athymic nude mice
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2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi171-vi171
Author(s):  
Hunter Bomba ◽  
Lauren Kass ◽  
Kevin Sheets ◽  
Abigail Carey-Ewend ◽  
Morgan Goetz ◽  
...  

Abstract BACKGROUND Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for anti-tumor payloads. However, iNSC persist for only two weeks in the murine GBM tumor resection cavity. We hypothesized that by encapsulating iNSCs in a scaffold matrix, we could increase both the persistence of the cells the therapeutic durability. METHODS iNSCs expressing TRAIL were encapsulated in a gelatin-thrombin matrix; fibrinogen was used to polymerize the matrix. SEM was used to explore interactions between iNSCs and the scaffold matrix. To evaluate persistence, iNSCs encapsulated in the matrix were implanted into mock resection cavities of athymic nude mice and followed via BLI. To study the impacts of encapsulation on iNSC efficacy, athymic nude mice were implanted with U87 or GBM8 tumors. Tumors were then resected, and iNSCs encapsulated in the matrix were implanted; tumor volume was monitored via BLI. RESULTS SEM images showed homogeneous distribution of iNSCs throughout the matrix; iNSCs were completed encased in the fibrin clot component of the matrix and did not adhere to gelatin. In vivo, encapsulated iNSCs persisted for nearly 100 days whereas iNSCs directly injected into the brain parenchyma persisted < 20 days. Using mice bearing GBM8 tumors, animals treated with a high dose of therapeutic encapsulated iNSCs survived ~60 days longer than animals treated with non-therapeutic cells. A similar trend was observed in animals inoculated with U87 tumors. While not statistically significant, 25% of mice treated with iNSCs encapsulated in the gelatin-thrombin matrix survived longer than those treated with iNSCs encapsulated in a fibrin-only matrix, suggesting additional benefit due to the gelatin component. FUTURE DIRECTIONS: Prospective experiments will explore the impact of the scaffold on iNSC phenotype, including proliferation, differentiation, and migration markers.


2021 ◽  
Vol 14 (4) ◽  
pp. 345
Author(s):  
Thong Teck Tan ◽  
Ruenn Chai Lai ◽  
Jayanthi Padmanabhan ◽  
Wei Kian Sim ◽  
Andre Boon Hwa Choo ◽  
...  

Mesenchymal-stem/stromal-cell-derived small extracellular vesicles (MSC-sEV) have been shown to ameliorate many diseases in preclinical studies. However, translating MSC-sEV into clinical use requires the development of scalable manufacturing processes for highly reproducible preparations of safe and potent MSC-sEVs. A major source of variability in MSC-sEV preparations is EV producer cells. To circumvent variability in producer cells, clonal immortalized MSC lines as EV producer lines are increasingly being used for sEV production. The use of sEVs from immortalized producer cells inevitably raises safety concerns regarding the tumorigenicity or tumor promoting potential of the EV products. In this study, cells from E1-MYC line, a MSC cell line immortalized with the MYC gene, were injected subcutaneously into athymic nude mice. At 84 days post-injection, no tumor formation was observed at the injection site, lungs, or lymph nodes. E1-MYC cells pre-and post-sEV production did not exhibit anchorage-independent growth in soft agar. Daily intraperitoneal injections of 1 or 5 μg sEVs from E1-MYC into athymic nude mice with FaDu human head and neck cancer xenografts for 28 days did not promote or inhibit tumor growth relative to the xenograft treated with vehicle control. Therefore, MYC-immortalized MSCs are not tumorigenic and sEVs from these MSCs do not promote tumor growth.


Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 586
Author(s):  
Nassrin Badroon ◽  
Nazia Abdul Majid ◽  
Fouad Al-Suede ◽  
Mansoureh Nazari V. ◽  
Nelli Giribabu ◽  
...  

Cardamonin (CADMN) exerts an in vitro antiproliferative and apoptotic actions against human hepatocellular carcinoma cells (HepG2). This study aimed to investigate the in vivo anti-tumorigenic action of CADMN against human hepatocellular carcinoma xenografts in an athymic nude mice, as well as to study the molecular docking and safety profile of this compound. Acute toxicity study demonstrated that CADMN is safe and well-tolerated up to 2000 mg/kg in ICR mice. Oral administration of 50 mg/kg/day of CADMN in xenografted nude mice showed a significant suppression in tumor growth as compared to untreated control group without pronounced toxic signs. Immunohistochemistry assay showed downregulation of proliferative proteins such as PCNA and Ki-67 in treated groups as compared to untreated control. Additionally, immunofluorescence analysis showed a significant downregulation in anti-apoptotic Bcl-2 protein, whereas pre-apoptotic Bax protein was significantly upregulated in nude mice treated with 25 and 50 mg/kg CADMN as compared to untreated mice. The findings also exhibited down-regulation of NF-κB-p65, and Ikkβ proteins, indicating that CADMN deactivated NF-κB pathway. The molecular docking studies demonstrated that CADMN exhibits good docking performance and binding affinities with various apoptosis and proliferation targets in hepatocellular cancer cells. In conclusion, CADMN could be a potential anticancer candidate against hepatocellular carcinoma. Other pharmacokinetics and pharmacodynamics properties, however, need to be further investigated in depth.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii3-ii3
Author(s):  
Rehan Saber ◽  
Masum Rahman ◽  
Ian E Olson ◽  
Karishma Rajani ◽  
Terry C Burns

Abstract INTRODUCTION Gliomas are the most common and deadly adult brain cancers with a median survival time of less than 18 months. Many therapeutics have failed translating into effective therapies due to incomplete understanding of the disease and heterogeneity of tumors between patients. There is a need for methods that allow for continual access and analysis of glioma biomarkers. We sought to establish a reliable method for quantifying the onco-metabolite, D2HG. After optimizing this method, we used microdialysate and microperfusate to test our hypothesis that analysis of D2HG in response to therapy can indicate therapeutic efficacy sooner than current methods permit. METHODS Microdialysate and microperfusate were collected from the tumor centers and lateral ventricles of athymic nude mice implanted with IDH1 mutant PDX line GBM196. We performed microdialysis and microperfusion on consecutive days to determine baseline D2HG concentration. Following a five day period of TMZ treatment, we collected another round of microdialysis and microperfusion one week after treatment and again two weeks after treatment. We then used our optimized D2HG enzymatic assay to quantify the changes in D2HG in response to therapy. RESULTS Using our enzymatic D2HG assay, we were able to quantify D2HG as low as 30nM (30fmol/uL). We found a ~20% decrease in D2HG concentration in the tumor center and right lateral ventricle after 1 week of TMZ treatment (n=2), and ~36% decrease after 2 weeks of TMZ treatment (n=2). CONCLUSION Using a D2HG quantification assay to monitor changes in concentration of D2HG in microdialysate/microperfusate can predict sensitivity to therapy.


2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii91-ii92
Author(s):  
Hunter Bomba ◽  
Kevin Sheets ◽  
Abigial Carey-Ewend ◽  
Morgan Goetz ◽  
Ingrid Findlay ◽  
...  

Abstract BACKGROUND Induced neural stem cells (iNSCs) have emerged as a promising therapeutic platform for glioblastoma (GBM). iNSCs have the innate ability to home to tumor foci, making them ideal carriers for anti-tumor payloads. However, iNSC persist for only two weeks in the murine GBM tumor resection cavity. We hypothesized that, by encapsulating iNSCs in a scaffold matrix, we could increase both the persistence of the cells the therapeutic durability. METHODS iNSCs expressing TRAIL were encapsulated in a gelatin-thrombin matrix; fibrinogen was used to polymerize the matrix. SEM was used to explore interactions between iNSCs and the scaffold matrix. To evaluate persistence, iNSCs encapsulated in the matrix were implanted into mock resection cavities of athymic nude mice and followed via BLI. To study the impacts of encapsulation on iNSC efficacy, athymic nude mice were implanted with U87 or GBM8 tumors. Tumors were then resected, and iNSCs encapsulated in the matrix were implanted; tumor volume was monitored via BLI. RESULTS SEM images showed homogeneous distribution of iNSCs throughout the matrix; iNSCs were completed encased in the fibrin clot component of the matrix and did not adhere to gelatin. In vivo, encapsulated iNSCs persisted for nearly 100 days whereas iNSCs directly injected into the brain parenchyma persisted < 20 days. Using mice bearing GBM8 tumors, animals treated with a high dose of therapeutic encapsulated iNSCs survived ~60 days longer than animals treated with non-therapeutic cells. A similar trend was observed in animals inoculated with U87 tumors. While not statistically significant, 25% of mice treated with iNSCs encapsulated in the gelatin-thrombin matrix survived longer than those treated with iNSCs encapsulated in a fibrin-only matrix, suggesting additional benefit due to the gelatin component. FUTURE DIRECTIONS Prospective experiments will explore the impact of the scaffold on iNSC phenotype, including proliferation, differentiation, and migration markers.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
James F. Hainfeld ◽  
Sharif M. Ridwan ◽  
F. Yaroslav Stanishevskiy ◽  
Henry M. Smilowitz

Abstract About 30% of breast cancers metastasize to the brain; those widely disseminated are fatal typically in 3–4 months, even with the best available treatments, including surgery, drugs, and radiotherapy. To address this dire situation, we have developed iodine nanoparticles (INPs) that target brain tumors after intravenous (IV) injection. The iodine then absorbs X-rays during radiotherapy (RT), creating free radicals and local tumor damage, effectively boosting the local RT dose at the tumor. Efficacy was tested using the very aggressive human triple negative breast cancer (TNBC, MDA-MB-231 cells) growing in the brains of athymic nude mice. With a well-tolerated non-toxic IV dose of the INPs (7 g iodine/kg body weight), tumors showed a heavily iodinated rim surrounding the tumor having an average uptake of 2.9% iodine by weight, with uptake peaks at 4.5%. This is calculated to provide a dose enhancement factor of approximately 5.5 (peaks at 8.0), the highest ever reported for any radiation-enhancing agents. With RT alone (15 Gy, single dose), all animals died by 72 days; INP pretreatment resulted in longer-term remissions with 40% of mice surviving 150 days and 30% surviving > 280 days.


2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Wei Zhang ◽  
Zhen Chen ◽  
Likun Chen ◽  
Fang Wang ◽  
Furong Li ◽  
...  

An amendment to this paper has been published and can be accessed via a link at the top of the paper.


2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 305-305
Author(s):  
Shirley Arbizu ◽  
Giuliana Noratto ◽  
Marjorie Layosa ◽  
Nara N Lage ◽  
Liezl Atienza ◽  
...  

Abstract Objectives To investigate in vivo the chemopreventive activity of dark sweet cherry (DSC) extracted total phenolics (WE) or fractions enriched in anthocyanins (ACN) or proanthocyanidins (PCN) in athymic nude mice xenografted with MDA-MB-453 breast cancer cells. Methods MDA-MB-453 breast cancer cells (1 × 106 cells) were xenografted into athymic nude mice. Mice were gavaged with WE, ACN, or PCN extracts (150 mg/kg body weight/day) for 36 days followed by animal termination. Main organs and tumors were dissected for protein analyses following standard molecular biology techniques and high-resolution nano-HPLC tandem mass spectrometry. Results Tumor volume growth was suppressed at similar levels by WE, ACN, and PCN compared to controls (C) without signs of toxicity in main organs. Tumor protein analysis revealed ERK1/2 phosphorylation induced by WE, ACN, and PCN at similar levels, which may be linked to apoptosis induction by stress regulated ERK1/2 activation. Immunohistochemistry analysis showed decreased tumor cell proliferation and Ki-67 H-scores with potency WE ≥ ACN ≥ PCN. Differential quantitative proteomic analysis of tumor tissues from ACN and C groups revealed the identity of 71 proteins associated with poor breast cancer prognosis that were expressed only in C group (66 proteins), or upregulated in C group (5 proteins) compared to ACN group (p < 0.05). Conclusions These findings revealed the potential of DSC phenolics for breast cancer invasion and metastasis chemoprevention. Funding Sources This work was supported by the Northwest Cherry Growers, Washington State Fruit Commission.


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