3DTF: a web server for predicting transcription factor PWMs using 3D structure-based energy calculations.

We present the webserver 3D transcription factor (3DTF) to compute position-specific weight matrices (PWMs) of transcription factors using a knowledge-based statistical potential derived from crystallographic data on protein-DNA complexes. Analysis of available structures that can be used to construct PWMs shows that there are hundreds of 3D structures from which PWMs could be derived, as well as thousands of proteins homologous to these. Therefore, we created 3DTF, which delivers binding matrices given the experimental or modeled protein-DNA complex. The webserver can be used by biologists to derive novel PWMs for transcription factors lacking known binding sites and is freely accessible at http://www.gene-regulation.com/pub/programs/3dtf/.

Feasibility of 6-month maintenance cetuximab after adjuvant concurrent chemoradiation plus cetuximab in squamous cell carcinoma of the head and neck.

BACKGROUND: Close resection margins < 5 mm (CM) or extra capsular extent at the lymph nodes (ECE) impair the prognosis of patients with squamous cell cancer of the head and neck (SCCHN) scheduled for adjuvant radiochemotherapy. We conducted a multicenter phase II study to investigate toxicity and efficacy of additional cetuximab administered concomitantly and as maintenance for the duration of 6 months following adjuvant radiochemotherapy., Ppreliminary results on feasibility and acute toxicity on skin and mucosa are presented in this article. METHODS: Patients with SCCHN following CM resection or with ECE were eligible for the study. In all, 61.6 Gy (1.8/2.0/2.2 Gy, days 1-36) were administered using an integrated boost intensity-modulated radiotherapy (IMRT) technique. Cisplatin (20 mg/m(2), days 1-5 and days 29-33) and 5-fluorouracil (5-FU) as continuous infusion (600 mg/m(2), days 1-5 + days 29-33) were given concurrently. Cetuximab was started 7 days prior to radiochemotherapy at 400 mg/m(2) followed by weekly doses of 250 mg/m(2). Maintenance cetuximab began after radiochemotherapy at 500 mg/m(2) every 2 weeks for 6 months. RESULTS: Of the 55 patients (46 male, 9 female, mean age 55.6, range 29-70 years) who finished radiochemotherapy, 50 were evaluable for acute toxicity concerning grade III/IV toxicities of skin and mucosa. Grade 3-4 (CTC 3.0) mucositis, radiation dermatitis, and skin reactions outside the radiation portals were documented for 46, 28, and 14 % of patients, respectively. One toxic death occurred (peritonitis at day 57). Cetuximab was terminated in 5 patients due to allergic reactions after the first application. In addition, 22 % of patients discontinued cetuximab within the last 2 weeks or at the end of radiochemotherapy. Of patients embarking on maintenance treatment, 80 % were still on cetuximab at 3 months and 63 % at 5 months. Concurrent and maintenance treatment with cetuximab could be administered as scheduled in 48 % of patients. CONCLUSION: Adjuvant radiochemotherapy with concomitant and maintenance cetuximab is feasible and acute toxicities are within the expected range. Compliance within the first 3-5 months is moderate.

Composite Module Analyst: identification of transcription factor binding site combinations using genetic algorithm.

Composite Module Analyst (CMA) is a novel software tool aiming to identify promoter-enhancer models based on the composition of transcription factor (TF) binding sites and their pairs. CMA is closely interconnected with the TRANSFAC database. In particular, CMA uses the positional weight matrix (PWM) library collected in TRANSFAC and therefore provides the possibility to search for a large variety of different TF binding sites. We model the structure of the long gene regulatory regions by a Boolean function that joins several local modules, each consisting of co-localized TF binding sites. Having as an input a set of co-regulated genes, CMA builds the promoter model and optimizes the parameters of the model automatically by applying a genetic-regression algorithm. We use a multicomponent fitness function of the algorithm which includes several statistical criteria in a weighted linear function. We show examples of successful application of CMA to a microarray data on transcription profiling of TNF-alpha stimulated primary human endothelial cells. The CMA web server is freely accessible at http://www.gene-regulation.com/pub/programs/cma/CMA.html. An advanced version of CMA is also a part of the commercial system ExPlaintrade mark (www.biobase.de) designed for causal analysis of gene expression data.

TRANSFAC and its module TRANSCompel: transcriptional gene regulation in eukaryotes.

The TRANSFAC database on transcription factors, their binding sites, nucleotide distribution matrices and regulated genes as well as the complementing database TRANSCompel on composite elements have been further enhanced on various levels. A new web interface with different search options and integrated versions of Match and Patch provides increased functionality for TRANSFAC. The list of databases which are linked to the common GENE table of TRANSFAC and TRANSCompel has been extended by: Ensembl, UniGene, EntrezGene, HumanPSD and TRANSPRO. Standard gene names from HGNC, MGI and RGD, are included for human, mouse and rat genes, respectively. With the help of InterProScan, Pfam, SMART and PROSITE domains are assigned automatically to the protein sequences of the transcription factors. TRANSCompel contains now, in addition to the COMPEL table, a separate table for detailed information on the experimental EVIDENCE on which the composite elements are based. Finally, for TRANSFAC, in respect of data growth, in particular the gain of Drosophila transcription factor binding sites (by courtesy of the Drosophila DNase I footprint database) and of Arabidopsis factors (by courtesy of DATF, Database of Arabidopsis Transcription Factors) has to be stressed. The here described public releases, TRANSFAC 7.0 and TRANSCompel 7.0, are accessible under http://www.gene-regulation.com/pub/databases.html.

ExPlain: finding upstream drug targets in disease gene regulatory networks.

Different signal transduction pathways leading to the activation of transcription factors (TFs) converge at key molecules that master the regulation of many cellular processes. Such crossroads of signalling networks often appear as "Achilles Heels" causing a disease when not functioning properly. Novel computational tools are needed for analysis of the gene expression data in the context of signal transduction and gene regulatory pathways and for identification of the key nodes in the networks. An integrated computational system, ExPlain (www.biobase.de) was developed for causal interpretation of gene expression data and identification of key signalling molecules. The system utilizes data from two databases (TRANSFAC and TRANSPATH) and integrates two programs: (1) Composite Module Analyst (CMA) analyses 5'-upstream regions of co-expressed genes and applies a genetic algorithm to reveal composite modules (CMs) consisting of co-occurring single TF binding sites and composite elements; (2) ArrayAnalyzer is a fast network search engine that analyses signal transduction networks controlling the activities of the corresponding TFs and seeks key molecules responsible for the observed concerted gene activation. ExPlain system was applied to microarray data on inflammatory bowel diseases (IBD). The results obtained suggest a number of highly interesting biological hypotheses about molecular mechanisms of pathological genetic disregulation.

[Technical construction, calibration and results with a new intraocular pressure sensor with telemetric transmission]. / Technischer Aufbau, Kalibrierung und Ergebnisse mit einem neuen intraokularen Drucksensor mit telemetrischer Ubertragung.

BACKGROUND: Presently intraocular pressure is measured indirectly by applanation or impression of the cornea. Only isolated values are available with this method. We present a new implantable system for direct and continuos measurement of the intraocular pressure. METHODS: An implantable system consisting of a miniaturized sensor and a telemetric unit was integrated in an intraocular lens. The eye pressure is determined by the sensor, modulated and transduced by the telemetric system. By an extracorporal receiver the signal is demodulated. The electric supply of the intraocular system is achieved by external electromagnetic induction. RESULTS: The telemetric transmission of the intraocular pressure can be achieved with an accuracy of +/- 1 mm Hg and a frequency of registration of 3 values per second. CONCLUSION: Clinical application necessitates further animal trials in vivo.

Assessment of pulmonary mechanics in mechanical ventilation: effects of imprecise breath detection, phase shift and noise.

OBJECTIVE: In mechanical ventilation, the assessment of pulmonary mechanics, mainly of total compliance (Crs), total resistance (Rrs), and intrinsic positive end-expiratory pressure (PEEPint), is clinically important. By using airway pressure (Paw) and flow (V'aw), the least squares fit (LSF) method allows the continuous calculation of these parameters. The objective of this work was to study the influence of imprecise breath detection, phase shift between airway pressure and flow signals, and noise on the determination of Crs, Rrs, and PEEPint. METHODS: Paw and V'aw were mathematically simulated as well as recorded in mechanically ventilated patients. Crs, Rrs, and PEEPint were computed off-line using the LSF method. The boundaries of the breath data window and the phase relationship between Paw and V'aw signals were manipulated and noise was superimposed. RESULTS: Both simulated and patient data gave similar results. Crs and Rrs were not sensitive to imprecise breath detection. If the first portion of the breath was missed, the mean relative error on PEEPint was 20% or 53% when the exact beginning of inspiration was missed by 0.1 or 0.3 sec, respectively. Paw lag of 66 ms with respect to V'aw yielded a relative error of -15 +/- 4% (mean +/- SD) for Rrs, -5 +/- 2% for Crs, and +13 +/- 16% for PEEPint. Paw lead of 66 ms with respect to V'aw yielded a relative error of +5 +/- 4% for Rrs, +7 +/- 3% for Crs, and +14 +/- 18% for PEEPint. Noise had very little impact on the accuracy of Crs, Rrs, and PEEPint. CONCLUSIONS: We conclude that the LSF method allows the assessment of Crs, Rrs, and PEEPint even with high levels of noise in patients with normal lungs provided that Paw and V'aw signals are precisely synchronised and a reliable breath detection algorithm is used.