scholarly journals High-dose drug heat map analysis for drug safety and efficacy in multi-spheroid brain normal cells and GBM patient-derived cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0251998
Author(s):  
Sang-Yun Lee ◽  
Yvonne Teng ◽  
Miseol Son ◽  
Bosung Ku ◽  
Ho Sang Moon ◽  
...  

To test the safety and efficacy of drugs via a high does drug heat map, a multi-spheroids array chip was developed by adopting a micropillar and microwell structure. In the chip, patient-derived cells were encapsulated in alginate and grown to maturity for more than 7 days to form cancer multi-spheroids. Multi-spheroids grown in conventional well plates require many cells and are easily damaged as a result of multiple pipetting during maintenance culture or experimental procedures. To address these issues, we applied a micropillar and microwell structure to the multi-spheroids array. Patient-derived cells from patients with Glioblastoma (GBM), the most common and lethal form of central nervous system cancer, were used to validate the array chip performance. After forming multi-spheroids with a diameter greater than 100μm in a 12×36 pillar array chip (25mm × 75mm), we tested 70 drug compounds (6 replicates) using a high-dose to determine safety and efficacy for drug candidates. Comparing the drug response of multi-spheroids derived from normal cells and cancer cells, we found that four compounds (Dacomitinib, Cediranib, LY2835219, BGJ398) did not show toxicity to astrocyte cell and were efficacious to patient-derived GBM cells.

2021 ◽  
Author(s):  
Sang-Yun Lee ◽  
Yvonne Teng ◽  
Miseol Son ◽  
Bosung Ku ◽  
Ho Sang Moon ◽  
...  

An organoid array chip was developed by adopting a micropillar and microwell structure to test safety and efficacy of drugs using high dose drug heat map. In the chip, we encapsulated patient-derived cells in alginate and grow them to maturity for more than 7 days to form cancer organoids. When screening drug compounds in a high-density organoid array due to lack of number of patient-derived cells, changing media without damage of organoids is a very tedious and difficult process. Organoids grown in conventional well plates needed too many cells and were also easily damaged due to multiple pipetting during maintenance culture or during experimental procedures. To solve those problem, we applied a micropillar and microwell structure to the organoid array. We used patient-derived cells from patients with Glioblastoma multiforme (GBM), the most common and lethal form of central nervous system cancer, to validate the array chip performance. After forming more than 100µm-diameter organoids in 12 [[EQUATION]] 36 pillar array chip (25mm [[EQUATION]] 75mm), we tested 70 drug compounds (6 replicates) with high high-dose to find out high safety and efficacy drug candidates. Comparing the drug response of organoids derived from normal cells and cancer cells, we identified four compounds (Dacomitinib, Cediranib, Ly2835219, BGJ398) as drug candidates without toxicity to GBM cells.


2017 ◽  
Vol 2017 ◽  
pp. 1-7 ◽  
Author(s):  
Dong Woo Lee ◽  
Sang-Yun Lee ◽  
Il Doh ◽  
Gyu Ha Ryu ◽  
Do-Hyun Nam

Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. To cure GBM patients, many target-specific chemotherapeutic agents have been developing. However, 2D monolayer cell-based toxicity and efficacy tests did not efficiently screen agents due to the pool reflection of in vivo microenvironments (cell-to-cell and cell-to-extracellular matrix interaction). In this study, we used a 3D cell-based, high-throughput screening method reflecting the microenvironments using a micropillar and microwell chip platform to draw a high-dose heat map of the cytotoxicity and efficacy of 70 compounds, with two DMSO controls. Moreover, the high-dose heat map model compared the responses of four 3D-cultured patient-derived GBM cells and astrocytes to high dosages of compounds with respect to efficacy and cytotoxicity, respectively, to discern the most efficacious drug for GBM. Among the 70 compounds tested, cediranib (a potent inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases) exhibited the lowest cytotoxicity to astrocytes and high efficacy to GBM cells in a high-dose heat map model.


2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Rehab Abdelhamid Aboshama ◽  
Ahmed Mohamed Abdelhakim ◽  
Mohammad Abrar Shareef ◽  
Abdulhadi A. AlAmodi ◽  
Mohammad Sunoqrot ◽  
...  

AbstractObjectivesTo compare the safety and efficacy between high dose and low dose oxytocin administration for labor augmentation.MethodsWe searched for the available studies during March 2020 in PubMed, Cochrane Library, Scopus, and ISI Web of science. All randomized clinical trials (RCTs) that assessed safety and efficacy of high dose vs. low dose oxytocin for labor augmentation were considered. The extracted data were entered into RevMan software. Dichotomous and continuous data were pooled as odds ratio (OR) and mean difference (MD) respectively, with the corresponding 95% confidence intervals (CI). Our main outcomes were cesarean delivery rate, spontaneous vaginal delivery rate, uterine hyperstimulation and tachysystole, and labor duration from oxytocin infusion.ResultsEight RCTs with 3,154 patients were included. High dose oxytocin did not reduce cesarean delivery rate compared to low dose oxytocin (OR=0.76, 95% CI [0.52, 1.10], p=0.15). After solving the reported heterogeneity, high dose oxytocin did not increase the rate of spontaneous vaginal deliveries vs. low dose oxytocin (OR=1.06, 95% CI [0.84, 1.32], p=0.64). Low dose oxytocin was linked to a significant decline in uterine hyperstimulation and tachysystole (p>0.001). A reduction in labor duration was found in high dose oxytocin group over low oxytocin regimen (MD=−1.02 h, 95% CI [−1.77, −0.27], p=0.008).ConclusionsWe found no advantages for high dose oxytocin over low dose oxytocin in labor augmentation except in reducing labor duration. Low dose oxytocin is safer as it decreases the incidence of uterine hyperstimulation and tachysystole. More trials are needed to confirm our findings.


2015 ◽  
Vol 61 (suppl_6) ◽  
pp. S652-S661 ◽  
Author(s):  
Dionysis Neofytos ◽  
Yao-Ting Huang ◽  
Kimberly Cheng ◽  
Nina Cohen ◽  
Miguel-Angel Perales ◽  
...  

2021 ◽  
pp. 106002802110098
Author(s):  
Linguang Gan ◽  
Xiaohong Zhao ◽  
Xiangjian Chen

Background: This study systematically evaluated the safety and efficacy of dexmedetomidine for procedural sedation and postoperative behaviors in a pediatric population as well as whether the results met the information required to draw conclusions. Objective: To evaluate the safety and efficacy evaluation of dexmedetomidine for procedural sedation and postoperative behaviors in a pediatric population. Methods: PubMed, Cochrane library, Web of Science and Ovid MEDLINE were searched to obtain randomized controlled trials (RCTs) comparing dexmedetomidine with control medicine and comparing different doses of dexmedetomidine. Results: There were a total of 16 RCTs for a total of 3240 patients. Dexmedetomidine slowed down the heart rate (HR; mean difference: −13.27; 95% CI: −16.41 to 10.14; P < 0.001) and reduced postoperative delirium (risk ratio [RR]: 0.31; 95% CI: 0.20-0.50; P < 0.001), the number of pain patients (RR: 0.48; 95% CI: 0.30-0.75; P = 0.002), and desaturation (RR: 0.34; 95% CI: 0.13-0.89; P = 0.03) compared with the control group. The limitation was that it was difficult to determine the range of low- and high-dose dexmedetomidine. Conclusion and Relevance: Dexmedetomidine slowed down intraoperative HR within the normal range, which might reduce myocardial oxygen consumption. It reduced postoperative pain and postoperative complications: delirium and desaturation. Dexmedetomidine showed no dose-dependent increase in the procedural sedation time of pediatric patients. Clinically, dexmedetomidine can improve pediatric procedural sedation and postoperative behavior, and it can be considered as a related medicine for safety in pediatric surgery.


2021 ◽  
pp. 1-13
Author(s):  
Hamid Reza Saeidi Borojeni ◽  
Farid Najafi ◽  
Fatemeh Khosravi Shadmani ◽  
Zahra Darabi ◽  
Mitra Darbandi ◽  
...  

<b><i>Background:</i></b> Primary brain tumors are among the main causes of death. This study aimed to determine the epidemiological features of the brain and central nervous system cancer in the Middle East and North Africa (MENA) region. <b><i>Methods:</i></b> In this study, data of the Global Burden of Disease (GBD) study were used to estimate the incidence, prevalence, deaths, disability-adjusted life years (DALYs), and mortality in 21 countries in the MENA region from 1990 to 2019 based on age and sex. The percentage of the changes of epidemiologic indicators was calculated between 1990 and 2019. <b><i>Results:</i></b> Palestine and Turkey had the highest rate of brain and central nervous system cancer in 2019. Saudi Arabia, Oman, Iraq, and Lebanon had the highest percentage of incidence rate changes from 1990 to 2019. The prevalence of brain and central nervous system cancer in the MENA region was increased from 7.51 (95% CI: 4.95–11.01) in 1990 to 16.45 (95% CI: 10.83–19.54) in 2019 (percentage of changes = 54.35%). The standardized age mortality rate in the MENA region was increased by 2.7% in 2019 compared to that in 1990. The rate of standardized age of DALY per 100,000 individuals in the MENA region decreased from 135.09 (95% CI: 92.57–199.92) in 1990 to 128.34 (95% CI: 87.81–151.3) in 2019. <b><i>Conclusion:</i></b> The incidence rate, prevalence, and standardized age mortality (per 100,000) had increased significantly in the MENA region in 2019 compared to those in 1990. Focusing on the diversity of the estimates of such indices in different countries of MENA can lead to the identification of important risk factors for brain cancer in future studies.


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