to assess the state--of--the--art in a given technology, and for research organizations who want to evaluate their contribution to the technological development in a given field. We demonstrated that the system can be used for Dental Science and produced the maps for an initial set of technologies in this field. We now plan to enlarge the set of mapped technologies in order to make the Collaboration Spotting system a useful reference tool for Dental Science research.

Nonlinear discriminant analysis and prognostic factor classification in node-negative primary breast cancer using probabilistic neural networks.

BACKGROUND: We used non-linear kernel discriminant analysis (KDA) to predict the outcome of 134 axillary node-negative primary breast cancer patients not treated with adjuvant therapy in a non censored database. MATERIAL: Posterior probabilities of relapse at 5 years were estimated using probabilistic neural networks (PNN) and a cross-validation (leave-one-out) technique to avoid overfitting the data. A stepwise method was used to construct the models to define the best combination of risk factors among eleven prognostic factors: age, menopausal status, Scarff-Bloom-Richardson grade, clinical tumor size, pathological tumor size, estrogen and progesterone receptor status, urokinase-type plasminogen activator, p53 protein level, c-erbB-2 protein and epidermal growth factor receptor. The different variables were tested individually and in combination to determine their prognostic power using a ROC indicator, which measures the separation between the probability distributions of the output neuron activations under the null hypothesis (no recurrence at 5 years) and under the alternative hypothesis (recurrence at 5 years). RESULTS: The best predictive one-dimensional model was obtained with uPA (ROC indicator = 0.75). A two-factor model including uPA and clinical tumor size (T) gave the best discrimination between recurrence and non recurrence at 5 years (ROC indicator = 0.84). Additional variables did not improve the accuracy of the prediction. The uPA-T model generated a map useful in predicting the posterior probability of cancer recurrence in a given patient. This representation allows the entire database to be easily visualized and each patient can be compared with the entire database. CONCLUSION: This is a powerful approach to analyze the impact of prognostic factors and it could find clinical applications in breast cancer.

Non-michaelian behavior of 5 alpha-reductase in human prostate.

An in-depth analysis of the kinetics of 5 alpha-reductase in human prostatic tissue gave findings inconsistent with the claim that the enzyme is michaelian. In both hyperplastic and malignant tissue, the time-course of the conversion of testosterone (T) into dihydrotestosterone (DHT) was non-linear under conditions ensuring less than 15% conversion of substrate and cofactor. An initial rapid phase of conversion was followed by a long steady-state phase. This time-dependent change in conversion rate was not due to enzyme denaturation, fast inhibition by substrate or product effects. It resulted from a true slow transient kinetic process induced in the reactive enzyme by the substrates. Under our experimental conditions at pH 5.5, 5 alpha-reductase appeared to undergo a conformational change from an initially highly reactive form to a less reactive form. Since this "hysteretic" behavior was correlated with apparently negative cooperativity in enzyme kinetics, we postulate that, as previously described for other key metabolic enzymes, regulation of 5 alpha-reductase activity in the prostate depends on the molecular flexibility of the enzyme and on changes in the cooperativity of different enzyme forms over time. This original non-michaelian behavior may explain the conflicting kinetics reported so far in the literature for this enzyme. The clinical implications of 5 alpha-reductase hysteresis and its involvement in the damping of DHT production within the prostate are discussed.

(De)phosphorylation agents influence 5 alpha-reduction of testosterone in human prostate.

The effects of ATP and of 2,4-dinitrophenol (DNP) on the kinetics of 5 alpha-reductase were studied in a microsomal preparation from hyperplastic human prostates. DNP decreased and ATP increased enzyme activity in a dose-dependent manner. Furthermore, in one and the same prostate, activity was inversely correlated to prostatic acid phosphatase (PAP) concentration. These observations provide strong support for the contention that in the human prostate 5 alpha-reductase activity and, consequently, dihydrotestosterone (DHT) production may be energy dependent and involve a phosphorylation step.

Radioligand purification prior to routine receptor assays.

The need to repurify the commercially available radioligands [3H]estradiol and [3H]testosterone before use in routine assays was investigated. Storage of these products for 2 months after delivery led to appreciable degradation of [3H]estradiol compared to [3H]testosterone. Unexpectedly, TLC and even HPLC procedures were ineffective in completely restoring the purity of [3H]-estradiol and the unremoved polar products induced important variations in our estrogen receptor assays. An increase in non-specific binding and a comcomitant decrease in total binding were observed resulting in an underestimation of specific binding sites and of the affinity constant. In some cases Scatchard analysis was not possible. We therefore strongly recommend the repurification of low-stability radioligands and propose an economic time-saving procedure for the purification of [3H]estradiol by solvent differential partition which requires no high-cost investment in apparatus.

Design of antiandrogens and their mechanisms of action: a case study (anandron).

The design of a new drug is conditioned by knowledge of the biochemical mechanisms involved in the etiology of the disease to be treated. With regard to endocrine pathologies, such knowledge can be obtained in the clinic from systematic assays of urinary and plasma hormones, enzyme activities and target tissue receptor concentrations. The present paper describes the results of our assays of plasma 3 alpha-androstanediol glucuronide, 5 alpha-reductase and androgen receptor in prostate cancer patients. The activity of the nonsteroid antiandrogen anandron is discussed in relation to these parameters: anandron may inhibit slightly adrenal androgen biosynthesis but, in particular, counters the action of these adrenal androgens on the prostate. It does not inhibit rat prostate 5 alpha-reductase activity but interacts with androgen receptor to exert an antiandrogen action.

Presence of C-19 steroids in mammary Shionogi carcinoma (SC 115) in castrated mice.

Intact and castrated male DD/S mice were inoculated with androgen-dependent cells (SC 115). All intact animals developed tumors after Day 12 of inoculation; however, six of seven castrated animals presented tumors 48 days postinoculation. The levels of steroids in both tumors were then examined. In castrated mice, dehydroepiandrosterone and androst-5-ene-3 beta, 17 beta-diol levels were diminished by 30% and 70%, respectively, while the amounts of testosterone and androstenedione were reduced by more than 90%. Our data also demonstrate that androstane-3 alpha, 17 beta-diol and androstane-3 beta, 17 beta-diol were decreased to 60% and dihydrotestosterone decreased to 6% of their normal value, respectively. This latter level (0.48 nM) was sufficient to still effect a potent androgenic response in the tumor. Besides, a highly significant correlation was found in these tumors between various C-19 steroids (dehydroepiandrosterone and androstane-3 alpha, 17 beta-diol, r = 0.97, P less than 0.01), suggesting a possible conversion of C-19 precursors into potent androgens in the tumors. Determination of the plasma steroid levels in the castrated animals clearly confirmed that potent androgenic steroids and precursors were still in the circulation 3 days after castration. It thus appears that C-19 steroids from adrenal origin may be also involved in "independent" tumor growth.

Metabolism of tritiated C19 steroids by Shionogi mouse mammary tumors.

In the present report, the metabolism of dehydroepiandrosterone, 5-androstene-3 beta, 17 beta-diol and androstenedione has been studied in two different Shionogi tumors, one is androgen-dependent ("androgen sensitive") and grows in intact male mice and the other is apparently androgen-independent ("androgen insensitive") since the cells continue to grow in castrated antiandrogen (Flutamide) treated male animals. Our data clearly show that both the sensitive and insensitive tumors contain 3 beta-hydroxysteroid delta 5-delta 4 isomerase which causes the transformation of C19 steroids into potent androgenic steroids. However, the androgen sensitive tumor is able to convert 5-androstene-3 beta, 17 beta-diol into 2-hydroxyestrogens while the rate of conversion is extremely low in the insensitive tumor. Most interestingly, the production of 5 alpha-reduced steroids observed in both tissues was clearly higher in insensitive tumor homogenates.