Showing papers by "University of Antwerp published in 1999"

Tree responses to rising CO2 in field experiments: implications for the future forest

Abstract: The need to assess the role of forests in the global cycling of carbon and how that role will change as the atmospheric concentration of CO2 increases has spawned many experiments over a range of scales. Experiments using open-top chambers have been established at many sites to test whether the short-term responses of tree seedlings described in controlled environments would be sustained over several growing seasons under field conditions. Here we review the results of those experiments, using the framework of the interacting cycles of carbon, water and nutrients, because that is the framework of the ecosystem models that are being used to address the decades-long response of forests. Our analysis suggests that most of what was learned in seedling studies was qualitatively correct. The evidence from field-grown trees suggests a continued and consistent stimulation of photosynthesis of about 60% for a 300 p.p.m. increase in [CO2], and there is little evidence of the long-term loss of sensitivity to CO2 that was suggested by earlier experiments with tree seedlings in pots. Despite the importance of respiration to a tree's carbon budget, no strong scientific consensus has yet emerged concerning the potential direct or acclimation response of woody plant respiration to CO2 enrichment. The relative effect of CO2 on above-ground dry mass was highly variable and greater than that indicated by most syntheses of seedling studies. Effects of CO2 concentration on static measures of response are confounded with the acceleration of ontogeny observed in elevated CO2. The trees in these open-top chamber experiments were in an exponential growth phase, and the large growth responses to elevated CO2 resulted from the compound interest associated with an increasing leaf area. This effect cannot be expected to persist in a closed-canopy forest where growth potential is constrained by a steady-state leaf area index. A more robust and informative measure of tree growth in these experiments is the annual increment in wood mass per unit leaf area, which increased 27% in elevated CO2. There is no support for the conclusion from many studies of seedlings that root-to-shoot ratio is increased by elevated CO2; the production of fine roots may be enhanced, but it is not clear that this response would persist in a forest. Foliar nitrogen concentrations were lower in CO2-enriched trees, but to a lesser extent than was indicated in seedling studies and only when expressed on a leaf mass basis. The prediction that leaf litter C/N ratio would increase was not supported in field experiments. Also contrasting with seedling studies, there is little evidence from the field studies that stomatal conductance is consistently affected by CO2; however, this is a topic that demands more study. Experiments with trees in open-top chambers under field conditions have provided data on longer-term, larger-scale responses of trees to elevated CO2 under field conditions, confirmed some of the conclusions from previous seedling studies, and challenged other conclusions. There remain important obstacles to using these experimental results to predict forest responses to rising CO2, but the studies are valuable nonetheless for guiding ecosystem model development and revealing the critical questions that must be addressed in new, larger-scale CO2 experiments.

Statistical texture characterization from discrete wavelet representations

Abstract: We conjecture that texture can be characterized by the statistics of the wavelet detail coefficients and therefore introduce two feature sets: (1) the wavelet histogram signatures which capture all first order statistics using a model based approach and (2) the wavelet co-occurrence signatures, which reflect the coefficients' second-order statistics. The introduced feature sets outperform the traditionally used energy. Best performance is achieved by combining histogram and co-occurrence signatures.

A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia

Abstract: Objective: To compare effects of risperidone with placebo (efficacy and tolerability) and haloperidol (tolerability) for treating demented patients with aggression and other behavioral symptoms. Methods: A 13-week double-blind study involving 344 patients with dementia randomly assigned to receive placebo or flexible doses (0.5 to 4 mg/d) of risperidone or haloperidol. Behavioral symptoms were assessed by the Behavior Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD), the Cohen-Mansfield Agitation Inventory (CMAI), and the Clinical Global Impression (CGI) scale. Tolerability assessments included the Extrapyramidal Symptom Rating Scale, sedation levels, Functional Assessment Staging, Mini-Mental State Examination, and incidence of adverse events. Results: The mean dose at endpoint was 1.1 mg/d of risperidone and 1.2 mg/d of haloperidol. Although not significant, a higher percentage of patients receiving risperidone than those receiving placebo showed clinical improvement (≥30% reduction from baseline to endpoint in BEHAVE-AD total score) at endpoint and week 12. Reductions in the BEHAVE-AD total score were significantly greater with risperidone than with placebo at week 12. In a further analysis of aggression, the most dominant symptom in these patients, BEHAVE-AD and CMAI aggression cluster scores were significantly reduced compared with placebo at endpoint and week 12. CGI scores were also significantly reduced at endpoint and week 12. Severity of extrapyramidal symptoms with risperidone did not differ significantly from that of placebo and was less than that of haloperidol. A post hoc analysis showed significantly greater reductions in the BEHAVE-AD aggressiveness score with risperidone than haloperidol at week 12. Conclusion: Low-dose risperidone (mean 1.1 mg/d) was well tolerated and associated with reductions in the severity and frequency of behavioral symptoms, particularly aggression, in elderly patients with dementia.

AHAM: a Dexter-based reference model for adaptive hypermedia

Abstract: Hypermedia applications offer users the impression that there are many meaningful ways to navigate through a large body of information nodes. This rich link structure not only creates orientation problems, it may also be a source of comprehension problems when users follow paths through the information which the author did not foresee. Adaptive techniques have been used by a number of researchers [1, 2, 4, 5, 6, 7, 8, 9, 10, 17, 19, 20, 22] in an attempt to offer guidance through and orientation support for rich link structures. The majority of these adaptive hypermedia systems (AHS) have been used in educational applications. The terminology used in this paper also has an educational “flavor”. However, there are some adaptive on-line information systems (or “kiosk”systems), adaptive information retrieval systems, and other adaptive hypermedia applications. In this paper we describe a reference model for adaptive hypermedia applications, called AHAM, which encompasses most features supported by adaptive systems that exist today or that are being developed (and have been published about). Our description of AHS is based on the Dexter model [15, 16], a widely used reference model for hypermedia. The description is kept somewhat informal in order to be able to explain AHAM rather than formally specify it. AHAM augments Dexter with features for doing adaptation based on a user model which persists beyond the duration of a session. Key aspects in AHAM are: Paul De Bra is also affiliated with the University of Antwerp, Belgium, and with the “Centrum voor Wiskunde en Informatica” (CWI) in Amsterdam. yGeert-Jan Houben is also affiliated with the University of Antwerp, Belgium, and with Origin in Eindhoven. The adaptation is based on a domain model, a user model and a teaching model which consists of pedagogical rules. We give a formal definition of each of these (sub)models (but only describe the pedagogical rules informally throughexamples). We distinguish the notions of concept, page and fragment. In some AHS these notions are confused. We provide a formalism which lets authors write pedagogical rules (about concepts) in such a way that they can be applied automatically. We illustrate various aspects of AHAM by means of some features of some well-known AHS [6, 10].

Effects of elevated (CO2) on photosynthesis in European forest species: a meta-analysis of model parameters

Abstract: The effects of elevated atmospheric CO2 concentration on growth of forest tree species are difficult to predict because practical limitations restrict experiments to much shorter than the average life-span of a tree. Long-term, processbased computer models must be used to extrapolate from shorter-term experiments. A key problem is to ensure a strong flow of information between experiments and models. In this study, meta-analysis techniques were used to summarize a suite of photosynthetic model parameters obtained from 15 field-based elevated [CO2] experiments on European forest tree species. The parameters studied are commonly used in modelling photosynthesis, and include observed light-saturated photosynthetic rates (Amax), the potential electron transport rate (Jmax), the maximum Rubisco activity (Vcmax) and leaf nitrogen concentration on mass (Nm) and area (Na) bases. Across all experiments, light-saturated photosynthesis was strongly stimulated by growth in elevated [CO2]. However, significant down-regulation of photosynthesis was also observed; when measured at the same CO2 concentration, photosynthesis was reduced by 10‐20%. The underlying biochemistry of photosynthesis was affected, as shown by a down-regulation of the parameters Jmax and Vcmax of the order of 10%. This reduction in Jmax and Vcmax was linked to the effects of elevated [CO2] on leaf nitrogen concentration. It was concluded that the current model is adequate to model photosynthesis in elevated [CO2]. Tables of model parameter values for different European forest species are given.

Sexual dimorphism of head size in Gallotia galloti: testing the niche divergence hypothesis by functional analyses

Abstract: 1. Two often cited hypotheses explaining sexual head size dimorphism in lizards are: sexual selection acting on structures important in intrasexual competition, and reduction of intersexual competition through food niche separation. 2. In this study some implicit assumptions of the latter hypothesis were tested, namely that an increase in gape distance and bite force should accompany the observed increase in head size. These assumptions are tested by recording bite forces, in vivo, for lizards of the species Gallotia galloti. In this species, male lizards have significantly larger heads than female conspecifics of similar snout–vent length. 3. Additionally, the average force needed to crush several potential prey species was determined experimentally and compared with the bite force data. This comparison clearly illustrates that animals of both sexes can bite much harder than required for most insect food items, which does not support the niche divergence hypothesis. The apparent ‘excess’ bite force in both sexes might be related to the partially herbivorous diet of the animals. 4. To unravel the origin of differences between sexes in bite capacity, the crushing phase of biting was modelled. The results of this model show different strategies in allocation of muscle tissue between both sexes. The origin of this difference is discussed and a possible evolutionary pathway of the development of the sexual dimorphism in the species is provided.

Representing text chunks

Abstract: Dividing sentences in chunks of words is a useful preprocessing step for parsing, information extraction and information retrieval. (Ramshaw and Marcus, 1995) have introduced a "convenient" data representation for chunking by converting it to a tagging task. In this paper we will examine seven different data representations for the problem of recognizing noun phrase chunks. We will show that the the data representation choice has a minor influence on chunking performance. However, equipped with the most suitable data representation, our memory-based learning chunker was able to improve the best published chunking results for a standard data set.

Representing Text Chunks

Abstract: Dividing sentences in chunks of words is a useful preprocessing step for parsing, information extraction and information retrieval. (Ramshaw and Marcus, 1995) have introduced a "convenient" data representation for chunking by converting it to a tagging task. In this paper we will examine seven different data representations for the problem of recognizing noun phrase chunks. We will show that the the data representation choice has a minor influence on chunking performance. However, equipped with the most suitable data representation, our memory-based learning chunker was able to improve the best published chunking results for a standard data set.

Non-syndromic hearing loss associated with enlarged vestibular aqueduct is caused by PDS mutations

Abstract: Enlarged vestibular aqueduct (EVA), known as the most common form of inner ear abnormality, has recently been of particular genetic interest because this anomaly is inherited in a recessive manner. The locus for non-syndromic sensorineural hearing loss with EVA has been mapped to the same chromosomal region, 7q31, as the Pendred syndrome locus. In the present study, seven mutations in the PDS gene (PDS), the gene responsible for Pendred syndrome, have been found in families of non-syndromic sensorineural hearing loss with EVA. One family is homozygous, three families are compound heterozygotes, and two families are heterozygous but with no other mutation detected. The present results provide evidence that mutations in PDS cause both syndromic and non-syndromic hearing loss.

A synchrotron radiation microtomography system for the analysis of trabecular bone samples.

Abstract: X-ray computed microtomography is particularly well suited for studying trabecular bone architecture, which requires three-dimensional (3-D) images with high spatial resolution. For this purpose, we describe a three-dimensional computed microtomography (μCT) system using synchrotron radiation, developed at ESRF. Since synchrotron radiation provides a monochromatic and high photon flux x-ray beam, it allows high resolution and a high signal-to-noise ratio imaging. The principle of the system is based on truly three-dimensional parallel tomographic acquisition. It uses a two-dimensional (2-D) CCD-based detector to record 2-D radiographs of the transmitted beam through the sample under different angles of view. The 3-D tomographic reconstruction, performed by an exact 3-D filtered backprojection algorithm, yields 3-D images with cubic voxels. The spatial resolution of the detector was experimentally measured. For the application to bone investigation, the voxel size was set to 6.65 μm, and the experimental spatial resolution was found to be 11 μm. The reconstructed linear attenuation coefficient was calibrated from hydroxyapatite phantoms. Image processing tools are being developed to extract structural parameters quantifying trabecular bone architecture from the 3-D μCT images. First results on human trabecular bone samples are presented.

Mutations in the CCN gene family member WISP3 cause progressive pseudorheumatoid dysplasia.

Abstract: Members of the CCN (for CTGF, cyr61/cef10, nov) gene family encode cysteine-rich secreted proteins with roles in cell growth and differentiation1. Cell-specific and tissue-specific differences in the expression and function of different CCN family members suggest they have non-redundant roles. Using a positional-candidate approach, we found that mutations in the CCN family member WISP3 are associated with the autosomal recessive skeletal disorder progressive pseudorheumatoid dysplasia (PPD; MIM 208230). PPD is an autosomal recessive disorder that may be initially misdiagnosed as juvenile rheumatoid arthritis2,3,4,5. Its population incidence has been estimated at 1 per million in the United Kingdom4, but it is likely to be higher in the Middle East and Gulf States6. Affected individuals are asymptomatic in early childhood2,3. Signs and symptoms of disease typically develop between three and eight years of age. Clinically and radiographically, patients experience continued cartilage loss and destructive bone changes as they age2,3,4,5,6,7, in several instances necessitating joint replacement surgery by the third decade of life. Extraskeletal manifestations have not been reported in PPD. Cartilage appears to be the primary affected tissue, and in one patient, a biopsy of the iliac crest revealed abnormal nests of chondrocytes and loss of normal cell columnar organization in growth zones5. We have identified nine different WISP3 mutations in unrelated, affected individuals, indicating that the gene is essential for normal post-natal skeletal growth and cartilage homeostasis.

Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13).

Abstract: We report that mutation of COL11A2 causes deafness previously mapped to the DFNA13 locus on chromosome 6p. We found two families (one American and one Dutch) with autosomal dominant, non-syndromic hearing loss to have mutations in COL11A2 that are predicted to affect the triple-helix domain of the collagen protein. In both families, deafness is non-progressive and predominantly affects middle frequencies. Mice with a targeted disruption of Col11a2 also were shown to have hearing loss. Electron microscopy of the tectorial membrane of these mice revealed loss of organization of the collagen fibrils. Our findings revealed a unique ultrastructural malformation of inner-ear architecture associated with non-syndromic hearing loss, and suggest that tectorial membrane abnormalities may be one aetiology of sensorineural hearing loss primarily affecting the mid-frequencies.

The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype

Abstract: Summary We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot‐ Marie‐Tooth (CMT) families and in two isolated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutation have one common ancestor. The mutation is associated with a clinically distinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduction velocities of the motor median nerve vary from ,38 m/s to normal values in these

Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies

Abstract: The peripheral myelin protein 22 gene (PMP22), the myelin protein zero gene (MPZ, P0), and the connexin 32 gene (Cx32, GJB1) code for membrane proteins expressed in Schwann cells of the peripheral nervous system (PNS). The early growth response 2 gene (EGR2) encodes a transcription factor that may control myelination in the PNS. Mutations in the respective genes, located on human chromosomes 17p11.2, 1q22-q23, Xq13.1, and 10q21.1-q22.1, are associated with several inherited peripheral neuropathies. To date, a genetic defect in one of these genes has been identified in over 1,000 unrelated patients manifesting a wide range of phenotypes, i.e., Charcot-Marie-Tooth disease type 1 (CMT1) and type 2 (CMT2), Dejerine-Sottas syndrome (DSS), hereditary neuropathy with liability to pressure palsies (HNPP), and congenital hypomyelination (CH). This large number of genetically defined patients provides an exceptional opportunity to examine the correlation between phenotype and genotype. Hum Mutat 13:11–28, 1999. © 1999 Wiley-Liss, Inc.

Structure and function of cardiac potassium channels.

Abstract: Recent advances in molecular biology have had a major impact on our understanding of the biophysical and molecular properties of ion channels. This review is focused on cardiac potassium channels which, in general, serve to control and limit cardiac excitability. Approximately 60 K+ channel subunits have been cloned to date. The (evolutionary) oldest potassium channel subunits consist of two transmembrane (Tm) segments with an intervening pore-loop (P). Channels formed by four 2Tm-1P subunits generally function as inwardly rectifying K(+)-selective channels (KirX.Y): they conduct substantial current near the resting potential but carry little or no current at depolarized potentials. The inward rectifier IK1 and the ligand-gated KATP and KACh channels are composed of such subunits. The second major class of K+ channel subunits consists of six transmembrane segments (S1-S6). The S5-P-S6 section resembles the 2Tm-1P subunit, and the additional membrane-spanning segments (especially the charged S4 segment) endow these 6Tm-1P channels with voltage-dependent gating. For both major families, four subunits assemble into a homo- or heterotetrameric channel, subject to specific subunit-subunit interactions. The 6Tm-1P channels are closed at the resting potential, but activate at different rates upon depolarization to carry sustained or transient outward currents (the latter due to inactivation by different mechanisms). Cardiac cells typically display at least one transient outward current and several delayed rectifiers to control the duration of the action potential. The molecular basis for each of these currents is formed by subunits that belong to different Kvx.y subfamilies and alternative splicing can contribute further to the diversity in native cells. These subunits display distinct pharmacological properties and drug-binding sites have been identified. Additional subunits have evolved by concatenation of two 2Tm-1P subunits (4Tm-2P); dimers of such subunits yield voltage-independent leak channels. A special class of 6Tm-1P subunits encodes the 'funny' pacemaker current which activates upon hyperpolarization and carries both Na+ and K+ ions. The regional heterogeneity of K+ currents and action potential duration is explained by the heterogeneity of subunit expression, and significant changes in expression occur in cardiac disease, most frequently a reduction. This electrical remodelling may also be important for novel antiarrhythmic therapeutic strategies. The recent crystallization of a 2Tm-1P channel enhances the outlook for more refined molecular approaches.

The Standardization of Terminology in Neurogenic Lower Urinary Tract Dysfunction With Suggestions for Diagnostic Procedures

Abstract: 1Department of Urology, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany 2Department of Urology, University of Essen Medical School, Essen, Germany 3Komaki Shimin Hospital, Johbushi, Komaki, Japan 4Urodynamics Laboratory, Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany 5University Hospital Innsbruck, Innsbruck, Austria 6Department of Urology, The Prince Henry Hospital, Little Bay, Sidney, Australia 7Geneva, Switzerland 8Department of Urology, University Hospital Antwerp, Antwerp, Belgium

Angiogenic cytokines in mesothelioma: a study of VEGF, FGF-1 and -2, and TGF beta expression.

Abstract: Vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF-1 and -2), and transforming growth factor beta (TGFbeta) are potent angiogenic cytokines. Malignant mesothelioma of the pleura presents with a high intra-tumoural microvascular density (IMD) which also has prognostic relevance. This study was designed to verify the immunohistochemical expression of the angiogenic cytokines in mesothelioma as well as in non-neoplastic human mesothelial cells and to study the individual as well as the combined expression of these cytokines in mesothelioma in relation to both IMD and prognosis. In addition, four mesothelioma cell lines were studied by ELISA for the secretion of VEGF and FGF-2 in their supernatants and were shown to contain high levels of both of these cytokines. Immunohistochemically, VEGF, FGF-1 and -2, and TGFbeta immunoreactivity was present in 81, 67, 92 and 96 per cent of mesotheliomas, and in 20, 50, 40, and 10 per cent of samples of the non-neoplastic mesothelium, respectively. Co-ordinate expression of the cytokines was observed whereby mesotheliomas expressed more than one cytokine. The combined immunohistochemical expression levels for all four cytokines correlated significantly with both IMD (p=0.01) and prognosis (p=0. 0013). When studied individually, high FGF-2 expression correlated best with more tumour aggressiveness and worse prognosis for mesothelioma (p=0.0011). There was no significant correlation between prognosis and immunoexpression of VEGF (p=0.07), FGF-1 (p=0.3), or TGFbeta (p=0.1), or between IMD and any of the cytokines studied individually. These data support the assertion that selective angiogenic cytokines might contribute to the progressive changes of mesothelioma by tumour angiogenesis.

Static secondary ion mass spectrometry (S-SIMS) Part 1: methodology and structural interpretation

Abstract: Static secondary ion mass spectrometry (S-SIMS) allows the chemical characterization of the constituents in the upper monomolecular layer of a solid sample Within the range of micro-analytical methods, S-SIMS occupies a rather unique position in that it combines monolayer sensitivity with the capability to generate molecular information In general, elemental ions, structural fragments, molecular and adduct ions are generated from both inorganic and organic molecules, including polymers The chemical analysis of the upper monolayer makes S-SIMS especially suited to the study of the interface chemistry in a variety of materials Polymer applications take an important place because S-SIMS allows a lot of information on these often intractable materials, eg, identification, detection of surface functionalities, study of segregation of copolymer components and molecular weight (MW) distributions In addition to the qualitative identification, S-SIMS allows high reproducibility and thereby permits quantitative studies with the aid of standards Finally, S-SIMS offers imaging capabilities to visualize directly the distribution of given components within the upper surface layer of solids Mapping with high lateral resolution is feasible for elemental ions and in favorable cases also for organic compounds This review aims at a comprehensive coverage of the S-SIMS literature of the past decade It comprises two parts, of which the first part deals with the more general aspects of the technique It begins with a brief tutorial review of instrumentation, methodology and current concepts of ion formation Particular attention is given to the link and difference with the matured dynamic SIMS method Finally, imaging in S-SIMS is discussed Application of S-SIMS to complex materials makes the interpretation of signals, in terms of the sample composition, intricate but crucial Therefore, the features of inorganic and organic mass spectra are surveyed to assess the structure specificity and the kind of information obtainable The second part of this review focuses on a variety of applications, primarily in the field of material sciences Detailed studies on the surface chemistry of catalysts are discussed The increasing importance of surface modification and tailoring to improve the interface properties has generated a wide range of applications Examples from different technologies and industrial processes, such as semiconductors, paint, composite materials and corrosion protection of metals, are highlighted Attention is devoted to the complementarity between S-SIMS and other micro-analytical surface techniques The review aims at being of interest on the one hand to the S-SIMS users looking for interesting application areas and on the other hand, to the application chemists searching a method, potentially capable of yielding specific information for their material analysis problem © 1999 John Wiley & Sons, Inc, Mass Spec Rev 18: 1–81, 1999

Pentagon adjacency as a determinant of fullerene stability

Abstract: Optimisation of geometries of all 40 fullerene isomers of C40, using methods from molecular mechanics and tight-binding to full abinitio SCF and DFT approaches, confirms minimisation of pentagon adjacency as a major factor in relative stability. The consensus predictions of 11 out of 12 methods are that the isomer of lowest total energy is the D2 cage with the smallest possible adjacency count, and that energies rise linearly with the number of adjacencies. Quantum mechanical methods predict a slope of 80–100 kJ mol-1 per adjacency. Molecular mechanics methods are outliers, with the Tersoff potential giving a different minimum and its Brenner modification a poor correlation and much smaller penalty.

Synthesis and Biological Evaluation of Dihydrobenzofuran Lignans and Related Compounds as Potential Antitumor Agents that Inhibit Tubulin Polymerization

Abstract: A series of 19 related dihydrobenzofuran lignans and benzofurans was obtained by a biomimetic reaction sequence involving oxidative dimerization of p-coumaric, caffeic, or ferulic acid methyl esters, followed by derivatization reactions. All compounds were evaluated for potential anticancer activity in an in vitro human disease-oriented tumor cell line screening panel that consisted of 60 human tumor cell lines arranged in nine subpanels, representing diverse histologies. Leukemia and breast cancer cell lines were relatively more sensitive to these agents than were the other cell lines. Compounds 2c and 2d, but especially 2b (methyl (E)-3-?2-(3, 4-dihydroxyphenyl)-7-hydroxy-3-methoxycarbonyl-2, 3-dihydro-1-benzofuran-5-ylprop-2-enoate), the dimerization product of caffeic acid methyl ester, containing a 3',4'-dihydroxyphenyl moiety and a hydroxyl group in position 7 of the dihydrobenzofuran ring, showed promising activity. The average GI(50) value (the molar drug concentration required for 50% growth inhibition) of 2b was 0.3 microM. Against three breast cancer cell lines, 2b had a GI(50) value of <10 nM. Methylation, reduction of the double bond of the C(3)-side chain, reduction of the methoxycarbonyl functionalities to primary alcohols, or oxidation of the dihydrobenzofuran ring to a benzofuran system resulted in a decrease or loss of cytotoxic activity. Compound 2b inhibited mitosis at micromolar concentrations in cell culture through a relatively weak interaction at the colchicine binding site of tubulin. In vitro it inhibited tubulin polymerization by 50% at a concentration of 13 +/- 1 microM. The 2R, 3R-enantiomer of 2b was twice as active as the racemic mixture, while the 2S,3S-enantiomer had minimal activity as an inhibitor of tubulin polymerization. These dihydrobenzofuran lignans (2-phenyl-dihydrobenzofuran derivatives) constitute a new group of antimitotic and potential antitumor agents that inhibit tubulin polymerization.

EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.

Abstract: Osteochondromas occur as sporadic solitary lesions or as multiple lesions, characterizing the hereditary multiple exostoses syndrome (EXT). Approximately 15% of all chondrosarcomas arise within the cartilaginous cap of an osteochondroma. EXT is genetically heterogeneous, and two genes, EXT1 and EXT2, located on 8q24 and 11p11-p12, respectively, have been cloned. It is still unclear whether osteochondroma is a developmental disorder or a true neoplasm. Furthermore, it is unclear whether inactivation of both alleles of an EXT gene, according to the tumor-suppressor model, is required for osteochondroma development, or whether a single EXT germline mutation acts in a dominant negative way. We therefore studied loss of heterozygosity and DNA ploidy in eight sporadic and six hereditary osteochondromas. EXT1- and EXT2-mutation analysis was performed in a total of 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas. We demonstrated osteochondroma to be a true neoplasm, since aneuploidy was found in 4 of 10 osteochondromas. Furthermore, LOH was almost exclusively found at the EXT1 locus in 5 of 14 osteochondromas. Four novel constitutional cDNA alterations were detected in exon 1 of EXT1. Two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild-type allele in three osteochondromas, indicating that, in cartilaginous cells of the growth plate, inactivation of both copies of the EXT1 gene is required for osteochondroma formation in hereditary cases. In contrast, no somatic EXT1 cDNA alterations were found in sporadic osteochondromas. No mutations were found in the EXT2 gene.

Platelet number and interleukin-6 correlate with VEGF but not with bFGF serum levels of advanced cancer patients.

Abstract: We have compared the platelet number and the serum concentration of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and interleukin-6 (IL-6) in 80 blood samples of 50 patients with advanced cancer. We have also measured the mitogenic effect of patient sera on endothelial cells in vitro in order to estimate the biological activity of serum VEGF. Serum VEGF concentration correlated with platelet number (r = 0.61; P < 10−4). Serum IL-6 levels correlated with platelet count (r = 0.36; P < 10−3), with serum VEGF levels (r = 0.55; P < 10−4) and with the calculated load of VEGF per platelet (r = 0.4; P = 3 × 10−4). Patients with thrombocytosis had a median VEGF serum concentration which was 3.2 times higher (P < 10−4) and a median IL-6 serum level which was 5.8 times higher (P = 0.03) than in other patients. Serum bFGF did not show an association with any of the other parameters. Patient sera with high VEGF and bFGF content stimulated endothelial cell proliferation significantly more than other sera (P = 4 × 10−3). These results support the role of platelets in the storage of biologically active VEGF. Platelets seem to prevent circulating VEGF from inducing the development of new blood vessels except at sites where coagulation takes place. IL-6, besides its thrombopoietic effect, also seems to affect the amount of VEGF stored in the platelets. This is in accordance with the indirect angiogenic action of IL-6 reported previously. The interaction of IL-6 with the angiogenic pathways in cancer might explain the stimulation of tumour growth occasionally observed during IL-6 administration. It also conforms to the worse outcome associated with high IL-6 levels and with thrombocytosis in several tumour types and benign angiogenic diseases. © 1999 Cancer Research Campaign

Mutations in the KCNQ4 gene are responsible for autosomal dominant deafness in four DFNA2 families.

Abstract: We have previously found linkage to chromosome 1p34 in five large families with autosomal dominant non-syndromic hearing impairment (DFNA2). In all five families, the connexin31 gene ( GJB3 ), located at 1p34 and responsible for non-syndromic autosomal dominant hearing loss in two small Chinese families, has been excluded as the responsible gene. Recently, a fourth member of the KCNQ branch of the K+channel family, KCNQ4, has been cloned. KCNQ4 was mapped to chromosome 1p34 and a single mutation was found in three patients from a small French family with non-syndromic autosomal dominant hearing loss. In this study, we have analysed the KCNQ4 gene for mutations in our five DFNA2 families. Missense mutations altering conserved amino acids were found in three families and an inactivating deletion was present in a fourth family. No KCNQ4 mutation could be found in a single DFNA2 family of Indonesian origin. These results indicate that at least two and possibly three genes responsible for hearing impairment are located close together on chromosome 1p34 and suggest that KCNQ4 mutations may be a relatively frequent cause of autosomal dominant hearing loss.