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PubMed2000

Endotoxin down-modulates granulocyte colony-stimulating factor receptor (CD114) on human neutrophils.

During infection, the development of nonresponsiveness to granulocyte colony-stimulating factor (G-CSF) may be influenced by the down-modulation of G-CSF receptor (G-CSFR) by cytokines. This down-modulation was studied during experimental human endotoxemia. Healthy volunteers received either 2 ng/kg endotoxin (lipopolysaccharide [LPS], n=20) or placebo (n=10) in a randomized, controlled trial. Endotoxin infusion increased the mean fluorescence intensity of the neutrophil activation marker CD11b >300% after 1 h (P<.001 vs. placebo). LPS infusion down-modulated G-CSFR expression in as early as 60 min (-17%; P=.001 vs. placebo). Down-modulation was almost maximal at 90 min and persisted for 6 h (-50% from baseline; P<.0001 vs. placebo). Plasma levels of G-CSF started to increase only after G-CSFR down-modulation had occurred and peaked 37-fold above baseline at 4 h (P<.0001 vs. placebo). In conclusion, LPS down-modulates G-CSFR expression in humans, which may render neutrophils less responsive to the effects of G-CSF and, thereby, compromise host defense mechanisms.

Adult↗

PubMed2004

High resolution MR based polymer dosimetry versus film densitometry: a systematic study based on the modulation transfer function approach.

Precise methods of modem radiation therapy such as intensity modulated radiotherapy (IMRT), brachytherapy (BT) and high LET irradiation allow for high dose localization in volumes of a few mm3. However, most dosimetry methods-ionization chambers, TLD arrangements or silicon detectors, for example-are not capable of detecting sub-mm dose variations or do not allow for simple dose imaging. Magnetic resonance based polymer dosimetry (MRPD) appears to be well suited to three-dimensional high resolution relative dosimetry but the spatial resolution based on a systematic modulation transfer function (MTF) approach has not yet been investigated. We offer a theoretical construct for addressing the spatial resolution in different dose imaging systems, i.e. the dose modulation transfer function (DMTF) approach, an experimental realization of this concept with a phantom and quantitative comparisons between two dosimetric systems: polymer gel and film dosimetry. Polymer gel samples were irradiated by Co-60 photons through an absorber grid which is characterized by periodic structures of different spatial period (a), the smallest one at width of a/2 = 280 microm. The modulation in dose under the grid is visualized via calibrated, high resolution, parameter-selective (T2) and dose images based on multi-echo MR imaging. The DMTF is obtained from the modulation depth of the spin-spin relaxation time (T2) after calibration. Voxel sizes below 0.04 mm3 could be achieved, which are significantly smaller than those reported in MR based dose imaging on polymer gels elsewhere, using a powerful gradient system and a highly sensitive small birdcage resonator on a whole-body 3T MR scanner. Dose modulations at 22% of maximum dose amplitude could be observed at about 2 line pairs per mm. The polymer DMTF results are compared to those of a typical clinical film-scanner system. This study demonstrates that MR based gel dosimetry at 200 microm pixel resolution might even be superior, with reference to relative spatial resolution, to the results of a standard film-scanner system offering a nominal scan resolution of 200 microm.

Calibration↗

PubMed2005

Calculations of neutron dose equivalent exposures from range-modulated proton therapy beams.

Passive beam spreading techniques have been used for most proton therapy treatments worldwide. This delivery method employs static scattering foils to spread the beam laterally and a range modulating wheel or ridge filter to spread the high dose region in depth to provide a uniform radiation dose to the treatment volume. Neutrons produced by interactions of the treatment beam with nozzle components, such as the range modulation wheel, can account for a large portion of the secondary dose delivered to healthy tissue outside the treatment volume. Despite this fact, little is known about the effects of range modulation on the secondary neutron exposures around passively scattered proton treatment nozzles. In this work, the neutron dose equivalent spectra per incident proton (H(E)/p) and total neutron dose equivalent per therapeutic absorbed dose (H/D) were studied using Monte Carlo techniques for various values of range modulation at 54 locations around a passive scattering proton therapy treatment nozzle. As the range modulator wheel step thickness increased from 1.0 to 11.5 cm, the peak values of H(E)/p decreased from approximately 1 x 10(-17) mSv Gy(-1) to approximately 2 x 10(-18) mSv Gy(-1) at 50 cm from isocentre along the beam's central axis. In general, H/D increased with increasing range modulation at all locations studied, and the maximum H/D exposures shifted away from isocentre.

Cyclotrons↗

PubMed2026

Identifying multigenic modules under selection in the tumor genome.

MOTIVATION: Genomic alterations in cancer arise from selective pressures acting on hallmark molecular modules, layered over a background of random mutagenic events. Methods to detect selection at the level of modules, as opposed to genes or nucleotides, are relatively underdeveloped. RESULTS: Here we present CanSRMaPP (Cancer Selection Recovery by Maximum Posterior Probability), a Bayesian model of the cancer genome that infers mutational selection on single genes and multi-genic modules while simultaneously modeling background events. Applying CanSRMaPP to lung adenocarcinoma genomes, we identify positive selection on 63 modules, yielding a model that parsimoniously explains the observed pattern of genetic alterations observed in new cancer cohorts. We further show that CanSRMaPP is adaptable to more tumor types and to alternative module definitions. We show that these modules serve as an effective scaffold for translating the cancer genome to molecular states, with prediction of cancer biomarker status as demonstration. AVAILABILITY: CanSRMaPP is freely available on GitHub. SUPPLEMENTARY INFORMATION: Supplementary Figs. S1-5, Supplementary Tables S1-5, and Supplementary Notes 1 and 2 are available at Bioinformatics online.

Journal Article↗

PubMed2006

The discovery of transcriptional modules by a two-stage matrix decomposition approach.

MOTIVATION: We address the problem of identifying gene transcriptional modules from gene expression data by proposing a new approach. Genes mostly interact with each other to form transcriptional modules for context-specific cellular activities or functions. Unraveling such transcriptional modules is important for understanding biological network, deciphering regulatory mechanisms and identifying biomarkers. METHOD: The proposed algorithm is based on two-stage matrix decomposition. We first model microarray data as non-linear mixtures and adopt the non-linear independent component analysis to reduce the non-linear distortion and separate the data into independent latent components. We then apply the probabilistic sparse matrix decomposition approach to model the 'hidden' expression profiles of genes across the independent latent components as linear weighted combinations of a small number of transcriptional regulator profiles. Finally, we propose a general scheme for identifying gene modules from the outcomes of the matrix decomposition. RESULTS: The proposed algorithm partitions genes into non-mutually exclusive transcriptional modules, independent from expression profile similarity measurement. The modules contain genes with not only similar but different expression patterns, and show the highest enrichment of biological functions in comparison with those by other methods. The usefulness of the algorithm was validated by a yeast microarray data analysis. AVAILABILITY: The software is available upon request to the authors.

Algorithms↗

PubMed2004

The functional and temporal characteristics of top-down modulation in visual selection.

Perceptual load of an attended task influences the processing of irrelevant background stimuli. In a series of behavioral, functional magnetic resonance (fMRI) and electroencephalography (EEG) experiments we examined the influence of working memory (WM) load related to a relevant visual stimulus on the processing of irrelevant backgrounds. We further addressed two open questions about the mechanism of load-dependent modulation: (i) is this modulation dependent on regional activity (i.e. phasic)? (ii) At what processing stage does this modulation take place? Load was manipulated by a WM task and concurrently the processing of irrelevant visual objects was assessed with fMRI and EEG. To examine the dependency of this modulation on intrinsic activity, we varied the activity level of visual areas by presenting objects with different levels of degradation. Activity in the lateral occipital complex (LOC) increased with object visibility and was phasically modulated by WM load. Event related potentials revealed that this phasic modulation occurred approximately 170 ms after stimulus onset, indicative of an early selection under high load. The results indicate a phasic modulatory effect of WM load on visual object processing in the LOC that is comparable to the effects found for perceptual load manipulations.

Adult↗

PubMed2005

Medullary taste responses are modulated by the bed nucleus of the stria terminalis.

Previous studies have shown a modulatory influence of limbic forebrain areas, such as the central nucleus of the amygdala and lateral hypothalamus, on the activity of taste-responsive cells in the nucleus of the solitary tract (NST). The bed nucleus of the stria terminalis (BST), which receives gustatory afferent information, also sends descending axons to the NST. The present studies were designed to investigate the role of the BST in the modulation of NST gustatory activity. Extracellular action potentials were recorded from 101 taste-responsive cells in the NST of urethane-anesthetized hamsters and analyzed for a change in excitability following bilateral electrical stimulation of the BST. The response of NST taste cells to stimulation of the BST was predominately inhibitory. Orthodromic inhibitory responses were observed in 29 of 101 (28.7%) NST taste-responsive cells, with four cells inhibited bilaterally. An increase in excitability was observed in seven of the 101 (6.9%) NST taste cells. Of the 34 cells showing these responses, 25 were modulated by the ipsilateral BST and 15 by the contralateral; four were inhibited bilaterally and two inhibited ipsilaterally and excited contralaterally. The duration of inhibitory responses (mean = 177.9 ms) was significantly longer than that of excitatory responses (35.4 ms). Application of subthreshold electrical stimulation to the BST during taste trials inhibited or excited the taste responses of every BST-responsive NST cell tested with this protocol. NST neurons that were most responsive to sucrose, NaCl, citric acid or quinine hydrochloride were all affected by BST stimulation, although citric acid-best cells were significantly more often modulated and NaCl-best less often modulated than expected by chance. These results combine with excitatory and inhibitory modulation of NST neurons by the insular cortex, lateral hypothalamus and central nucleus of the amygdala to demonstrate extensive centrifugal modulation of brainstem gustatory neurons.

Animals↗

PubMed1998

Characterization of modulation of western equine encephalomyelitis virus by Culex tarsalis (Diptera: Culicidae) maintained at 32 degrees C following parenteral infection.

Two lines of Culex tarsalis Coquillett genetically selected for low or high western equine encephalomyelitis (WEE) virus production (low viral producer [LVP] or high viral producer [HVP], respectively) modulated WEE (i.e., decreased the concentration of virus to < 10(4) plaque-forming units after intrathoracic inoculation). The LVP line modulated WEE more than HVP, and modulation was most pronounced at 32 degrees C. At 15 degrees C, viral replication to high titers occurred in both lines. When infected LVP were transferred to 15 degrees C after 4 d extrinsic incubation at 32 degrees C, replication of WEE to high titers did not occur. Mosquitoes transferred from 15 degrees C after replication to high titers occurred; to 32 degrees C did significantly modulate WEE titer. Incubation at 32 degrees C prior to infection had no effect on the degree or timing of WEE modulation in both LVP and HVP lines. Most LVP infected following feeding on a high dose of WEE had salivary gland infection barriers. Viral modulation by Cx. tarsalis was an alphavirus phenomenon, and was not restricted to WEE.

Animals↗

PubMed2005

Prediction of functional modules based on comparative genome analysis and Gene Ontology application.

We present a computational method for the prediction of functional modules encoded in microbial genomes. In this work, we have also developed a formal measure to quantify the degree of consistency between the predicted and the known modules, and have carried out statistical significance analysis of consistency measures. We first evaluate the functional relationship between two genes from three different perspectives--phylogenetic profile analysis, gene neighborhood analysis and Gene Ontology assignments. We then combine the three different sources of information in the framework of Bayesian inference, and we use the combined information to measure the strength of gene functional relationship. Finally, we apply a threshold-based method to predict functional modules. By applying this method to Escherichia coli K12, we have predicted 185 functional modules. Our predictions are highly consistent with the previously known functional modules in E.coli. The application results have demonstrated that our approach is highly promising for the prediction of functional modules encoded in a microbial genome.

Bayes Theorem↗

PubMed1998

An investigation into the behavioural characteristics of orthodontic elastomeric modules.

The object of the study was to investigate the behavioural characteristics of orthodontic elastomeric modules with regard to their effect on frictional resistance and their failure load forces, and involved the use of an experimental laboratory-based study. Six cohorts were assembled employing five types of module and two bracket types. Straight lengths of 0.018 x 0.025-inch stainless steel were pulled through the ligated brackets and frictional resistance was measured using an Instron universal testing machine. Recordings were repeated over a 4-week period, during which time the cohorts were placed in a simulated oral environment. Failure load forces of new and used modules were also recorded, and frictional resistance and failure load forces. Analysis of variance revealed that the Minitwin cohort exhibited significantly higher frictional resistance and that the clear modules demonstrated the lowest levels of friction. Time soaked in a simulated oral environment had a variable effect on frictional resistance. A wide range of failure load forces was seen for the five types of module and all types showed a reduction in failure load force following their soaking in the simulated oral environment. There was variation in performance of the different modules both in friction testing and failure load testing.

Analysis of Variance↗

PubMed1991

Clinical relevance of biochemical modulation of 5-fluorouracil.

Biochemical modulation is a special type of combination chemotherapy which aims to selectively improve the therapeutic index by increasing the antitumor effect and protecting against toxic side effects. Biochemical modulation seems to be an attractive way to circumvent quantitative and qualitative heterogeneity of tumors. In the past decade a number of biochemical modulation approaches have been tested to improve the activity of 5-fluorouracil (5FU). 5FU itself has only modest anticancer activity but has been shown to be a very attractive target for biochemical modulation. A number of the combinations have been ineffective in the clinic despite extensive testing in a number of schedules. Some other combinations were initially tested in an inappropriate schedule, but were active when applied in another schedule. The latter was made possible by a systematic preclinical development of combinations with a proper translation to the clinic accompanied by pharmacodynamic evaluation. This review describes a number of biochemical modulation combinations, both inactive and active. The main conclusion is that properly applied biochemical modulation schedules may lead to successful use in the clinic.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1994

Biochemical modulation of 'classical' multidrug resistance by BIBW22BS, a potent derivative of dipyridamole.

BACKGROUND: Modulators of the 'classical' multidrug resistance (mdr) phenotype have low efficacy in patients with solid tumors. We analyzed BIBW22BS, 4-[N-(2-hydroxy-2-met- hyl-propyl)-ethanolamino]-2,7-bis(cis-2,6-dimethyl-morpho- lino)-6-phenylpteridine, a derivative of dipyridamole, for its higher potential to modulate mdr. MATERIALS AND METHODS: Four human malignant cell lines: BRO, A2780, GLC4, SW1573, the Pgp-positive sublines: BRO/mdr1.1, 2780AD and the non-Pgp sublines: GLC4/ADR, SW1573/2R120 were used in vitro to investigate BIBW22BS as a modulator of the antiproliferative effects of vincristine and doxorubicin and to compare the potency of BIBW22BS with that of dipyridamole, verapamil, bepridil and flunarizine. BRO/mdr1.1 s.c. well-established xenografts in nude mice were used to study the modulating properties of BIBW22BS 50 mg/kg i.v. followed after one h by vincristine 1 mg/kg i.p. or doxorubicin 8 mg/kg i.p. weekly x 2. RESULTS: BIBW22BS was 20- to 100-fold more potent than dipyridamole in the reversal of resistance in the Pgp-positive sublines. Reversal of resistance was obtained in a dose-dependent manner and was complete at concentrations of 0.5-2.5 microM. At non-toxic, equimolar concentrations of 1.0 microM BIBW22BS showed higher modulating potency than the calcium-channel blockers. BIBW22BS did not affect resistance in the non-Pgp sublines. BRO/mdr1.1 s.c. xenografts have stable multidrug-resistance characteristics upon serial transplantation. BIBW22BS, vincristine, or doxorubicin as single agents were not effective in vivo, while the addition of BIBW22BS could significantly reduce the tumor growth expressed as the T/C% of vincristine from 109% to 48% and that of doxorubicin from 55% to 32%. However, reversal of vincristine resistance in BRO/mdr1.1 xenografts was not complete when compared to the efficacy of vincristine in BRO xenografts. CONCLUSION: The results encourage the further preclinical development of BIBW22BS as a modulator of 'classical' multidrug resistance in cancer patients.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1987

Unusual electrocardiographic patterns of modulated parasystole.

Modulation of a parasystolic rhythm implies that the latter is affected by nonparasystolic beats in predictable ways. When modulation occurs the diagnosis of ventricular parasystole cannot be made by applying the well-known 'classical' criteria. This report deals with clinical tracings from three cases having modulated parasystole with unusual characteristics. Case 1 showed a 24-hour diurnal variability of parasystolic modulation characterized by its occurrence during only part of the period of sleep (from 1 to 5 am). In case 2, modulated ventricular parasystole produced episodes of intermittent ventricular bigeminy with fixed coupling resembling those attributed to a reentry mechanism. The proper diagnosis was made when the sinus cycle length changed abruptly. Finally, in case 3, the idionodal rhythm from a patient with complete AV block was shown to be not only parasystolic, but also modulated. In addition, the idionodal rhythm was entrained (captured) in a concealed fashion by paced beats so that the post-pacing events did not conform with those occurring during overdrive pacing of parasystolic nonmodulated, or nonparasystolic, idionodal rhythms. These findings constitute the clinical counterpart of experimental studies performed with microelectrode techniques.

Adult↗

PubMed2005

Large-scale modelling as a route to multiple surface comparisons of the CCP module family.

Numerous mammalian proteins are constructed from a limited repertoire of module-types. Proteins belonging to the regulators of complement activation family--crucial for ensuring a complement-mediated immune response is targeted against infectious agents--are composed solely of complement control protein (CCP) modules. In the current study, CCP module sequences were grouped to allow selection of the most appropriate experimentally determined structures to serve as templates in an automated large-scale structure modelling procedure. The resulting 135 individual CCP module models, valuable in their own right, are available at the online database http://www.bru.ed.ac.uk/~dinesh/ccp-db.html. Comparisons of surface properties within a particular family of modules should be more informative than sequence alignments alone. A comparison of surface electrostatic features was undertaken for the first 28 CCP modules of complement receptor type 1 (CR1). Assignments to clusters based on surface properties differ from assignments to clusters based on sequences. This observation might reflect adaptive evolution of surface-exposed residues involved in protein-protein interactions. This illustrative example of a multiple surface-comparison was indeed able to pinpoint functional sites in CR1.

Amino Acid Sequence↗

PubMed2000

Rapid and direct modulation of GABAA receptors by halothane.

BACKGROUND: Hypotheses regarding the nature of channel modulation by volatile anesthetics have focused primarily on "membrane actions" of anesthetics and more recently on direct actions of volatile agents on receptor proteins themselves. With the recognition that many channels are subject to modulation by intracellular enzymes, such as protein kinases and phosphatases, and recent demonstrations that the activity of these modulators themselves may be altered by anesthetic agents, a third possibility has been suggested:-anesthetic actions on channels may be indirect, produced, for example, via direct effects on intracellular enzyme systems. METHODS: To determine the contribution of indirect versus direct modulation, the authors compared effects of the volatile anesthetic halothane on gamma-aminobutyric acid A receptors under two conditions: in the whole cell configuration with intact intracellular regulatory systems, and in the excised patch configuration, in which intracellular signaling systems have been disrupted. They also evaluated the effects of rapid application and withdrawal of anesthetic to determine the time course of onset and offset of the anesthetic actions on these channels. RESULTS: Characteristic changes in gamma-aminobutyric acid A receptor function occurred in excised patches as in whole cells, did not require alteration of receptor phosphorylation, and were rapid (onset and offset of anesthetic action occurred within milliseconds). CONCLUSIONS: These results are not consistent with indirect modulation but rather indicate that volatile agents modulate gamma-aminobutyric acid A receptors by direct action on the channel complex or surrounding lipid membrane.

Adenosine Triphosphate↗

PubMed1996

Students' use of anatomy modules in problem-based medical education at McMaster University.

BACKGROUND: The McMaster University Faculty of Health Sciences has a collection of self-directed anatomy learning modules that are available to help medical students prepare for tutorial discussions of health care problems. How students use this resource has never been adequately surveyed. METHOD: The rates of, patterns of, and reasons for module use among the 200 students in their first and second years were surveyed by questionnaire in late 1992. Responses were analyzed with contingency tables. RESULTS: Questionnaires were completed by 80 students (52 in their first year and 28 in their second). Anatomy module use depended not only on the students' levels in the program (i.e., curriculum years), but also on their pre-medical backgrounds in biology. The students did not use modules because their tutors and clinical-skills preceptors required it. The students who worked through modules considered themselves better prepared for tutorials, where their learning was evaluated. CONCLUSION: Though use of this resource varied among individuals, most McMaster students believed that module use helped them to make useful contributions to tutorial discussions.

Adult↗

PubMed1999

Modulation of P-glycoprotein function in human lymphocytes and Caco-2 cell monolayers by HIV-1 protease inhibitors.

OBJECTIVES: To determine the effect of the protease inhibitors ritonavir, nelfinavir and indinavir on the P-glycoprotein (P-gp)-mediated transport of saquinavir in Caco-2 cell monolayers. To study the modulation of P-gp function in human lymphocytes by saquinavir, ritonavir, nelfinavir and indinavir. METHODS: We examined the effect of the protease inhibitors on P-gp function in human lymphocytes by using Rhodamine 123 (Rh 123; a fluorescent substrate of P-gp) by flow cytometry. Efflux of Rh 123 correlates with P-gp function and inhibition of P-gp results in dye retention. Verapamil, a P-gp modulator and inhibitor of active transport at 4 degrees C was used as a positive control. The transport of [14C]saquinavir (1 microM) across Caco-2 cell monolayers was investigated, alone and in the presence of verapamil and ketoconazole (500 microM) and the protease inhibitors at 100 microM. Caco-2 cells are an in vitro model of the intestinal epithelium that is widely used for the study of P-gp function. The transport of saquinavir was determined in both the apical to basolateral (AP-BL) and basolateral to apical (BL-AP) directions. RESULTS: Saquinavir and ritonavir (10 microM) markedly inhibited Rh 123 efflux with an increase in fluorescence intensity similar to that obtained with verapamil. A small but statistically significant increase in fluorescence intensity was observed with nelfinavir; however indinavir did not modulate Rh 123 efflux. In Caco-2 cells the apparent permeability coefficient for BL-AP efflux of saquinavir exceeded that for AP-BL efflux by a factor of 26: this is indicative of an active efflux pump. Known P-gp modulators caused a decrease in BL-AP efflux and an increase in AP-BL transport. The protease inhibitors displayed some P-gp modulation with ritonavir having the most potent effect. CONCLUSIONS: We have demonstrated that saquinavir is a substrate for P-gp and that ritonavir, nelfinavir and indinavir modulate P-gp function in both human lymphocytes and Caco-2 cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Recombinant human activated protein C: a system modulator of vascular function for treatment of severe sepsis.

OBJECTIVE: To review the mechanisms of action and rationale for the use of recombinant human activated protein C in the treatment of severe sepsis. Specifically, we focus on the mechanisms of action in the protein C pathway that converge to modulate the pathophysiology of severe inflammatory disease and sepsis. This analysis includes a discussion of the role of activated protein C in directly modulating cell system biology, independent of antithrombotic activity. DATA SOURCES/STUDY SELECTION: Published research and review articles relating to the protein C pathway, recombinant human protein C, and the role of protein C in sepsis. Data were also derived from broad gene profiling in model systems of endothelial dysfunction. DATA EXTRACTION AND SYNTHESIS: Relevant studies were included to support discussion of the unique mechanistic aspect of protein C and its role in the pathogenesis of severe sepsis. We discuss the potential of activated protein C as a unique system modulator for the treatment of severe sepsis and other systemic inflammatory responses that result in microvascular coagulopathy, endothelial dysfunction, and vascular bed failure. CONCLUSIONS: The protein C pathway plays a unique role in modulating vascular function. As an antithrombotic/profibrinolytic agent, it plays a clear role in maintaining vascular patency. Moreover, it has anti-inflammatory properties and appears to play a unique role as an antiapoptotic and endothelial cell survival factor. In states of systemic inflammatory activation, loss of protein C due to consumptive processes results in a compromised ability to modulate coagulation as well as inflammatory and cell survival functions. This compromise leads to vascular dysfunction, end-organ failure, and death. Replacement with recombinant human activated protein C offers a system-modulating approach to improved outcome.

Anti-Inflammatory Agents, Non-Steroidal↗