scholarly journals Disease modeling and drug screening using human airway organoids: a systematic review

Organoid ◽  
2021 ◽  
Vol 1 ◽  
pp. e8
Author(s):  
Do Hyun Kim ◽  
Sung Won Kim
Keyword(s):  
Drug Screening ◽  
Drug Testing ◽  
Disease Modeling ◽  
Human Life ◽  
Screening Tools ◽  
Dust Particles ◽  
Disease Models ◽  
Respiratory Illnesses ◽  
Human Airway ◽  
New Treatment

Increasing levels of fine environmental dust particles due to industrialization and emerging respiratory illnesses, such as coronavirus disease 2019, pose serious threats to human life. The use of organoids for disease modeling and drug screening has been proposed as a new treatment approach for respiratory diseases. As discussed in this review, various pathogen models, genetic disease models, and patient-derived lung cancer organoid models have been reported for disease modeling and drug testing using human airway organoids. Despite these promising recent advances, several issues must be addressed before the disease modeling potential of human airway organoids can be fully realized. If systematic methods to produce mature airway organoids can be developed, and reproducible organoid models can be implemented using standardized protocols, airway organoids will likely become valuable respiratory disease models and drug screening tools.

scholarly journals Engineering the Vasculature of Stem-Cell-Derived Liver Organoids

Biomolecules ◽  
2021 ◽  
Vol 11 (7) ◽  
pp. 966
Author(s):  
Xv Zhang ◽  
Liling Tang ◽  
Qian Yi
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Drug Screening ◽  
Disease Modeling ◽  
Liver Development ◽  
Embryonic Liver ◽  
Hepatic Cells ◽  
Hepatic Vessels ◽  
Liver Organoids ◽  
Application Prospects

The vasculature of stem-cell-derived liver organoids can be engineered using methods that recapitulate embryonic liver development. Hepatic organoids with a vascular network offer great application prospects for drug screening, disease modeling, and therapeutics. However, the application of stem cell-derived organoids is hindered by insufficient vascularization and maturation. Here, we review different theories about the origin of hepatic cells and the morphogenesis of hepatic vessels to provide potential approaches for organoid generation. We also review the main protocols for generating vascularized liver organoids from stem cells and consider their potential and limitations in the generation of vascularized liver organoids.

scholarly journals Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

2017 ◽  
Vol 23 (12) ◽  
pp. 1424-1435 ◽  
Author(s):  
Laura Broutier ◽  
Gianmarco Mastrogiovanni ◽  
Monique MA Verstegen ◽  
Hayley E Francies ◽  
Lena Morrill Gavarró ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Drug Screening ◽  
Disease Modeling ◽  
Primary Liver Cancer ◽  
Organoid Cultures

scholarly journals Engineered heart tissue models from hiPSC-derived cardiomyocytes and cardiac ECM for disease modeling and drug testing applications

2019 ◽  
Vol 92 ◽  
pp. 145-159 ◽  
Author(s):  
Idit Goldfracht ◽  
Yael Efraim ◽  
Rami Shinnawi ◽  
Ekaterina Kovalev ◽  
Irit Huber ◽  
...  
Keyword(s):  
Drug Testing ◽  
Disease Modeling ◽  
Heart Tissue ◽  
Engineered Heart Tissue ◽  
Tissue Models

TMOD-29. STANDARDIZED GENERATION OF TUMOR-ORGANOIDS AS NOVEL DRUG SCREENING MODEL IN MENINGIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi221-vi222
Author(s):  
Gerhard Jungwirth ◽  
Tao Yu ◽  
Cao Junguo ◽  
Catharina Lotsch ◽  
Andreas Unterberg ◽  
...  
Keyword(s):  
Drug Screening ◽  
Cancer Biology ◽  
Drug Testing ◽  
Large Scale ◽  
Ex Vivo ◽  
Cell Types ◽  
Cellular Heterogeneity ◽  
Drug Responses ◽  
Novel Drug ◽  
Tumor Organoids

Abstract Tumor-organoids (TOs) are novel, complex three-dimensional ex vivo tissue cultures that under optimal conditions accurately reflect genotype and phenotype of the original tissue with preserved cellular heterogeneity and morphology. They may serve as a new and exciting model for studying cancer biology and directing personalized therapies. The aim of our study was to establish TOs from meningioma (MGM) and to test their usability for large-scale drug screenings. We were capable of forming several hundred TO equal in size by controlled reaggregation of freshly prepared single cell suspension of MGM tissue samples. In total, standardized TOs from 60 patients were formed, including eight grade II and three grade III MGMs. TOs reaggregated within 3 days resulting in a reducted diameter by 50%. Thereafter, TO size remained stable throughout a 14 days observation period. TOs consisted of largely viable cells, whereas dead cells were predominantly found outside of the organoid. H&E stainings confirmed the successful establishment of dense tissue-like structures. Next, we assessed the suitability and reliability of TOs for a robust large-scale drug testing by employing nine highly potent compounds, derived from a drug screening performed on several MGM cell lines. First, we tested if drug responses depend on TO size. Interestingly, drug responses to these drugs remained identical independent of their sizes. Based on a sufficient representation of low abundance cell types such as T-cells and macrophages an overall number of 25.000 cells/TO was selected for further experiments revealing FDA-approved HDAC inhibitors as highly effective drugs in most of the TOs with a mean z-AUC score of -1.33. Taken together, we developed a protocol to generate standardized TO from MGM containing low abundant cell types of the tumor microenvironment in a representative manner. Robust and reliable drug responses suggest patient-derived TOs as a novel drug testing model in meningioma research.

Cost Analysis of the Country of Georgia’s Street Level Drug Testing Policy

2017 ◽  
Vol 10 (2) ◽  
Author(s):  
Dessa Bergen-Cico ◽  
David Otiashvili ◽  
Irma Kirtadze ◽  
Tomas Zabransky ◽  
Vano Tsertsvadze
Keyword(s):  
Drug Use ◽  
Cost Analysis ◽  
Drug Screening ◽  
Drug Testing ◽  
Impact Analysis ◽  
Positive Impact ◽  
National Sample ◽  
Labor Costs ◽  
Street Level ◽  
Use Behavior

AbstractBackgroundIn 2006 the country of Georgia implemented Article 45 of the Administrative code and Article 273 of the Criminal Code of Georgia, a public policy that enable police to detain any individual, anywhere, at any time on grounds of suspicion of drug use; and require them to submit to urine screening to test for the presence of illegal drugs and their metabolites. This policy is referred to as the street drug testing policy. Positive drug screening results in fines and potential jail time. The purpose of this paper is to conduct a cost analysis of this policy and assess the execution of the policy and the extent to which the policy meets its stated aims.MethodsThis study employed cost analysis methodology to calculate annual direct material and labor costs associated with carrying out Georgia’s street level drug testing policy. These costs encompassed law enforcement, drug testing, associated judicial processes, imprisonment and income offset through fines collected during the two years covered in this study (2008 and 2014). In addition, we measured: fidelity of the execution of the policy measured by the accuracy of the percentage of people detained who were found to actually have used drugs; and the policy’s effectiveness in deterring drug use among those who tested positive. Impact on drug use behavior was measured through impact analysis interviews conducted with a national sample of 500 detainees who tested positive for drugs under Article 45 and Article 273.ResultsUsing conservative financial estimates the cost of carrying out the policy offset by fine revenues broke even in 2008 (−111,889 GEL); however, by 2014 the costs increased 20 % in conjunction with an 18 % increase in the number of people detained for testing. However, the percentage of people who tested positive for drugs declined 39 % indicating decreased fidelity in the execution of the policy; accompanied by a financial imbalance of −10,277,909 GEL. Moreover, effectiveness analysis revealed that within one month of being detained and having tested positive for drug use, over 90 % of individuals had returned to pre-detention drug use levels, and within 12 months 100 % of detainees had resumed prior drug use behaviors.ConclusionThe financial costs associated with Georgia’s street level drug screening policy has rapidly increased while becoming decreasingly accurate and efficient in its execution. Moreover, data indicates that the policy is not effective in reducing or stopping drug use among those who tested positive. In conclusion, it is fiscally unsustainable to continue the policy as it is being executed and the policy is ineffective in changing drug use behavior among people who use illegal substances.

scholarly journals From NAFLD to MAFLD: Aligning Translational In Vitro Research to Clinical Insights

Biomedicines ◽  
2022 ◽  
Vol 10 (1) ◽  
pp. 161
Author(s):  
Alexandra Gatzios ◽  
Matthias Rombaut ◽  
Karolien Buyl ◽  
Joery De Kock ◽  
Robim M. Rodrigues ◽  
...  
Keyword(s):  
Liver Disease ◽  
Drug Development ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Drug Testing ◽  
Disease Modeling ◽  
In Vitro Models ◽  
Alcoholic Fatty Liver ◽  
Short Term Exposure

Although most same-stage non-alcoholic fatty liver disease (NAFLD) patients exhibit similar histologic sequelae, the underlying mechanisms appear to be highly heterogeneous. Therefore, it was recently proposed to redefine NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) in which other known causes of liver disease such as alcohol consumption or viral hepatitis do not need to be excluded. Revised nomenclature envisions speeding up and facilitating anti-MAFLD drug development by means of patient stratification whereby each subgroup would benefit from distinct pharmacological interventions. As human-based in vitro research fulfils an irrefutable step in drug development, action should be taken as well in this stadium of the translational path. Indeed, most established in vitro NAFLD models rely on short-term exposure to fatty acids and use lipid accumulation as a phenotypic benchmark. This general approach to a seemingly ambiguous disease such as NAFLD therefore no longer seems applicable. Human-based in vitro models that accurately reflect distinct disease subgroups of MAFLD should thus be adopted in early preclinical disease modeling and drug testing. In this review article, we outline considerations for setting up translational in vitro experiments in the MAFLD era and allude to potential strategies to implement MAFLD heterogeneity into an in vitro setting so as to better align early drug development with future clinical trial designs.

Abstract 241: Retinoic Acid Promotes Metabolic Maturation of Human Embryonic Stem Cell-derived Cardiomyocytes

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Shumei Miao ◽  
Xing Fang ◽  
Xiaoxiao Wang ◽  
Lingqun Ye ◽  
Jingsi Yang ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Retinoic Acid ◽  
Heart Development ◽  
Drug Testing ◽  
Disease Modeling ◽  
Time Window ◽  
Embryonic Stem ◽  
Early Time ◽  
Control Group ◽  
Cardiomyocyte Differentiation

Cardiomyocytes differentiated from human embryonic stem cells (hESCs) represent a promising cell source for heart repair, disease modeling and drug testing. However, improving the differentiation efficiency and maturation of hESC-derived cardiomyocytes (hESC-CMs) is still a major concern. Retinoic acid (RA) signaling plays multiple roles in heart development, and studies on RA can provide clues for understanding cardiomyocyte differentiation and maturation. In this study, we studied the roles of RA during cardiomyocyte differentiation and maturation, systematically. After adding RA at different stages of cardiomyocyte differentiation, we compared the efficiency of differentiation by quantitative real-time PCR and flow cytometry. We found that RA treatment at the lateral mesoderm stage (days 2-4) significantly improved cardiomyocyte differentiation, as evidenced by the upregulation of TNNT2, NKX2.5 and MYH6 on day 10 of differentiation. In addition, flow cytometry showed that the proportion of differentiated cardiomyocytes in the RA-treated group was significantly higher than that in control group. Furthermore, RA was added at different time intervals after purification to induce cardiomyocyte maturation. Our results demonstrated that RA treatment on days 15-20 increased cardiomyocyte area, sarcomere length, multinucleation and mitochondrial copy number, and promoted RNA splicing switch. Importantly, RA-treated cardiomyocytes showed decreased glycolysis and enhanced mitochondrial oxidative phosphorylation, with the increased utilization of fatty acid and exogenous pyruvate but not glutamine. In conclusion, our data indicated that RA treatment at an early time window (days 2-4) promotes the efficiency of cardiomyocyte differentiation and that RA treatment post beating (days 15-20) promotes cardiomyocyte metabolic maturation. The biphasic effects of RA provide new insights for improving cardiomyocyte differentiation and quality.

scholarly journals Pancreatic cancer-derived organoids – a disease modeling tool to predict drug response

2020 ◽  
Vol 8 (5) ◽  
pp. 594-606 ◽  
Author(s):  
Pierre-Olivier Frappart ◽  
Karolin Walter ◽  
Johann Gout ◽  
Alica K Beutel ◽  
Mareen Morawe ◽  
...  
Keyword(s):  
Drug Testing ◽  
Disease Modeling ◽  
Individualized Medicine ◽  
Expression Patterns ◽  
Culture Conditions ◽  
Ductal Adenocarcinoma ◽  
Small Scale ◽  
Comparative Genomic

Background Organotypic cultures derived from pancreatic ductal adenocarcinoma (PDAC) termed pancreatic ductal cancer organoids (PDOs) recapitulate the primary cancer and can be derived from primary or metastatic biopsies. Although isolation and culture of patient-derived pancreatic organoids were established several years ago, pros and cons for individualized medicine have not been comprehensively investigated to date. Methods We conducted a feasibility study, systematically comparing head-to-head patient-derived xenograft tumor (PDX) and PDX-derived organoids by rigorous immunohistochemical and molecular characterization. Subsequently, a drug testing platform was set up and validated in vivo. Patient-derived organoids were investigated as well. Results First, PDOs faithfully recapitulated the morphology and marker protein expression patterns of the PDXs. Second, quantitative proteomes from the PDX as well as from corresponding organoid cultures showed high concordance. Third, genomic alterations, as assessed by array-based comparative genomic hybridization, revealed similar results in both groups. Fourth, we established a small-scale pharmacotyping platform adjusted to operate in parallel considering potential obstacles such as culture conditions, timing, drug dosing, and interpretation of the results. In vitro predictions were successfully validated in an in vivo xenograft trial. Translational proof-of-concept is exemplified in a patient with PDAC receiving palliative chemotherapy. Conclusion Small-scale drug screening in organoids appears to be a feasible, robust and easy-to-handle disease modeling method to allow response predictions in parallel to daily clinical routine. Therefore, our fast and cost-efficient assay is a reasonable approach in a predictive clinical setting.

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