Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 20
Filter
Add more filters










Publication year range
1.
Am J Hematol ; 2024 Jun 10.
Article in English | MEDLINE | ID: mdl-38856176

ABSTRACT

Novel therapies have improved outcomes for multiple myeloma (MM) patients, but most ultimately relapse, making treatment decisions for relapsed/refractory MM (RRMM) patients increasingly challenging. We report the final analysis of a single-arm, phase 2 study evaluating the oral proteasome inhibitor (PI) ixazomib combined with daratumumab and dexamethasone (IDd; NCT03439293). Sixty-one RRMM patients (ixazomib/daratumumab-naïve; 1-3 prior therapies) were enrolled to receive IDd (28-day cycles) until disease progression/unacceptable toxicity. Median age was 69 years; 14.8% of patients had International Staging System stage III disease; 14.8% had received three prior therapies. Patients received a median of 16 cycles of IDd. In 59 response-evaluable patients, the overall response rate was 64.4%; the confirmed ≥very good partial response (VGPR) rate (primary endpoint) was 30.5%. Rates of ≥VGPR in patient subgroups were: high-risk cytogenetics (n = 15, 26.7%), expanded high-risk cytogenetics (n = 24, 29.2%), aged ≥75 years (n = 12, 16.7%), lenalidomide-refractory (n = 21, 28.6%), and prior PI/IMiD therapy (n = 58, 31.0%). With a median follow-up of 31.6 months, median progression-free survival was 16.8 months (95% confidence interval: 10.1-23.7). Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 54.1% of patients; 44.3% had serious TEAEs; TEAEs led to dose modifications/reductions/discontinuations in 62.3%/36.1%/16.4%. There were five on-study deaths. Any-grade and grade ≥3 peripheral neuropathy occurred in 18.0% and 1.6% of patients. Quality of life was generally maintained throughout treatment. IDd showed a positive risk-benefit profile in RRMM patients and was active in clinically relevant subgroups with no new safety signals.

2.
Clin Pharmacol Ther ; 114(1): 220-229, 2023 07.
Article in English | MEDLINE | ID: mdl-37186295

ABSTRACT

Ixazomib has been approved in several countries as single-agent maintenance therapy in newly diagnosed multiple myeloma, in both posttransplant and transplant-ineligible settings, based on two phase III studies. In these maintenance studies, patients were initially administered 3 mg ixazomib, escalating to 4 mg if the initial dose level was well tolerated through Cycles 1-4. Here, we report the results of exposure-response analyses of TOURMALINE-MM4, wherein relationships between exposure and clinical response, dose adjustments, and selected adverse events were evaluated. Similar progression-free survival benefits were observed across the range of ixazomib exposures achieved in the study. Moreover, increased ixazomib exposures corresponded to a higher probability of maintaining complete response. Exposure was not a significant predictor (P > 0.05) of hematological adverse events (anemia, neutropenia, thrombocytopenia) and peripheral neuropathy; however, higher exposures did correlate to increased probabilities of experiencing diarrhea, vomiting, nausea, rash, and fatigue. While ixazomib exposure was not predictive of dose reductions, lower apparent clearance values (corresponding to higher systemic exposures) were correlated with a reduced likelihood of escalating to the 4 mg dose. Thus, the dose titration approach balanced patient benefit and risk; it ensured that only patients for whom the 3 mg dose was safe/tolerable escalated to the higher dose, while maximizing the fraction of patients (85%) who were able to derive additional clinical benefit at 4 mg. Collectively, these results highlight the value of safety-driven personalized dosing to maximize patient benefit/risk.


Subject(s)
Multiple Myeloma , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Boron Compounds/adverse effects , Dexamethasone , Multiple Myeloma/diagnosis , Multiple Myeloma/drug therapy , Silicates/therapeutic use
3.
Gene Ther ; 30(7-8): 581-586, 2023 08.
Article in English | MEDLINE | ID: mdl-35132205

ABSTRACT

Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) is an adeno-associated virus serotype five gene therapy under investigation for the treatment of hemophilia A. Herein, we assessed the potential for germline transmission of AAV5-hFVIII-SQ in mice. Male B6.129S6-Rag2tm1Fwa N12 mice received a single intravenous dose of vehicle or 6 × 1013 vg/kg AAV5-hFVIII-SQ. Vehicle and AAV5-hFVIII-SQ-treated mice were mated with naïve females 4 days after dosing, when the concentration of vector genomes was expected to be at its peak in semen, and 37 days after dosing, when a full spermatogenesis cycle was estimated to be complete. Quantitative PCR was used to evaluate the presence of transgene DNA in liver and testes from F0 males dosed with AAV5-hFVIII-SQ and liver tissue of F1 offspring. Transgene DNA was detected in liver and testes of all F0 males dosed with AAV5-hFVIII-SQ, confirming successful transduction. Importantly, no transgene DNA was detected in any tested F1 offspring derived from F0 males dosed with AAV5-hFVIII-SQ. Using a novel 2-stage statistical model that takes into account the number of males dosed with AAV5-hFVIII-SQ and the number of offspring sired by these males, we estimate that the risk of germline transmission is <5% with a 99.2% confidence level.


Subject(s)
Factor VIII , Genetic Vectors , Male , Animals , Mice , Factor VIII/genetics , Genetic Vectors/genetics , Genetic Therapy , Administration, Intravenous , Dependovirus/genetics
4.
Mol Ther Methods Clin Dev ; 26: 519-531, 2022 Sep 08.
Article in English | MEDLINE | ID: mdl-36092364

ABSTRACT

Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) gene transfer provided reduced bleeding for adult clinical trial participants with severe hemophilia A. However, pediatric outcomes are unknown. Using a mouse model of hemophilia A, we investigated the effect of vector dose and age at treatment on transgene production and persistence. We dosed AAV5-hFVIII-SQ to neonatal and adult mice based on body weight or at a fixed dose and assessed human factor VIII-SQ variant (hFVIII-SQ) expression through 16 weeks. AAV5-hFVIII-SQ dosed per body weight in neonatal mice did not result in meaningful plasma hFVIII-SQ protein levels in adulthood. When treated with the same total vector genomes per mouse as adult mice, neonates maintained hFVIII-SQ expression into adulthood, although plasma levels were 3- to 4-fold lower versus mice dosed as adults. Mice <1 week old initially exhibited high hFVIII-SQ plasma levels and maintained meaningful levels into adulthood, despite a partial decline potentially due to age-related body mass and blood volume increases. Spatial transduction patterns differed between mice dosed as neonates versus adults. No features of hepatotoxicity or endoplasmic reticulum stress were observed with dosing at any age. These data suggest that young mice require the same total vector genomes as adult mice to sustain hFVIII-SQ plasma levels.

5.
CPT Pharmacometrics Syst Pharmacol ; 11(8): 1085-1099, 2022 08.
Article in English | MEDLINE | ID: mdl-35598166

ABSTRACT

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE-MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time-to-event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M-protein] and progression-free survival [PFS]) outcomes observed in TOURMALINE-MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M-protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M-protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens.


Subject(s)
Boron Compounds , Glycine , Multiple Myeloma , Boron Compounds/adverse effects , Clinical Trials, Phase III as Topic , Diarrhea , Exanthema , Glycine/adverse effects , Glycine/analogs & derivatives , Humans , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Prospective Studies , Silicates
6.
Blood ; 136(22): 2524-2534, 2020 11 26.
Article in English | MEDLINE | ID: mdl-32915950

ABSTRACT

Adeno-associated virus (AAV)-based gene therapies can restore endogenous factor VIII (FVIII) expression in hemophilia A (HA). AAV vectors typically use a B-domain-deleted FVIII transgene, such as human FVIII-SQ in valoctocogene roxaparvovec (AAV5-FVIII-SQ). Surprisingly, the activity of transgene-produced FVIII-SQ was between 1.3 and 2.0 times higher in one-stage clot (OS) assays than in chromogenic-substrate (CS) assays, whereas recombinant FVIII-SQ products had lower OS than CS activity. Transgene-produced and recombinant FVIII-SQ showed comparable specific activity (international units per milligram) in the CS assay, demonstrating that the diverging activities arise in the OS assay. Higher OS activity for transgene-produced FVIII-SQ was observed across various assay kits and clinical laboratories, suggesting that intrinsic molecular features are potential root causes. Further experiments in 2 participants showed that transgene-produced FVIII-SQ accelerated early factor Xa and thrombin formation, which may explain the higher OS activity based on a kinetic bias between OS and CS assay readout times. Despite the faster onset of coagulation, global thrombin levels were unaffected. A correlation with joint bleeds suggested that both OS and CS assay remained clinically meaningful to distinguish hemophilic from nonhemophilic FVIII activity levels. During clinical development, the CS activity was chosen as a surrogate end point to conservatively assess hemostatic efficacy and enable comparison with recombinant FVIII-SQ products. Relevant trials are registered on clinicaltrials.gov as #NCT02576795 and #NCT03370913 and, respectively, on EudraCT (European Union Drug Regulating Authorities Clinical Trials Database; https://eudract.ema.europa.eu) as #2014-003880-38 and #2017-003215-19.


Subject(s)
Factor VIII , Genetic Therapy , Hemophilia A , Parvovirinae , Transgenes , Dependovirus , Factor VIII/genetics , Factor VIII/metabolism , Hemophilia A/blood , Hemophilia A/genetics , Hemophilia A/therapy , Humans , Male
7.
Nat Commun ; 9(1): 4766, 2018 11 13.
Article in English | MEDLINE | ID: mdl-30425246

ABSTRACT

This Article contains errors in Supplementary Table 3, which are described in the Author Correction associated with this Article. The simulation results in the Article were based on the correct formula and thus the results are not affected by this correction. The errors have not been fixed in the original Article.

8.
Nat Commun ; 8(1): 1689, 2017 11 22.
Article in English | MEDLINE | ID: mdl-29162798

ABSTRACT

In the absence of antibiotic-mediated selection, sensitive bacteria are expected to displace their resistant counterparts if resistance genes are costly. However, many resistance genes persist for long periods in the absence of antibiotics. Horizontal gene transfer (primarily conjugation) could explain this persistence, but it has been suggested that very high conjugation rates would be required. Here, we show that common conjugal plasmids, even when costly, are indeed transferred at sufficiently high rates to be maintained in the absence of antibiotics in Escherichia coli. The notion is applicable to nine plasmids from six major incompatibility groups and mixed populations carrying multiple plasmids. These results suggest that reducing antibiotic use alone is likely insufficient for reversing resistance. Therefore, combining conjugation inhibition and promoting plasmid loss would be an effective strategy to limit conjugation-assisted persistence of antibiotic resistance.


Subject(s)
Drug Resistance, Bacterial/genetics , Plasmids/genetics , Conjugation, Genetic , Escherichia coli/drug effects , Escherichia coli/genetics , Genetic Engineering , Genetic Techniques , Microbial Consortia/drug effects , Microbial Consortia/genetics , Models, Genetic , Synthetic Biology
9.
Mol Syst Biol ; 13(10): 948, 2017 10 23.
Article in English | MEDLINE | ID: mdl-29061668

ABSTRACT

The postantibiotic effect (PAE) refers to the temporary suppression of bacterial growth following transient antibiotic treatment. This effect has been observed for decades for a wide variety of antibiotics and microbial species. However, despite empirical observations, a mechanistic understanding of this phenomenon is lacking. Using a combination of modeling and quantitative experiments, we show that the PAE can be explained by the temporal dynamics of drug detoxification in individual cells after an antibiotic is removed from the extracellular environment. These dynamics are dictated by both the export of the antibiotic and the intracellular titration of the antibiotic by its target. This mechanism is generally applicable for antibiotics with different modes of action. We further show that efflux inhibition is effective against certain antibiotic motifs, which may help explain mixed cotreatment success.


Subject(s)
Anti-Bacterial Agents/pharmacokinetics , Escherichia coli/growth & development , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Escherichia coli/metabolism , Escherichia coli Proteins/metabolism , Inactivation, Metabolic , Microfluidic Analytical Techniques , Models, Theoretical
10.
Nat Microbiol ; 1(6): 16044, 2016 04 11.
Article in English | MEDLINE | ID: mdl-27572835

ABSTRACT

It is generally assumed that antibiotics can promote horizontal gene transfer. However, because of a variety of confounding factors that complicate the interpretation of previous studies, the mechanisms by which antibiotics modulate horizontal gene transfer remain poorly understood. In particular, it is unclear whether antibiotics directly regulate the efficiency of horizontal gene transfer, serve as a selection force to modulate population dynamics after such gene transfer has occurred, or both. Here, we address this question by quantifying conjugation dynamics in the presence and absence of antibiotic-mediated selection. Surprisingly, we find that sublethal concentrations of antibiotics from the most widely used classes do not significantly increase the conjugation efficiency. Instead, our modelling and experimental results demonstrate that conjugation dynamics are dictated by antibiotic-mediated selection, which can both promote and suppress conjugation dynamics. Our findings suggest that the contribution of antibiotics to the promotion of horizontal gene transfer may have been overestimated. These findings have implications for designing effective antibiotic treatment protocols and for assessing the risks of antibiotic use.


Subject(s)
Anti-Bacterial Agents/pharmacology , Conjugation, Genetic/drug effects , Escherichia coli/drug effects , Escherichia coli/genetics , Selection, Genetic , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial/drug effects , Humans , Microbial Sensitivity Tests , Microfluidic Analytical Techniques , Models, Biological , Molecular Dynamics Simulation , Plasmids/drug effects
11.
Biomaterials ; 61: 239-45, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26005763

ABSTRACT

Culturing and measuring bacterial population dynamics are critical to develop insights into gene regulation or bacterial physiology. Traditional methods, based on bulk culture to obtain such quantification, have the limitations of higher cost/volume of reagents, non-amendable to small size of population and more laborious manipulation. To this end, droplet-based microfluidics represents a promising alternative that is cost-effective and high-throughput. However, difficulties in manipulating the droplet environment and monitoring encapsulated bacterial population for long-term experiments limit its utilization. To overcome these limitations, we used an electrode-free injection technology to modulate the chemical environment in droplets. This ability is critical for precise control of bacterial dynamics in droplets. Moreover, we developed a trapping device for long-term monitoring of population dynamics in individual droplets for at least 240 h. We demonstrated the utility of this new microfluidic system by quantifying population dynamics of natural and engineered bacteria. Our approach can further improve the analysis for systems and synthetic biology in terms of manipulability and high temporal resolution.


Subject(s)
Bacteria/cytology , Bacteria/isolation & purification , Batch Cell Culture Techniques/instrumentation , Cell Separation/instrumentation , Flow Injection Analysis/instrumentation , Lab-On-A-Chip Devices , Bioreactors/microbiology , Equipment Design , Equipment Failure Analysis , Micromanipulation/instrumentation
12.
Nat Chem Biol ; 11(3): 182-8, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25689336

ABSTRACT

Bacteria have developed resistance against every antibiotic at a rate that is alarming considering the timescale at which new antibiotics are developed. Thus, there is a critical need to use antibiotics more effectively, extend the shelf life of existing antibiotics and minimize their side effects. This requires understanding the mechanisms underlying bacterial drug responses. Past studies have focused on survival in the presence of antibiotics by individual cells, as genetic mutants or persisters. Also important, however, is the fact that a population of bacterial cells can collectively survive antibiotic treatments lethal to individual cells. This tolerance can arise by diverse mechanisms, including resistance-conferring enzyme production, titration-mediated bistable growth inhibition, swarming and interpopulation interactions. These strategies can enable rapid population recovery after antibiotic treatment and provide a time window during which otherwise susceptible bacteria can acquire inheritable genetic resistance. Here, we emphasize the potential for targeting collective antibiotic tolerance behaviors as an antibacterial treatment strategy.


Subject(s)
Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/physiology , Animals , Anti-Bacterial Agents/therapeutic use , Bacteria/drug effects , Bacterial Infections/drug therapy , Bacterial Infections/microbiology , Drug Resistance, Bacterial/drug effects , Humans
13.
Chem Biol ; 21(12): 1601-2, 2014 Dec 18.
Article in English | MEDLINE | ID: mdl-25525988

ABSTRACT

Numerous bacterial species utilize quorum sensing to communicate, but crosstalk often complicates the dynamics of mixed populations. In this issue of Chemistry & Biology, Wu and colleagues take advantage of synthetic gene circuits to elucidate interactions between two quorum sensing systems, with potential applications to fields from infectious diseases to biosynthesis.


Subject(s)
Models, Biological , Quorum Sensing , Synthetic Biology
14.
Nat Commun ; 5: 4750, 2014 Sep 01.
Article in English | MEDLINE | ID: mdl-25175461

ABSTRACT

A body of evidence has shown that the control of E2F transcription factor activity is critical for determining cell cycle entry and cell proliferation. However, an understanding of the precise determinants of this control, including the role of other cell-cycle regulatory activities, has not been clearly defined. Here, recognizing that the contributions of individual regulatory components could be masked by heterogeneity in populations of cells, we model the potential roles of individual components together with the use of an integrated system to follow E2F dynamics at the single-cell level and in real time. These analyses reveal that crossing a threshold amplitude of E2F accumulation determines cell cycle commitment. Importantly, we find that Myc is critical in modulating the amplitude, whereas cyclin D/E activities have little effect on amplitude but do contribute to the modulation of duration of E2F activation, thereby affecting the pace of cell cycle progression.


Subject(s)
Cell Cycle/genetics , Cyclin D/genetics , Cyclin E/genetics , E2F1 Transcription Factor/genetics , Proto-Oncogene Proteins c-myc/genetics , Animals , Bacterial Proteins/genetics , Bacterial Proteins/metabolism , Cell Cycle/drug effects , Cell Line , Cyclin D/metabolism , Cyclin E/metabolism , E2F1 Transcription Factor/metabolism , Fibroblasts/cytology , Fibroblasts/drug effects , Fibroblasts/metabolism , Gene Expression Regulation , Genes, Reporter , Humans , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Mice , NIH 3T3 Cells , Piperazines/pharmacology , Promoter Regions, Genetic , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-myc/metabolism , Purines/pharmacology , Pyridines/pharmacology , Rats , Signal Transduction , Single-Cell Analysis , Time-Lapse Imaging
15.
PLoS One ; 9(8): e105408, 2014.
Article in English | MEDLINE | ID: mdl-25141235

ABSTRACT

Many cellular decision processes, including proliferation, differentiation, and phenotypic switching, are controlled by bistable signaling networks. In response to transient or intermediate input signals, these networks allocate a population fraction to each of two distinct states (e.g. OFF and ON). While extensive studies have been carried out to analyze various bistable networks, they are primarily focused on responses of bistable networks to sustained input signals. In this work, we investigate the response characteristics of bistable networks to transient signals, using both theoretical analysis and numerical simulation. We find that bistable systems exhibit a common property: for input signals with short durations, the fraction of switching cells increases linearly with the signal duration, allowing the population to integrate transient signals to tune its response. We propose that this allocation algorithm can be an optimal response strategy for certain cellular decisions in which excessive switching results in lower population fitness.


Subject(s)
Bacteria/metabolism , Models, Biological , Phenotype , Signal Transduction , Bacteria/genetics , Bacterial Physiological Phenomena
16.
Proc Natl Acad Sci U S A ; 111(5): 1969-74, 2014 Feb 04.
Article in English | MEDLINE | ID: mdl-24449896

ABSTRACT

Dispersal is necessary for spread into new habitats, but it has also been shown to inhibit spread. Theoretical studies have suggested that the presence of a strong Allee effect may account for these counterintuitive observations. Experimental demonstration of this notion is lacking due to the difficulty in quantitative analysis of such phenomena in a natural setting. We engineered Escherichia coli to exhibit a strong Allee effect and examined how the Allee effect would affect the spread of the engineered bacteria. We showed that the Allee effect led to a biphasic dependence of bacterial spread on the dispersal rate: spread is promoted for intermediate dispersal rates but inhibited at low or high dispersal rates. The shape of this dependence is contingent upon the initial density of the source population. Moreover, the Allee effect led to a tradeoff between effectiveness of population spread and survival: increasing the number of target patches during dispersal allows more effective spread, but it simultaneously increases the risk of failing to invade or of going extinct. We also observed that total population growth is transiently maximized at an intermediate number of target patches. Finally, we demonstrate that fluctuations in cell growth may contribute to the paradoxical relationship between dispersal and spread. Our results provide direct experimental evidence that the Allee effect can explain the apparently paradoxical effects of dispersal on spread and have implications for guiding the spread of cooperative organisms.


Subject(s)
Escherichia coli/growth & development , Genetic Engineering , Microbial Viability , Models, Biological , Movement
17.
ACS Synth Biol ; 3(4): 220-7, 2014 Apr 18.
Article in English | MEDLINE | ID: mdl-24011134

ABSTRACT

Quorum sensing (QS) enables bacteria to sense and respond to changes in their population density. It plays a critical role in controlling different biological functions, including bioluminescence and bacterial virulence. It has also been widely adapted to program robust dynamics in one or multiple cellular populations. While QS systems across bacteria all appear to function similarly-as density-dependent control systems-there is tremendous diversity among these systems in terms of signaling components and network architectures. This diversity hampers efforts to quantify the general control properties of QS. For a specific QS module, it remains unclear how to most effectively characterize its regulatory properties in a manner that allows quantitative predictions of the activation dynamics of the target gene. Using simple kinetic models, here we show that the dominant temporal dynamics of QS-controlled target activation can be captured by a generic metric, 'sensing potential', defined at a single time point. We validate these predictions using synthetic QS circuits in Escherichia coli. Our work provides a computational framework and experimental methodology to characterize diverse natural QS systems and provides a concise yet quantitative criterion for selecting or optimizing a QS system for synthetic biology applications.


Subject(s)
Models, Biological , Quorum Sensing/physiology , Escherichia coli/physiology , Signal Transduction , Synthetic Biology
18.
Mol Syst Biol ; 8: 617, 2012.
Article in English | MEDLINE | ID: mdl-23047527

ABSTRACT

The inoculum effect (IE) refers to the decreasing efficacy of an antibiotic with increasing bacterial density. It represents a unique strategy of antibiotic tolerance and it can complicate design of effective antibiotic treatment of bacterial infections. To gain insight into this phenomenon, we have analyzed responses of a lab strain of Escherichia coli to antibiotics that target the ribosome. We show that the IE can be explained by bistable inhibition of bacterial growth. A critical requirement for this bistability is sufficiently fast degradation of ribosomes, which can result from antibiotic-induced heat-shock response. Furthermore, antibiotics that elicit the IE can lead to 'band-pass' response of bacterial growth to periodic antibiotic treatment: the treatment efficacy drastically diminishes at intermediate frequencies of treatment. Our proposed mechanism for the IE may be generally applicable to other bacterial species treated with antibiotics targeting the ribosomes.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Bacteria/growth & development , Chloramphenicol/pharmacology , Colony Count, Microbial , Escherichia coli/drug effects , Escherichia coli/growth & development , Heat-Shock Response/drug effects , Kanamycin/pharmacology , Kinetics , Microbial Sensitivity Tests , Models, Biological , Proteolysis/drug effects , Ribosomes/drug effects , Ribosomes/metabolism , Salmonella typhimurium/drug effects , Salmonella typhimurium/growth & development
19.
Article in English | MEDLINE | ID: mdl-21096365

ABSTRACT

Drug bioavailability is a major failing point of new pharmaceuticals i.e. drugs fail to reach their target or fail to stay there long enough for therapeutic effect. Compounding this issue, significant variability exists between patients and how they metabolize and distribute a drug. We present WebPK, a web-based tool for simulation of custom pharmacokinetic models. Model parameters can be entered manually or uploaded as a file. Simulation computations are performed on the server side, and thus require minimal client resources, which makes WebPK suitable for mobile devices. Time series biodistribution data are returned to the user in graphical and numerical form for quick interpretation or archiving. Results generated from WebPK are consistent with previously published pharmacokinetic models. This work is expected to provide physicians with access to easy simulation of patient pharmacokinetic profiles, which will allow for the prescription of more efficient and personalized drug regimens. URL: http://webpk.bme.gatech.edu.


Subject(s)
Computer Simulation , Drug Design , Models, Biological , Pharmacokinetics , Software , Animals , Computer Graphics , Humans , Internet , Software Design , User-Computer Interface , Workflow
20.
Article in English | MEDLINE | ID: mdl-27536739

ABSTRACT

We developed a scalable distributed computing system using the Berkeley Open Interface for Network Computing (BOINC) to align next-generation sequencing (NGS) data quickly and accurately. NGS technology is emerging as a promising platform for gene expression analysis due to its high sensitivity compared to traditional genomic microarray technology. However, despite the benefits, NGS datasets can be prohibitively large, requiring significant computing resources to obtain sequence alignment results. Moreover, as the data and alignment algorithms become more prevalent, it will become necessary to examine the effect of the multitude of alignment parameters on various NGS systems. We validate the distributed software system by (1) computing simple timing results to show the speed-up gained by using multiple computers, (2) optimizing alignment parameters using simulated NGS data, and (3) computing NGS expression levels for a single biological sample using optimal parameters and comparing these expression levels to that of a microarray sample. Results indicate that the distributed alignment system achieves approximately a linear speed-up and correctly distributes sequence data to and gathers alignment results from multiple compute clients.

SELECTION OF CITATIONS
SEARCH DETAIL
...