scholarly journals Analysis of Static Molecular Gradients in a High-Throughput Drug Screening Microfluidic Assay

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6385
Author(s):  
Roman G. Szafran ◽  
Benita Wiatrak
Keyword(s):  
High Throughput ◽  
Concentration Profile ◽  
Drug Screening ◽  
High Throughput Drug Screening ◽  
Analytical Protocol ◽  
The Mean ◽  
Gradient Generation ◽  
Mathematical Relationships ◽  
Mean Concentration ◽  
Active Substances

In this study, we thoroughly analyzed molecular gradient generation, its stability over time, and linearity in our high-throughput drug screening microfluidic assay (HTS). These parameters greatly affect the precision and accuracy of the device’s analytical protocol. As part of the research, we developed a mathematical model of dependence of the concentration profile on the initial concentrations of active substances in reservoirs and the number of tilts, as well as the dependence of the active substance concentration profiles in the culture chambers on the concentration profile of the reference dye in the indicator chamber. The mean concentration prediction error of the proposed equations ranged from 1.4% to 2.4% for the optimized parameters of the procedure and did not increase with the incubation time. The concentration profile linearity index, Pearson’s correlation coefficient reached −0.997 for 25 device tilts. The observed time stability of the profiles was very good. The mean difference between the concentration profile after 5 days of incubation and the baseline profile was only 7.0%. The newly created mathematical relationships became part of the new HTS biochip operating protocols, which are detailed in the article.

scholarly journals The Lattice-Boltzmann Modeling of Microflows in a Cell Culture Microdevice for High-Throughput Drug Screening

2021 ◽  
Vol 11 (19) ◽  
pp. 9140
Author(s):  
Roman G. Szafran ◽  
Mikita Davykoza
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Lattice Boltzmann ◽  
Plug Flow ◽  
Algebraic Solution ◽  
Duct Flow ◽  
Mean Velocity ◽  
Navier Stokes Equation ◽  
High Throughput Drug Screening ◽  
The Mean

The aim of our research was to develop a numerical model of microflows occurring in the culture chambers (CC) of a microfluidic device of our construction for high-throughput drug screening. The incompressible fluid flow model is based on the lattice-Boltzmann equation, with an external body force term approximated by the He-Shan-Doolen scheme and the Bhatnagar-Gross-Krook approximation of the collision operator. The model accuracy was validated by the algebraic solution of the Navier–Stokes equation (NSE) for a fully developed duct flow, as well as experimentally. The mean velocity prediction error for the middle-length cross-section of CC was 1.0%, comparing to the NSE algebraic solution. The mean error of volumetric flow rate prediction was 6.1%, comparing to the experimental results. The analysis of flow hydrodynamics showed that the discrepancies from the plug-flow-like velocity profile are observed close to the inlets only, and do not influence cell cultures in the working area of CC. Within its workspace area, the biochip provides stable and homogeneous fully developed laminar flow conditions, which make the procedures of gradient generation, cell seeding, and cell-staining repeatable and uniform across CC, and weakly dependent on perturbations.

High-Throughput Drug Screening of FDA-Approved Cancer Drugs Reveals Novel Therapies for Patients with Chordomas

2019 ◽  
Author(s):  
Philip Tatman ◽  
Anthony Fringuello ◽  
Denise Damek ◽  
Samy Youssef ◽  
Randy Jensn ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Novel Therapies ◽  
Cancer Drugs ◽  
High Throughput Drug Screening

High-Throughput Drug Screening of ECM Deposition Inhibitors for Antifibrotic Drug Discovery

2019 ◽  
Author(s):  
Michael Gerckens ◽  
Hani Alsafadi ◽  
Darcy Wagner ◽  
Katharina Heinzelmann ◽  
Kenji Schorpp ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Drug Screening ◽  
High Throughput Drug Screening

Therapeutic stratification of acute leukemia using high throughput drug screening

2020 ◽  
Author(s):  
S Bhatia ◽  
H Ahlert ◽  
N Dienstbier ◽  
J Schliehe-Diecks ◽  
M Sönnichsen ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
High Throughput ◽  
Drug Screening ◽  
High Throughput Drug Screening

scholarly journals High-throughput drug screening identifies the ATR-CHK1 pathway as a therapeutic vulnerability of CALR mutated hematopoietic cells

2021 ◽  
Vol 11 (7) ◽  
Author(s):  
Ruochen Jia ◽  
Leon Kutzner ◽  
Anna Koren ◽  
Kathrin Runggatscher ◽  
Peter Májek ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Synthetic Lethality ◽  
Myeloproliferative Neoplasms ◽  
Hematopoietic Cells ◽  
Replication Stress ◽  
Phase Cell ◽  
Nuclear Staining ◽  
Wild Type ◽  
High Throughput Drug Screening

AbstractMutations of calreticulin (CALR) are the second most prevalent driver mutations in essential thrombocythemia and primary myelofibrosis. To identify potential targeted therapies for CALR mutated myeloproliferative neoplasms, we searched for small molecules that selectively inhibit the growth of CALR mutated cells using high-throughput drug screening. We investigated 89 172 compounds using isogenic cell lines carrying CALR mutations and identified synthetic lethality with compounds targeting the ATR-CHK1 pathway. The selective inhibitory effect of these compounds was validated in a co-culture assay of CALR mutated and wild-type cells. Of the tested compounds, CHK1 inhibitors potently depleted CALR mutated cells, allowing wild-type cell dominance in the co-culture over time. Neither CALR deficient cells nor JAK2V617F mutated cells showed hypersensitivity to ATR-CHK1 inhibition, thus suggesting specificity for the oncogenic activation by the mutant CALR. CHK1 inhibitors induced replication stress in CALR mutated cells revealed by elevated pan-nuclear staining for γH2AX and hyperphosphorylation of RPA2. This was accompanied by S-phase cell cycle arrest due to incomplete DNA replication. Transcriptomic and phosphoproteomic analyses revealed a replication stress signature caused by oncogenic CALR, suggesting an intrinsic vulnerability to CHK1 perturbation. This study reveals the ATR-CHK1 pathway as a potential therapeutic target in CALR mutated hematopoietic cells.

scholarly journals Genotype-Selective Combination Therapies for Melanoma Identified by High-Throughput Drug Screening

2012 ◽  
Vol 3 (1) ◽  
pp. 52-67 ◽  
Author(s):  
Matthew A. Held ◽  
Casey G. Langdon ◽  
James T. Platt ◽  
Tisheeka Graham-Steed ◽  
Zongzhi Liu ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Combination Therapies ◽  
High Throughput Drug Screening

scholarly journals MEASUREMENT OF SEDIMENT SUSPENSION IN COMBINATIONS OF WAVES AND CURRENTS

1972 ◽  
Vol 1 (13) ◽  
pp. 55
Author(s):  
J. Kirkegarrd Jensen ◽  
Torben Sorenson
Keyword(s):  
Thin Layer ◽  
Concentration Profile ◽  
Field Data ◽  
Concentration Profiles ◽  
Sediment Suspension ◽  
Calculated Concentration ◽  
Waves And Currents ◽  
The Mean ◽  
Mean Concentration ◽  
Good Agreement

The paper describes a procedure for obtaining field data on the mean concentration of sediments in combination of waves and currents outside the breaker zone, as well as some results of such measurements. It is assumed that the current turbulence alone is responsible for the maintenance of the concentration profile above a thin layer close to the bottom, in which pick-up of sediments due to wave agitation takes place. This assumption gives a good agreement between field data and calculated concentration profiles.

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