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Paul Janssen

Publications and source records attributed to Paul Janssen.

At least 19 recordsLinked to original sources
PubMed2006

Heterogeneity in disease free survival between centers: lessons learned from an EORTC breast cancer trial.

BACKGROUND: Large phase III clinical trials convey a lot of important information besides the main analysis of the treatment effect. For example, the use of multicenter clinical trial data to identify prognostic indices is now common. In addition, the study of heterogeneity in patient outcome between centers has received considerable attention in recent years. In this paper, we explain and illustrate a method used to investigate such heterogeneity with data from an early breast cancer clinical trial. METHODS: The inclusion of a random effect for center in a Cox proportional hazards model allows us to study the heterogeneity in time-to-event outcomes between centers. Such a model has the major advantage that it provides a measure of the spread of outcomes over centers. This technique is illustrated using data from EORTC trial 10854, a randomized phase III trial comparing perioperative chemotherapy with no perioperative chemotherapy for early breast cancer; 2793 patients were entered by 14 centers. RESULTS: Substantial heterogeneity between centers was detected for disease-free survival. This can be explained by the geographical area in which the center is located, with better outcomes achieved in France as compared with southern Europe and South Africa. None of the prognostic factors considered could explain this heterogeneity. CONCLUSION: Although clinical trials are run with the objective of removing as much heterogeneity as possible, some heterogeneity in the outcome of patients between centers may remain, as was the case in our study. The use of a random effect for center within a Cox PH model is an excellent method to investigate this heterogeneity. Such types of analyses, although exploratory, provide further insight into possible factors which may have an impact on the patient's outcome.

Breast Neoplasms↗
PubMed2005

A Bayesian approach to jointly estimate centre and treatment by centre heterogeneity in a proportional hazards model.

When multicentre clinical trial data are analysed, it has become more and more popular to look for possible heterogeneity in outcome between centres. However, beyond the investigation of such heterogeneity, it is also interesting to consider heterogeneity in treatment effect over centres. For time-to-event outcomes, this may be investigated by including a random centre effect and a random treatment by centre interaction in a Cox proportional hazards model. Assuming independence between the random effects, we propose a Bayesian approach to fit our proposed model. The parameters of interest are the variance components sigma(0) (2) and sigma(1) (2) of these random effects, which can be interpreted as a measure of centre and treatment effect over centres heterogeneity of the hazard. These variance components are estimated from their marginal posterior density after integrating out the fixed treatment effect and the random effects. As this integration cannot be performed analytically, the marginal posterior density is approximated using the Laplace integration technique. Statistical inference is then based on the characteristics of the posterior marginal density, such as the mode and the standard deviation. We demonstrate the proposed technique using data from a pooled database of seven EORTC bladder cancer clinical trials. Substantial centre and treatment effect over centres heterogeneity in disease-free interval was found.

Bayes Theorem↗
PubMed2005

Microbial ecology of the closed artificial ecosystem MELiSSA (Micro-Ecological Life Support System Alternative): reinventing and compartmentalizing the Earth's food and oxygen regeneration system for long-haul space exploration missions.

MELiSSA is a bioregenerative life support system designed by the European Space Agency (ESA) for the complete recycling of gas, liquid and solid wastes during long distance space exploration. The system uses the combined activity of different living organisms: microbial cultures in bioreactors, a plant compartment and a human crew. In this minireview, the development of a short-cut ecological system for the biotransformation of organic waste is discussed from a microorganism's perspective. The artificial ecological model--still in full development--that is inspired by Earth's own geomicrobiological ecosystem serves as an ideal study object on microbial ecology and will become an indispensable travel companion in manned space exploration.

Bacteria↗
PubMed2005

CoGenT++: an extensive and extensible data environment for computational genomics.

MOTIVATION: CoGenT++ is a data environment for computational research in comparative and functional genomics, designed to address issues of consistency, reproducibility, scalability and accessibility. DESCRIPTION: CoGenT++ facilitates the re-distribution of all fully sequenced and published genomes, storing information about species, gene names and protein sequences. We describe our scalable implementation of ProXSim, a continually updated all-against-all similarity database, which stores pairwise relationships between all genome sequences. Based on these similarities, derived databases are generated for gene fusions--AllFuse, putative orthologs--OFAM, protein families--TRIBES, phylogenetic profiles--ProfUse and phylogenetic trees. Extensions based on the CoGenT++ environment include disease gene prediction, pattern discovery, automated domain detection, genome annotation and ancestral reconstruction. CONCLUSION: CoGenT++ provides a comprehensive environment for computational genomics, accessible primarily for large-scale analyses as well as manual browsing.

Chromosome Mapping↗
PubMed2005

Pairwise non-parametric non-inferiority tests in 3 x 3 cross-over trials: should we adjust for period?

Before an active compound can be registered as a drug, it needs to be demonstrated that it does not cause particular unwanted compound specific side effects. Demonstrating non-inferiority of an active drug with placebo with respect to an unwanted side effect is often based on pharmacodynamic 3 x 3 cross-over trials, with the third treatment arm consisting of a positive control. The main comparison then is the pairwise comparison between active drug and placebo. In this paper, two different non-parametric methods with adjustment for period effect are compared with the non-parametric non-adjusted test and the parametric period-adjusted test with respect to size and power. The non-parametric test with period adjustment based on rank alignment has generally the largest power, but its size exceeds the nominal significance level. The non-parametric test with period adjustment based on stratification has low power for trials with a small number of subjects. The non-parametric test without period adjustment is a valid alternative in such cases, but its power decreases substantially in the presence of period effects. In the case of unbalanced designs, however, only the non-parametric test with period adjustment based on stratification can be used.

Belgium↗
PubMed2005

Measuring genome conservation across taxa: divided strains and united kingdoms.

Species evolutionary relationships have traditionally been defined by sequence similarities of phylogenetic marker molecules, recently followed by whole-genome phylogenies based on gene order, average ortholog similarity or gene content. Here, we introduce genome conservation--a novel metric of evolutionary distances between species that simultaneously takes into account, both gene content and sequence similarity at the whole-genome level. Genome conservation represents a robust distance measure, as demonstrated by accurate phylogenetic reconstructions. The genome conservation matrix for all presently sequenced organisms exhibits a remarkable ability to define evolutionary relationships across all taxonomic ranges. An assessment of taxonomic ranks with genome conservation shows that certain ranks are inadequately described and raises the possibility for a more precise and quantitative taxonomy in the future. All phylogenetic reconstructions are available at the genome phylogeny server: .

Bacteria↗
PubMed2005

The non-linear effect (determined by the penalised partial-likelihood approach) of milk-protein concentration on time to first insemination in Belgian dairy cows.

The time to first insemination in dairy cows depends partly on the energy balance of the cow. Because milk-protein concentration is related to the energy balance, we investigated whether milk-protein concentration predicted the hazard of being inseminated. The main objective of the paper is to demonstrate that the relationship between milk-protein concentration and the hazard of being inseminated was not linear and that this non-linear relationship was modelled adequately using cubic-splines. The semiparametric Cox model was used to introduce protein concentration into the model as a time-varying covariate and additionally herd was added to the model as a frailty term to adjust for the clustering of the cows within a herd. We extended the penalised partial-likelihood technique to fit the frailty model with cubic-splines for the effect of the protein concentration. The model was fitted for a large database consisting of 5114 multiparous cows from 181 different farms. Low milk-protein concentration (<2.7%) was associated with a negative energy balance and this probably led to the decreased hazard. On the other hand, high milk-protein concentration (>4.0%) was linked with low milk production and it was probably a farmer's decision not to inseminate such cows, leading to the observed decreased hazard.

Animals↗
PubMed2005

[Alexithymia in a clinical sample].

OBJECTIVES: The Toronto Alexithymia Scale (TAS-20), is currently the most widely used measure of alexithymia. An alternative measure of alexithymic characteristics is the Levels of Emotional Awareness Scale (LEAS). Aim of the study was to investigate, wether LEAS and TAS-20 scores are associated with interpersonal problems, sociodemografic variables, and psychological strain in a construct conform direction. METHODS: 146 psychosomatically ill in-patients completed the TAS-20, the LEAS, the Symptom Check List (SCL-90-R) and the inventory for the assessment of interpersonal problems (IIP-D). RESULTS: Low emotional awareness (LEAS) was associated with male gender, absence of a stable partnership and low educational level. In contrast to LEAS, TAS-20 was significantly correlated with the majority of the SCL-90-R and IIP scales. CONCLUSIONS: The correlations between TAS-20 and IIP scales may be an indication for the validity of the measurement. The association between low emotional awareness and sociodemografic variables are costructconform and indicate a strong relationship between LEAS and variables, that represent real life.

Adult↗
PubMed2005

Duration adjustment of acute exposure guideline level values for trichloroethylene using a physiologically-based pharmacokinetic model.

Acute Exposure Guideline Level (AEGL) recommendations are developed for 10-minute, 30-minute, 1-hour, 4-hours, and 8-hours exposure durations and are designated for three levels of severity: AEGL-1 represents concentrations above which acute exposures may cause noticeable discomfort including irritation; AEGL-2 represents concentrations above which acute exposure may cause irreversible health effects or impaired ability to escape; and AEGL-3 represents concentrations above which exposure may cause life-threatening health effects or death. The default procedure for setting AEGL values across durations when applicable data are unavailable involves estimation based on Haber's rule, which has an underlying assumption that cumulative exposure is the determinant of toxicity. For acute exposure to trichloroethylene (TCE), however, experimental data indicate that momentary tissue concentration, and not the cumulative amount of exposure, is important. We employed an alternative approach to duration adjustments in which a physiologically-based pharmacokinetic (PBPK) model was used to predict the arterial blood concentrations [TCE(a)] associated with adverse outcomes appropriate for AEGL-1, -2, or -3-level effects. The PBPK model was then used to estimate the atmospheric concentration that produces equivalent [TCE(a)] at each of the AEGL-specific exposure durations. This approach yielded [TCE(a)] values of 4.89 mg/l for AEGL-1, 18.7 mg/l for AEGL-2, and 310 mg/l for AEGL-3. Duration adjustments based on equivalent target tissue doses should provide similar degrees of toxicity protection at different exposure durations.

Animals↗
PubMed2004

Penalized partial likelihood for frailties and smoothing splines in time to first insemination models for dairy cows.

In many epidemiological studies time to event data are clustered and the physiological relationship between (time-dependent) covariates and the log hazard is often not linear as assumed in the Cox model. Introducing frailties in the Cox model can account for the clustering of the data and smoothing splines can be used to describe nonlinear relations. These two extensions of the Cox model are introduced jointly and it is shown how penalized partial likelihood techniques can be used to fit the extended model. We demonstrate the need for such a model to study the relation between the physiological covariates milk ureum and protein concentration and the log hazard of first insemination in dairy cows, with the farms as clusters.

Animals↗
PubMed2004

In vitro evaluation of nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 as human immunodeficiency virus microbicides.

The nonnucleoside reverse transcriptase inhibitors UC-781 and TMC120-R147681 (Dapivirine) effectively prevented human immunodeficiency virus (HIV) infection in cocultures of monocyte-derived dendritic cells and T cells, representing primary targets in sexual transmission. Both drugs had a favorable therapeutic index. A 24-h treatment with 1,000 nM UC-781 or 100 nM TMC120-R147681 prevented cell-free HIV infection, whereas 10-fold-higher concentrations blocked cell-associated HIV.

Anilides↗
PubMed2004

A series of diaryltriazines and diarylpyrimidines are highly potent nonnucleoside reverse transcriptase inhibitors with possible applications as microbicides.

An in vitro model of monocyte-derived dendritic cells (MO-DC) and CD4(+) T cells, representing the primary targets of sexual human immunodeficiency virus (HIV) transmission, was used to evaluate the antiviral and immune suppressive activity of new classes of nonnucleoside reverse transcriptase inhibitors, diaryltriazines (DATAs) and diarylpyrimidines (DAPYs), compared to the reference compounds UC-781 and PMPA. Antiviral activity (as reflected by the 50% effective concentration [EC(50)]) was determined by treating HIV-infected MO-DC/CD4(+)-T-cell cocultures with a dose range of a compound during 14 days, followed by analysis of supernatants in HIV p24 antigen enzyme-linked immunosorbent assay. A limited, 24-h treatment evaluated the compounds as microbicides. Viral rescue was evaluated in a PCR by monitoring proviral DNA in secondary cultures with phytohemagglutinin-interleukin-2 blasts. We determined 50% immunosuppressive concentrations in mixed leukocyte cultures of MO-DC and allogeneic T cells, with compound either continuously present or present only during the first 24 h. The EC(50) values of DATA and DAPY compounds ranged from 0.05 to 3 nM compared to 50 nM for UC-781 and 89 nM for PMPA. When evaluated in the "microbicide" setting, the most potent compounds completely blocked HIV infection at 10 to 100 nM. The immunosuppressive concentrations were well above the EC(50), resulting in favorable therapeutic indices for all compounds tested. The DATA and DAPY compounds described here are more potent than earlier reverse transcriptase inhibitors and show favorable pharmacological profiles in vitro. They could strengthen the antiretroviral armamentarium and might be useful as microbicides.

Anti-Infective Agents↗
PubMed2004

TMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1.

Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are potent inhibitors of human immunodeficiency virus type 1 (HIV-1); however, currently marketed NNRTIs rapidly select resistant virus, and cross-resistance within the class is extensive. A parallel screening strategy was applied to test candidates from a series of diarylpyrimidines against wild-type and resistant HIV strains carrying clinically relevant mutations. Serum protein binding and metabolic stability were addressed early in the selection process. The emerging clinical candidate, TMC125, was highly active against wild-type HIV-1 (50% effective concentration [EC50] = 1.4 to 4.8 nM) and showed some activity against HIV-2 (EC50 = 3.5 microM). TMC125 also inhibited a series of HIV-1 group M subtypes and circulating recombinant forms and a group O virus. Incubation of TMC125 with human liver microsomal fractions suggested good metabolic stability (15% decrease in drug concentration and 7% decrease in antiviral activity after 120 min). Although TMC125 is highly protein bound, its antiviral effect was not reduced by the presence of 45 mg of human serum albumin/ml, 1 mg of alpha1-acid glycoprotein/ml, or 50% human serum. In an initial screen for activity against a panel of 25 viruses carrying single and double reverse transcriptase amino acid substitutions associated with NNRTI resistance, the EC50 of TMC125 was <5 nM for 19 viruses, including the double mutants K101E+K103N and K103N+Y181C. TMC125 also retained activity (EC50 < 100 nM) against 97% of 1,081 recent clinically derived recombinant viruses resistant to at least one of the currently marketed NNRTIs. TMC125 is a potent next generation NNRTI, with the potential for use in individuals infected with NNRTI-resistant virus.

Cell Line↗
PubMed2003

COmplete GENome Tracking (COGENT): a flexible data environment for computational genomics.

SUMMARY: We present a database of fully sequenced and published genomes to facilitate the re-distribution of data and ensure reproducibility of results in the field of computational genomics. For its design we have implemented an extremely simple yet powerful schema to allow linking of genome sequence data to other resources. AVAILABILITY: http://maine.ebi.ac.uk:8000/services/cogent/

Computational Biology↗
PubMed2003

Beyond 100 genomes.

By the end of 2002, we witnessed the landmark submission of the 100th complete genome sequence in the databases. An overview of these genomes reveals certain interesting trends and provides valuable insights into possible future developments.

Animals↗
PubMed2003

Protein-protein interactions as a target for drugs in proteomics.

Protein-protein interactions play a central role in numerous processes in the cell and are one of the main fields of functional proteomics. This review highlights the methods of bioinformatics and functional proteomics of protein-protein interaction investigation. The structures and properties of contact surfaces, forces involved in protein-protein interactions, kinetic and thermodynamic parameters of these reactions were considered. The properties of protein contact surfaces depend on their functions. The contact surfaces of permanent complexes resemble domain contacts or the protein core and it is reasonable to consider such complex formation as a continuation of protein folding. Characteristics of contact surfaces of temporary protein complexes share some similarities with active sites of enzymes. The contact surfaces of the temporary protein complexes have unique structure and properties and they are more conservative in comparison with active site of enzymes. So they represent prospective targets for a new generation of drugs. During the last decade, numerous investigations were undertaken to find or design small molecules that block protein dimerization or protein(peptide)-receptor interaction, or, on the contrary, to induce protein dimerization.

Computational Biology↗
PubMed2002

Interferon-gamma-induced calcium influx in T lymphocytes of multiple sclerosis and rheumatoid arthritis patients: a complementary mechanism for T cell activation?

Autoreactive T lymphocytes are considered to play a crucial role in orchestrating a chronic inflammation in the central nervous system (CNS) of multiple sclerosis (MS) patients and in the joints of rheumatoid arthritis (RA) patients. However, it has been suggested that the majority of T cells in the immune infiltrate are nonspecifically recruited into the CNS and into the inflamed joint. In addition, several lines of evidence suggest an important role for interferon-gamma (IFN-gamma) in the pathogenesis of MS and RA. We have studied whether peripheral blood T cells from patients with autoimmune diseases are more susceptible to activation in the presence of IFN-gamma. The results indicate that IFN-gamma mediates a sustained elevated [Ca(2+)](i) in T cells of (active) MS and RA patients as compared to healthy controls and patients with common viral infections. No [Ca(2+)](i) increase was observed in Ca(2+)-free medium, excluding an effect of IFN-gamma on Ca(2+)-release from intracellular stores. Although the IFN-gamma-activated Ca(2+)-influx is insufficient to induce T cell proliferation in vitro, our data indicate a significantly augmented proliferation in response to suboptimal doses of PHA in the presence of IFN-gamma. This study suggests that the IFN-gamma-induced Ca(2+)-influx can act as a complementary mechanism in the activation of blood T lymphocytes from MS and RA patients.

Adult↗