Biomedical subjects
Publications and source records attributed to René Roy.
Several oligomannoside clusters having a hundred-fold increase in affinities toward E. coli were synthesized by Cu(I)-catalyzed [1,3]-dipolar cycloadditions using pentaerythritol scaffolds bearing either alkyne or azide functionalities.
A furanocoumarin glycoside new named turbinatocoumarin (1) was isolated from the twigs of Dorstenia turbinata. The structure of turbinatocoumarin (1) was assigned as 5-methoxy-3-[3-(beta-glucopyranosyloxy)-2-hydroxy-3-methylbutyl]psoralen by means of spectroscopic analysis. Known compounds have also been isolated from this genus and identified as (2'S, 3'R)-3'-hydroxymarmesin (2), 5-methoxy-3-(3-methyl-2,3-dihydroxybutyl)psoralen (3), psoralen (4), kanzonol C (5) which was isolated for the first time from this genus, 4-hydroxylonchocarpin (6), umbelliferone, 4-hydroxy-3-methoxybenzaldehyde and 4-methoxyphenol. As part of our continuing search for potential naturally-occurring antitumor drug candidates, the inhibition of matrix metalloproteinase (MMP)-2 secretion from brain tumor-derived glioblastoma cells by the isolated compounds 1, 3, 5, and 6 was evaluated by zymography and compared to the documented naturally-occurring MMP secretion inhibitors chlorogenic acid (CHL) and epigallocatechin-3-gallate (EGCg). Among the compounds tested, the inhibiting MMP secretion concentrations ranged from 0.025 to 250 microM with up to 80% inhibition. The inhibitory activities of compounds 5 and 6 were found comparable to the common reference compounds CHL and EGCg. This suggests that alternate sources can be explored and exploited for the availability of chemopreventive molecules.
[reaction: see text] Stereoselective isomerization of C-allyl glycosides into (E)-C-vinyl glycosides or (Z)-exo-glycals was carried out in the presence of the cationic iridium(I) catalyst [(Ph(2)MeP)(2)Ir(cod)PF(6)]. The products of the isomerization were affected by the relative 1,2-stereochemical relationships and by the nature of the protecting groups. These effects are discussed along with a plausible reaction mechanism.
Galactosides and lactosides bearing triazoles or isoxazoles, regiospecifically prepared by [1,3]-dipolar cycloadditions between alkynes, azides or nitrile oxides, provided specific galectin-1 and -3 inhibitors with potencies as low as 20 microM.
Phase transfer catalyzed reaction was used for the high yielding synthesis of aryl 1-thio-beta-d-galacto- and lacto-pyranosides carrying a panel of substituents on the phenyl groups. Best galectin-1 inhibitors were simple p-nitrophenyl thiogalactoside 5a for the monosaccharide and o-nitrophenyl thiolactoside 6f or napthylsulfonyl lactoside 8c, both being 20 times better relative to natural ligands. Relative inhibitory properties as low as 2500 and 40 microM were observed, respectively. The electronic effects of the lactoside aglycons directly influenced the electrostatic potential at O-3, which was associated with the inhibitory potencies against galectin-1.
With highly conformal radiation therapy techniques such as intensity-modulated radiation therapy, radiosurgery, and tomotherapy becoming more common in clinical practice, the use of these narrow beams requires a higher level of precision in quality assurance and dosimetry. Plastic scintillators with their water equivalence, energy independence, and dose rate linearity have been shown to possess excellent qualities that suit the most complex and demanding radiation therapy treatment plans. The primary disadvantage of plastic scintillators is the presence of Cerenkov radiation generated in the light guide, which results in an undesired stem effect. Several techniques have been proposed to minimize this effect. In this study, we compared three such techniques-background subtraction, simple filtering, and chromatic removal-in terms of reproducibility and dose accuracy as gauges of their ability to remove the Cerenkov stem effect from the dose signal. The dosimeter used in this study comprised a 6-mm(3) plastic scintillating fiber probe, an optical fiber, and a color charge-coupled device camera. The whole system was shown to be linear and the total light collected by the camera was reproducible to within 0.31% for 5-s integration time. Background subtraction and chromatic removal were both found to be suitable for precise dose evaluation, with average absolute dose discrepancies of 0.52% and 0.67%, respectively, from ion chamber values. Background subtraction required two optical fibers, but chromatic removal used only one, thereby preventing possible measurement artifacts when a strong dose gradient was perpendicular to the optical fiber. Our findings showed that a plastic scintillation dosimeter could be made free of the effect of Cerenkov radiation.
The purpose of this study is to determine the impact of edema on the dose delivered to the target volume. An evaluation of the edema characteristics was first made, and then a dynamical dosimetry algorithm was developed and used to compare its results to a standard clinical (static) dosimetry. Source positions and prostate contours extracted from 66 clinical cases on images taken at different points in time (planning, implant day, post-implant evaluation) were used, via the mean interseed distance, to characterize edema [initial increase (deltar0), half-life (tau)]. An algorithm was developed to take into account the edema by summing a time series of dose-volume histograms (DVHs) with a weight based on the fraction of the dose delivered during the time interval considered. The algorithm was then used to evaluate the impact of edema on the dosimetry of permanent implants by comparing its results to those of a standard clinical dosimetry. The volumetric study yielded results as follows: the initial prostate volume increase was found to be 1.58 (ranging from 1.15 to 2.48) and the edema half-life, approximately 30 days (range: 3 to 170 days). The dosimetric differences in D90 observed between the dynamic dosimetry and the clinical one for a single case were up to 15 Gy and depended on the edema half-life and the initial volume increase. The average edema half-life, 30 days, is about 3 times longer than the previously reported 9 days. Dosimetric differences up to 10% of the prescription dose are observed, which can lead to differences in the quality assertion of an implant. The study of individual patient edema resorption with time might be necessary to extract meaningful clinical correlation or biological parameters in permanent implants.
The purpose is to evaluate the impact of interseed attenuation and prostate composition for prostate treatment plans with 125I permanent seed implants using the Monte Carlo (MC) method. The effect of seed density (number of seeds per prostate unit volume) is specifically investigated. The study focuses on treatment plans that were generated for clinical cases. For each plan, four different dose calculation techniques are compared: TG-43 based calculation, superposition MC, full MC with water prostate, and full MC with realistic prostate tissue. The prostate tissue description is from the ICRP report 23 (W. S. Snyer, M. J. Cook, E. S. Nasset, L. R. Karkhausen, G. P. Howells, and I. H. Tipton, "Report of the task group on reference man," Technical Report 23, International Commission on Radiological Protection, 1974). According to the comparisons, the seed density has an influence on interseed attenuation. A plan with a typical low seed density (42 0.6 mCi seeds in a 26 cm3 prostate) suffers a 1.2% drop in the CTV D90 value due to interseed attenuation. A drop of 3.0% is calculated for a higher seed density (75 0.3 mCi seeds, same prostate). The influence of the prostate composition is similar for all seed densities and prostate sizes. The difference between MC simulations in water and MC simulations in prostate tissue is between 4.4% and 4.8% for the D90 parameter. Overall, the effect on D90 is ranging from 5.8% to 12.8% when comparing clinically approved TG-43 and MC simulations in prostate tissue. The impact varies from one patient to the other and depends on the prostate size and the number of seeds. This effect can reach a significant level when reporting correlations between clinical effect and deposited dose.
The purpose of the present study is to introduce a compression algorithm for the CT (computed tomography) data used in Monte Carlo simulations. Performing simulations on the CT data implies large computational costs as well as large memory requirements since the number of voxels in such data reaches typically into hundreds of millions voxels. CT data, however, contain homogeneous regions which could be regrouped to form larger voxels without affecting the simulation's accuracy. Based on this property we propose a compression algorithm based on octrees: in homogeneous regions the algorithm replaces groups of voxels with a smaller number of larger voxels. This reduces the number of voxels while keeping the critical high-density gradient area. Results obtained using the present algorithm on both phantom and clinical data show that compression rates up to 75% are possible without losing the dosimetric accuracy of the simulation.
This study presents the first QSAR model for Galectin-3 glycomimetic inhibitors based on docked structures to the carbohydrate recognition domain (CRD). Quantitative numerical methods such as PLS (Partial Least Squares) and ANN (Artificial Neural Networks) have been used and compared on QSAR models to establish correlations between molecular properties and binding affinity values (Kd). Training and validation of QSAR predictive models was performed on a master dataset consisting of 136 compounds. The molecular structures and binding affinities (Kd) (136 compounds) were obtained from the literature. To address the issue of dimensionality reduction, molecular descriptors were selected with PLS contingency approach, ANN, PCA (Principal Component Analysis) and GA (Genetic Algorithms) for the best predictive Galectin-3 binding affinity (Kd). Final sets comprising 56, 31 and 35 descriptors were obtained with PLS, PCA and ANN, respectively. The objective of this prototype QSAR model is to serve as a first guideline for the design of novel and potent Gal-3 selective inhibitors with emphasis on modification at both C-3' and at O-3 positions.
The jack bean lectin concanavalin A (ConA) and the Dioclea grandiflora lectin (DGL) are highly homologous Man/Glc-specific members of the Diocleinae subtribe. Both lectins bind, cross-link, and precipitate with carbohydrates possessing multiple terminal nonreducing Man residues. The present study investigates the binding and cross-linking interactions of ConA and DGL with a series of synthetic divalent carbohydrates that possess spacer groups with increasing flexibility and length between terminal alpha-mannopyranoside residues. Isothermal titration microcalorimetry was used to determine the thermodynamics of binding of the two lectins to the divalent analogs, and kinetic light scattering and electron microscopy studies were used to characterize the cross-linking interactions of the lectins with the carbohydrates. The results demonstrated that divalent analogs with flexible spacer groups between the two terminal Man residues possess higher affinities for the two lectins as compared with those with inflexible spacer groups. Furthermore, despite their high degree of homology, ConA and DGL exhibit differences in their kinetics of cross-linking and precipitation with the divalent analogs. Electron microscopy shows the loss of organized cross-linked lattices of the two lectins with analogs possessing increased distance between the terminal Man residues. The loss of lattice patterns with the analogs is distinct for each lectin. These results have important implications for the interactions of lectins with multivalent carbohydrate receptors in biological systems.
The unusual chlorinated coumarinolignan, 5-chloropropacin, along with several other known compounds have been isolated from the roots of Mondia whitei. The structure of the chlorinated coumarinolignan was determined by NMR and mass spectroscopic analyses.
Scintillation dosimetry is a promising avenue for evaluating dose patterns delivered by intensity-modulated radiation therapy plans or for the small fields involved in stereotactic radiosurgery. However, the increase in signal has been the goal for many authors. In this paper, a comparison is made between plastic scintillating fibers and plastic scintillator. The collection of scintillation light was measured experimentally for four commercial models of scintillating fibers (BCF-12, BCF-60, SCSF-78, SCSF-3HF) and two models of plastic scintillators (BC-400, BC-408). The emission spectra of all six scintillators were obtained by using an optical spectrum analyzer and they were compared with theoretical behavior. For scintillation in the blue region, the signal intensity of a singly clad scintillating fiber (BCF-12) was 120% of that of the plastic scintillator (BC-400). For the multiclad fiber (SCSF-78), the signal reached 144% of that of the plastic scintillator. The intensity of the green scintillating fibers was lower than that of the plastic scintillator: 47% for the singly clad fiber (BCF-60) and 77% for the multiclad fiber (SCSF-3HF). The collected light was studied as a function of the scintillator length and radius for a cylindrical probe. We found that symmetric detectors with nearly the same spatial resolution in each direction (2 mm in diameter by 3 mm in length) could be made with a signal equivalent to those of the more commonly used asymmetric scintillators. With augmentation of the signal-to-noise ratio in consideration, this paper presents a series of comparisons that should provide insight into selection of a scintillator type and volume for development of a medical dosimeter.
Glycoconjugate vaccines provide effective prophylaxis against bacterial infections. To date, however, no commercial vaccine has been available in which the key carbohydrate antigens are produced synthetically. We describe the large-scale synthesis, pharmaceutical development, and clinical evaluation of a conjugate vaccine composed of a synthetic capsular polysaccharide antigen of Haemophilus influenzae type b (Hib). The vaccine was evaluated in clinical trials in Cuba and showed long-term protective antibody titers that compared favorably to licensed products prepared with the Hib polysaccharide extracted from bacteria. This demonstrates that access to synthetic complex carbohydrate-based vaccines is feasible and provides a basis for further development of similar approaches for other human pathogens.
We have developed an algorithm to automatically generate anatomy-based MLC fields. For each beam, a first field is adjusted to the projection of the target in a beam's eye view, allowing subsequent fields to be derived from this conformal field by removing the overlapping surface of each organ at risk, respectively. The projections are based on a surface sampling of the anatomical structures. On top of the MLC mechanical constraints, verification constraints are imposed on the MLC segments, in order to get reliable dosimetry using a commercial dose calculation engine. Thus, in each direction, the aperture's cross-section must be greater than a specified threshold, in our case 2 cm. Furthermore, junctions are not tolerated in order to avoid underdosage, for instance from the tongue-and-groove effect. The use of such MLC fields simplifies the verification process. The performance of the algorithm is illustrated for head and neck, thorax and prostate cases. Only a fraction of a second of CPU time is required to perform the segmentation for each beam.
As an alternative between manual planning and beamlet-based IMRT, we have developed an optimization system for inverse planning with anatomy-based MLC fields. In this system, named Ballista, the orientation (table and gantry), the wedge filter and the field weights are simultaneously optimized for every beam. An interesting feature is that the system is coupled to Pinnacle3 by means of the PinnComm interface, and uses its convolution dose calculation engine. A fully automatic MLC segmentation algorithm is also included. The plan evaluation is based on a quasi-random sampling and on a quadratic objective function with penalty-like constraints. For efficiency, optimal wedge angles and wedge orientations are determined using the concept of the super-omni wedge. A bound-constrained quasi-Newton algorithm performs field weight optimization, while a fast simulated annealing algorithm selects the optimal beam orientations. Moreover, in order to generate directly deliverable plans, the following practical considerations have been incorporated in the system: collision between the gantry and the table as well as avoidance of the radio-opaque elements of a table top. We illustrate the performance of the new system on two patients. In a rhabdomyosarcoma case, the system generated plans improving both the target coverage and the sparing of the parotide, as compared to a manually designed plan. In the second case presented, the system successfully produced an adequate plan for the treatment of the prostate while avoiding both hip prostheses. For the many cases where full IMRT may not be necessary, the system efficiently generates satisfactory plans meeting the clinical objectives, while keeping the treatment verification much simpler.
Galectin-3 is unique among the galectin family of animal lectins in its biological activities and structure. Most members of the galectin family including galectin-1 possess apoptotic activities, whereas galectin-3 possesses anti-apoptotic activity. Galectin-3 is also the only chimera type galectin and consists of a nonlectin N-terminal domain and a C-terminal carbohydrate-binding domain. Recent sedimentation equilibrium and velocity studies show that murine galectin-3 is a monomer in the absence and presence of LacNAc, a monovalent sugar. However, quantitative precipitation studies in the present report indicate that galectin-3 precipitates as a pentamer with a series of divalent pentasaccharides with terminal LacNAc residues. Furthermore, the kinetics of precipitation are fast, on the order of seconds. This indicates that although the majority of galectin-3 in solution is a monomer, a rapid equilibrium exists between the monomer and a small percentage of pentamer. The latter, in turn, precipitates with the divalent oligosaccharides, resulting in rapid conversion of monomer to pentamer by mass action equilibria. Mixed quantitative precipitation experiments and electron microscopy suggest that galectin-3 forms heterogenous, disorganized cross-linking complexes with the multivalent carbohydrates. This contrasts with galectin-1 and many plant lectins that form homogeneous, organized cross-linked complexes. The results are discussed in terms of the biological properties of galectin-3.
The interplay of mammalian lectins such as galectins with cellular glycoconjugates is intimately involved in crucial reaction pathways including tumor cell adhesion, migration or growth regulation. These clinically relevant functions explain the interest in designing glycoclusters with potent activity to interfere with lectin binding. In view of the perspective for medical applications the following objective arises: to correlate topological factors of ligand display most favorably to reactivity against endogenous lectins. To date, plant agglutinins have commonly been used as models. Properly addressing this issue we first prepared di- to tetravalent clusters from 2-propynyl lactoside under mild oxidative homocoupling conditions and using the Sonogashira palladium-catalyzed cross-coupling reaction with triiodobenzene or pentaerythritol cores. These products were tested for bioactivity in a competitive solid-phase assay using different labeled sugar receptors as probes, i,e. the beta-trefoil mistletoe lectin, the natural lactoside-binding immunoglobulin G fraction from human serum and three mammalian galectins from two subgroups. The lactose headgroups in the derivatives retained ligand properties. Differences in inhibitory capacity were marked between the galectins. In contrast to homodimeric proto-type galectins-1 and -7 significant inhibition of galectin-3 binding with a 7-fold increase in relative potency was observed for the trivalent compound. In comparison, the binding of the beta-trefoil mistletoe agglutinin was reduced best by tetravalent substances The result for galectin-3 was independently confirmed by haemagglutination and cytofluorometric cell binding assays. These data underline the feasibility of galectin-type target selectivity by compound design despite using an identical headgroup (lactose) in synthesis.