scholarly journals Dr. Sim: Similarity Learning for Transcriptional Phenotypic Drug discovery

2021 ◽  
Author(s):  
Zhiting Wei ◽  
Sheng Zhu ◽  
Xiaohan Chen ◽  
Chenyu Zhu ◽  
Bin Duan ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Great Success ◽  
Similarity Learning ◽  
Integrated Network ◽  
High Throughput Data ◽  
Drug Mechanism ◽  
Perturbation Data

Transcriptional phenotypic drug discovery has achieved great success, and various compound perturbation-based data resources, such as Connectivity Map (CMap) and Library of Integrated Network-Based Cellular Signatures (LINCS), have been presented. Computational strategies fully mining these resources for phenotypic drug discovery have been proposed, and among them, a fundamental issue is to define the proper similarity between the transcriptional profiles to elucidate the drug mechanism of actions and identify new drug indications. Traditionally, this similarity has been defined in an unsupervised way, and due to the high dimensionality and the existence of high noise in those high-throughput data, it lacks robustness with limited performance. In our study, we present Dr. Sim, which is a general learning-based framework that automatically infers similarity measurement rather than being manually designed and can be used to characterize transcriptional phenotypic profiles for drug discovery with generalized good performance. We evaluated Dr. Sim on comprehensively publicly available in vitro and in vivo datasets in drug annotation and repositioning using high-throughput transcriptional perturbation data and indicated that Dr. Sim significantly outperforms the existing methods and is proved to be a conceptual improvement by learning transcriptional similarity to facilitate the broad utility of high-throughput transcriptional perturbation data for phenotypic drug discovery. The source code and usage of Dr. Sim is available at https://github.com/bm2-lab/DrSim/.

scholarly journals Recent Advances in In-Vitro Assays for Type 2 Diabetes Mellitus: An Overview

2020 ◽  
Vol 16 (1) ◽  
pp. 13-23
Author(s):  
Nazmina Vhora ◽  
Ujjal Naskar ◽  
Aishwarya Hiray ◽  
Abhijeet S. Kate ◽  
Alok Jain
Keyword(s):  
Type 2 Diabetes ◽  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Antidiabetic Activity ◽  
Screening Methods ◽  
Selection Of

BACKGROUND: A higher rate of attenuation of molecules in drug discovery has enabled pharmaceutical companies to enhance the efficiency of their hit identification and lead optimization. Selection and development of appropriate in-vitro and in-vivo strategies may improve this process as primary and secondary screening utilize both strategies. In-vivo approaches are too relentless and expensive for assessing hits. Therefore, it has become indispensable to develop and implement suitable in-vitro screening methods to execute the required activities and meet the respective targets. However, the selection of an appropriate in-vitro assay for specific evaluation of cellular activity is no trivial task. It requires thorough investigation of the various parameters involved. AIM: In this review, we aim to discuss in-vitro assays for type 2 diabetes (T2D), which have been utilized extensively by researchers over the last five years, including target-based, non-target based, low-throughput, and high-throughput screening assays. METHODS: The literature search was conducted using databases including Scifinder, PubMed, ScienceDirect, and Google Scholar to find the significant published articles. DISCUSSION and CONCLUSION: The accuracy and relevance of in-vitro assays have a significant impact on the drug discovery process for T2D, especially in assessing the antidiabetic activity of compounds and identifying the site of effect in high-throughput screening. The report reviews the advantages, limitations, quality parameters, and applications of the probed invitro assays, and compares them with one another to enable the selection of the optimal method for any purpose. The information on these assays will accelerate numerous procedures in the drug development process with consistent quality and accuracy.

scholarly journals High Throughput Screening of Pharmacokinetics and Metabolism in Drug Discovery (II) —Investigation on In vitro and In vivo Correlation in Drug Metabolism Screening—

2005 ◽  
Vol 125 (1) ◽  
pp. 131-139 ◽  
Author(s):  
Hiroshi KOMURA ◽  
Kenichi MATSUDA ◽  
Yukie SHIGEMOTO ◽  
Iichiro KAWAHARA ◽  
Rieko ANO ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Drug Metabolism ◽  
High Throughput ◽  
High Throughput Screening

scholarly journals A cross-species drug discovery pipeline to identify and validate new treatments for osteosarcoma

2020 ◽  
Author(s):  
Jason A. Somarelli ◽  
Gabrielle Rupprecht ◽  
Erdem Altunel ◽  
Etienne M. Flamant ◽  
Sneha Rao ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
Nuclear Export ◽  
Complex Disease ◽  
Rare Cancers ◽  
Synergistic Cytotoxicity ◽  
New Treatments ◽  
Discovery Pipeline

AbstractPurposeOsteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease.Experimental designTo overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline.ResultsCoupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity.ConclusionsThese collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.

scholarly journals 1341. Development of a Series of High-Throughput Screens to Identify Leads for Nontuberculous Mycobacteria Drug Design

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S485-S485
Author(s):  
Sarah McGuffin ◽  
Steven Mullen ◽  
Julie Early ◽  
Tanya Parish
Keyword(s):  
Drug Discovery ◽  
Drug Development ◽  
High Throughput ◽  
Nontuberculous Mycobacteria ◽  
Human Infection ◽  
Attrition Rate ◽  
In Vitro Assays ◽  
Vitro Assay

Abstract Background Nontuberculous mycobacteria (NTM), particularly Mycobacterium avium complex and Mycobacterium abscessus complex, cause significant morbidity and mortality in patients with impaired host immunity or pre-existing structural lung conditions. NTM infections are increasing at an alarming rate worldwide and there is a dearth of progress in regard to the development of efficacious and tolerable drugs to treat such infections. Traditional drug discovery screens do not account for the diverse physiological conditions, microenvironments, and compartments that the bacilli encounter during human infection. In order to help populate the NTM drug pipeline, and explore the disconnect between in vitro activity, in vivo activity, and clinical outcomes, we are developing a high throughput in vitro assay platform that will more closely model the unique infection-relevant conditions encountered by NTM. Methods We are developing and validating a suite of in vitro assays that screen compounds for activity against extracellular planktonic bacteria, extracellular bacteria within biofilms, intracellular bacteria, and nutrient-starved non-replicating bacteria. Results We are using both the smooth and rough morphotypes of M. abscessus and M. avium. We have validated high throughput assays to pharmaceutical standards for replicating and non-replicating M. abscessus. We have also tested a panel of 18 known anti-mycobacterial compounds. Assay development is currently underway to test compounds for activity against NTM in biofilm and inside macrophages as well. Conclusion To enhance hit identification for scaffolds to use as starting points for NTM drug development, focused libraries of compounds that have undergone significant preclinical profiling and/or compounds with known activity against M. tuberculosis (TB) will be screened. Such a “piggyback” approach usurps advances made in TB drug development and leverages them for NTM drug discovery. This will help expedite novel drug development, reduce attrition rate, and offer a shorter route to clinical use as it exploits the prior investment in medicinal chemistry, pharmacology, and toxicology. Disclosures All authors: No reported disclosures.

Surface Modification by Nanobiomaterials for Vascular Tissue Engineering Applications

2020 ◽  
Vol 27 (10) ◽  
pp. 1634-1646 ◽  
Author(s):  
Huey-Shan Hung ◽  
Shan-hui Hsu
Keyword(s):  
Tissue Engineering ◽  
Vascular Tissue ◽  
Thrombus Formation ◽  
Vascular Grafts ◽  
Vascular Tissue Engineering ◽  
Great Success ◽  
Natural Polymers ◽  
Vascular Biomaterials

Treatment of cardiovascular disease has achieved great success using artificial implants, particularly synthetic-polymer made grafts. However, thrombus formation and restenosis are the current clinical problems need to be conquered. New biomaterials, modifying the surface of synthetic vascular grafts, have been created to improve long-term patency for the better hemocompatibility. The vascular biomaterials can be fabricated from synthetic or natural polymers for vascular tissue engineering. Stem cells can be seeded by different techniques into tissue-engineered vascular grafts in vitro and implanted in vivo to repair the vascular tissues. To overcome the thrombogenesis and promote the endothelialization effect, vascular biomaterials employing nanotopography are more bio-mimic to the native tissue made and have been engineered by various approaches such as prepared as a simple surface coating on the vascular biomaterials. It has now become an important and interesting field to find novel approaches to better endothelization of vascular biomaterials. In this article, we focus to review the techniques with better potential improving endothelization and summarize for vascular biomaterial application. This review article will enable the development of biomaterials with a high degree of originality, innovative research on novel techniques for surface fabrication for vascular biomaterials application.

Current Approaches to Drug Discovery for Chagas Disease: Methodological Advances

2019 ◽  
Vol 22 (8) ◽  
pp. 509-520
Author(s):  
Cauê B. Scarim ◽  
Chung M. Chin
Keyword(s):  
Drug Discovery ◽  
Chagas Disease ◽  
Drug Candidates ◽  
Lead Compounds ◽  
New Drug ◽  
Compound Libraries ◽  
Screening Assays ◽  
Cruzi Infection

Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease.

scholarly journals High-throughput screening and rational design of biofunctionalized surfaces with optimized biocompatibility and antimicrobial activity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Zhou Fang ◽  
Junjian Chen ◽  
Ye Zhu ◽  
Guansong Hu ◽  
Haoqian Xin ◽  
...  
Keyword(s):  
Antimicrobial Activity ◽  
High Throughput ◽  
High Throughput Screening ◽  
Rational Design ◽  
Click Reaction ◽  
Reaction Times ◽  
Great Promise ◽  
Biomaterial Surfaces

AbstractPeptides are widely used for surface modification to develop improved implants, such as cell adhesion RGD peptide and antimicrobial peptide (AMP). However, it is a daunting challenge to identify an optimized condition with the two peptides showing their intended activities and the parameters for reaching such a condition. Herein, we develop a high-throughput strategy, preparing titanium (Ti) surfaces with a gradient in peptide density by click reaction as a platform, to screen the positions with desired functions. Such positions are corresponding to optimized molecular parameters (peptide densities/ratios) and associated preparation parameters (reaction times/reactant concentrations). These parameters are then extracted to prepare nongradient mono- and dual-peptide functionalized Ti surfaces with desired biocompatibility or/and antimicrobial activity in vitro and in vivo. We also demonstrate this strategy could be extended to other materials. Here, we show that the high-throughput versatile strategy holds great promise for rational design and preparation of functional biomaterial surfaces.

scholarly journals O23: CHARACTERISING PATIENT-DERIVED COLORECTAL CANCER TISSUE-ORIGINATED ORGANOIDAL SPHEROIDS FOR HIGH-THROUGHPUT MICROFLUIDIC APPLICATIONS

2021 ◽  
Vol 108 (Supplement_1) ◽  
Author(s):  
MI Khot ◽  
M Levenstein ◽  
R Coppo ◽  
J Kondo ◽  
M Inoue ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Fluid Flow ◽  
High Throughput ◽  
Microfluidic Devices ◽  
In Vitro Models ◽  
Fluorescent Imaging ◽  
Cancer Tissue ◽  
Cell Models

Abstract Introduction Three-dimensional (3D) cell models have gained reputation as better representations of in vivo cancers as compared to monolayered cultures. Recently, patient tumour tissue-derived organoids have advanced the scope of complex in vitro models, by allowing patient-specific tumour cultures to be generated for developing new medicines and patient-tailored treatments. Integrating 3D cell and organoid culturing into microfluidics, can streamline traditional protocols and allow complex and precise high-throughput experiments to be performed with ease. Method Patient-derived colorectal cancer tissue-originated organoidal spheroids (CTOS) cultures were acquired from Kyoto University, Japan. CTOS were cultured in Matrigel and stem-cell media. CTOS were treated with 5-fluorouracil and cytotoxicity evaluated via fluorescent imaging and ATP assay. CTOS were embedded, sectioned and subjected to H&E staining and immunofluorescence for ABCG2 and Ki67 proteins. HT29 colorectal cancer spheroids were produced on microfluidic devices using cell suspensions and subjected to 5-fluorouracil treatment via fluid flow. Cytotoxicity was evaluated through fluorescent imaging and LDH assay. Result 5-fluorouracil dose-dependent reduction in cell viability was observed in CTOS cultures (p<0.01). Colorectal CTOS cultures retained the histology, tissue architecture and protein expression of the colonic epithelial structure. Uniform 3D HT29 spheroids were generated in the microfluidic devices. 5-fluorouracil treatment of spheroids and cytotoxic analysis was achieved conveniently through fluid flow. Conclusion Patient-derived CTOS are better complex models of in vivo cancers than 3D cell models and can improve the clinical translation of novel treatments. Microfluidics can streamline high-throughput screening and reduce the practical difficulties of conventional organoid and 3D cell culturing. Take-home message Organoids are the most advanced in vitro models of clinical cancers. Microfluidics can streamline and improve traditional laboratory experiments.

FRET-Based Probe for High-Throughput DNA Intercalator Drug Discovery and In Vivo Imaging

ACS Sensors ◽  
2021 ◽  
Author(s):  
Chandrashekhar U. Murade ◽  
Samata Chaudhuri ◽  
Ibtissem Nabti ◽  
Hala Fahs ◽  
Fatima S. M. Refai ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput ◽  
In Vivo Imaging ◽  
Dna Intercalator

scholarly journals Human Adipose-Derived Stromal/Stem Cell Culture and Analysis Methods for Adipose Tissue Modeling In Vitro: A Systematic Review

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1378
Author(s):  
Peyton Gibler ◽  
Jeffrey Gimble ◽  
Katie Hamel ◽  
Emma Rogers ◽  
Michael Henderson ◽  
...  
Keyword(s):  
Systematic Review ◽  
Adipose Tissue ◽  
Drug Discovery ◽  
3D Culture ◽  
Human Adipose Tissue ◽  
Culture Methods ◽  
Adipose Tissue Engineering ◽  
The Impact

Human adipose-derived stromal/stem cells (hASC) are widely used for in vitro modeling of physiologically relevant human adipose tissue. These models are useful for the development of tissue constructs for soft tissue regeneration and 3-dimensional (3D) microphysiological systems (MPS) for drug discovery. In this systematic review, we report on the current state of hASC culture and assessment methods for adipose tissue engineering using 3D MPS. Our search efforts resulted in the identification of 184 independent records, of which 27 were determined to be most relevant to the goals of the present review. Our results demonstrate a lack of consensus on methods for hASC culture and assessment for the production of physiologically relevant in vitro models of human adipose tissue. Few studies have assessed the impact of different 3D culture conditions on hASC adipogenesis. Additionally, there has been a limited use of assays for characterizing the functionality of adipose tissue in vitro. Results from this study suggest the need for more standardized culture methods and further analysis on in vitro tissue functionality. These will be necessary to validate the utility of 3D MPS as an in vitro model to reduce, refine, and replace in vivo experiments in the drug discovery regulatory process.

Sign in / Sign up

Export Citation Format

Share Document