8 results
Search Results
2. Mechanism of action, potency and efficacy: considerations for cell therapies.
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Simon Jr., Carl G., Bozenhardt, Erich H., Celluzzi, Christina M., Dobnik, David, Grant, Melanie L., Lakshmipathy, Uma, Nebel, Thiana, Peltier, Linda, Ratcliffe, Anthony, Sherley, James L., Stacey, Glyn N., Taghizadeh, Rouzbeh R., Tan, Eddie H. P., and Vessillier, Sandrine
- Subjects
CELLULAR therapy ,CELL culture ,CLINICAL trials ,TREATMENT effectiveness ,ANIMAL models in research - Abstract
One of the most challenging aspects of developing advanced cell therapy products (CTPs) is defining the mechanism of action (MOA), potency and efficacy of the product. This perspective examines these concepts and presents helpful ways to think about them through the lens of metrology. A logical framework for thinking about MOA, potency and efficacy is presented that is consistent with the existing regulatory guidelines, but also accommodates what has been learned from the 27 US FDA-approved CTPs. Available information regarding MOA, potency and efficacy for the 27 FDA-approved CTPs is reviewed to provide background and perspective. Potency process and efficacy process charts are introduced to clarify and illustrate the relationships between six key concepts: MOA, potency, potency test, efficacy, efficacy endpoint and efficacy endpoint test. Careful consideration of the meaning of these terms makes it easier to discuss the challenges of correlating potency test results with clinical outcomes and to understand how the relationships between the concepts can be misunderstood during development and clinical trials. Examples of how a product can be "potent but not efficacious" or "not potent but efficacious" are presented. Two example applications of the framework compare how MOA is assessed in cell cultures, animal models and human clinical trials and reveals the challenge of establishing MOA in humans. Lastly, important considerations for the development of potency tests for a CTP are discussed. These perspectives can help product developers set appropriate expectations for understanding a product's MOA and potency, avoid unrealistic assumptions and improve communication among team members during the development of CTPs. [ABSTRACT FROM AUTHOR]
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- 2024
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3. A review of animal models utilized in preclinical studies of approved gene therapy products: trends and insights.
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Soufizadeh, Parham, Mansouri, Vahid, and Ahmadbeigi, Naser
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GENE therapy ,ANIMAL models in research ,MEDICAL research ,GENETIC models ,ENGINEERING models - Abstract
Scientific progress heavily relies on rigorous research, adherence to scientific standards, and transparent reporting. Animal models play a crucial role in advancing biomedical research, especially in the field of gene therapy. Animal models are vital tools in preclinical research, allowing scientists to predict outcomes and understand complex biological processes. The selection of appropriate animal models is critical, considering factors such as physiological and pathophysiological similarities, availability, and ethical considerations. Animal models continue to be indispensable tools in preclinical gene therapy research. Advancements in genetic engineering and model selection have improved the fidelity and relevance of these models. As gene therapy research progresses, careful consideration of animal models and transparent reporting will contribute to the development of effective therapies for various genetic disorders and diseases. This comprehensive review explores the use of animal models in preclinical gene therapy studies for approved products up to September 2023. The study encompasses 47 approved gene therapy products, with a focus on preclinical trials. This comprehensive analysis serves as a valuable reference for researchers in the gene therapy field, aiding in the selection of suitable animal models for their preclinical investigations. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Effects of quercetin on polycystic ovary syndrome in animal models: a systematic review and meta-analysis.
- Author
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Su, Pingping, Chen, Chao, Pang, Liang, Wu, Kai, and Sun, Yun
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POLYCYSTIC ovary syndrome ,QUERCETIN ,VASCULAR endothelial growth factors ,OVULATION ,GRANULOSA cell tumors ,ANIMAL models in research - Abstract
Background: Metformin is an insulin sensitizer that is widely used for the treatment of insulin resistance in polycystic ovary syndrome patients. However, metformin can cause gastrointestinal side effects. Purpose: This study showed that the effects of quercetin are comparable to those of metformin. Therefore, this study aimed to systematically evaluate the efficacy of quercetin in treating PCOS. Methods: The present systematic search of the Chinese National Knowledge Infrastructure (CNKI), Wanfang Data Information Site, Chinese Scientific Journals Database (VIP), SinoMed, Web of Science, and PubMed databases was performed from inception until February 2024. The methodological quality was then assessed by SYRCLE's risk of bias tool, and the data were analyzed by RevMan 5.3 software. Results: Ten studies were included in the meta-analysis. Compared with those in the model group, quercetin in the PCOS group had significant effects on reducing fasting insulin serum (FIS) levels (P = 0.0004), fasting blood glucose (FBG) levels (P = 0.01), HOMA-IR levels (P < 0.00001), cholesterol levels (P < 0.0001), triglyceride levels (P = 0.001), testosterone (T) levels (P < 0.00001), luteinizing hormone (LH) levels (P = 0.0003), the luteinizing hormone/follicle stimulating hormone (LH/FSH) ratio (P = 0.01), vascular endothelial growth factor (VEGF) levels (P < 0.00001), malondialdehyde (MDA) levels (P = 0.03), superoxide dismutase (SOD) levels (P = 0.01) and GLUT4 mRNA expression (P < 0.00001). Conclusion: This meta-analysis suggested that quercetin has positive effects on PCOS treatment. Quercetin can systematically reduce insulin, blood glucose, cholesterol, and triglyceride levels in metabolic pathways. In the endocrine pathway, quercetin can regulate the function of the pituitary-ovarian axis, reduce testosterone and luteinizing hormone (LH) levels, and lower the ratio of LH to follicle-stimulating hormone (FSH). Quercetin can regulate the expression of the GLUT4 gene and has antioxidative effects at the molecular level. [ABSTRACT FROM AUTHOR]
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- 2024
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5. The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.
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Marr, Alexander R., Halpin, Madeline, Corbin, Dominique L., Asemelash, Yerdanos, Sher, Steven, Gordon, Britten K., Whipp, Ethan C., Mitchell, Shaneice, Harrington, Bonnie K., Orwick, Shelley, Benrashid, Samon, Goettl, Virginia M., Yildiz, Vedat, Mitchell, Andrew D., Cahn, Olivia, Mims, Alice S., Larkin, Karilyn T. M., Long, Meixao, Blachly, James, and Woyach, Jennifer A.
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ACUTE myeloid leukemia ,HEMATOLOGIC malignancies ,WNT signal transduction ,CELL physiology ,CYTARABINE ,ANIMAL models in research ,NUCLEOPHOSMIN - Abstract
Acute myeloid leukemia (AML) is a highly aggressive hematologic cancer with poor survival across a broad range of molecular subtypes. Development of efficacious and well-tolerable therapies encompassing the range of mutations that can arise in AML remains an unmet need. The bromo- and extra-terminal domain (BET) family of proteins represents an attractive therapeutic target in AML due to their crucial roles in many cellular functions, regardless of any specific mutation. Many BET inhibitors (BETi) are currently in pre-clinical and early clinical development, but acquisition of resistance continues to remain an obstacle for the drug class. Novel methods to circumvent this development of resistance could be instrumental for the future use of BET inhibitors in AML, both as monotherapy and in combination. To date, many investigations into possible drug combinations of BETi with CDK inhibitors have focused on CDK9, which has a known physical and functional interaction with the BET protein BRD4. Therefore, we wished to investigate possible synergy and additive effects between inhibitors of these targets in AML. Here, we describe combination therapy with the multi-CDK inhibitor dinaciclib and the BETi PLX51107 in pre-clinical models of AML. Dinaciclib and PLX51107 demonstrate additive effects in AML cell lines, primary AML samples, and in vivo. Further, we demonstrate novel activity of dinaciclib through inhibition of the canonical/β-catenin dependent Wnt signaling pathway, a known resistance mechanism to BETi in AML. We show dinaciclib inhibits Wnt signaling at multiple levels, including downregulation of β-catenin, the Wnt co-receptor LRP6, as well as many Wnt pathway components and targets. Moreover, dinaciclib sensitivity remains unaffected in a setting of BET resistance, demonstrating similar inhibitory effects on Wnt signaling when compared to BET-sensitive cells. Ultimately, our results demonstrate rationale for combination CDKi and BETi in AML. In addition, our novel finding of Wnt signaling inhibition could have potential implications in other cancers where Wnt signaling is dysregulated and demonstrates one possible approach to circumvent development of BET resistance in AML. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Establishment and pathophysiological evaluation of a novel model of acute compartment syndrome in rats.
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Dong, Qi, Long, Yubin, Jin, Lin, Hou, Guanlin, Li, Guoqiang, Wang, Tao, Jia, Huiyang, Yin, Yingchao, Guo, Junfei, Ma, Huijie, Xu, Sujuan, Zhang, Yingze, and Hou, Zhiyong
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COMPARTMENT syndrome ,RATS ,BLOOD flow ,ANIMAL models in research ,ANIMAL disease models - Abstract
Background: Researches have used intra-compartmental infusion and ballon tourniquest to create high intra-compartmental pressure in animal models of Acute Compartment Syndrome (ACS). However, due to the large differences in the modeling methods and the evaluation criteria of ACS, further researches of its pathophysiology and pathogenesis are hindered. Currently, there is no ideal animal model for ACS and this study aimed to establish a reproducible, clinically relevant animal model. Methods: Blunt trauma and fracture were caused by the free falling of weights (0.5 kg, 1 kg, 2 kg) from a height of 40 cm onto the lower legs of rats, and the application of pressures of 100 mmHg, 200 mmHg, 300 mmHg and 400 mmHg to the lower limbs of rats using a modified pressurizing device for 6 h. The intra-compartmental pressure (ICP) and the pressure change (ΔP) of rats with single and combined injury were continuously recorded, and the pathophysiology of the rats was assessed based on serum biochemistry, histological and hemodynamic changes. Results: The ΔP caused by single injury method of different weights falling onto the lower leg did not meet the diagnosis criteria for ACS (< 30 mmHg). On the other hand, a combined injury method of a falling weight of 1.0 kg and the use of a pressurizing device with pressure of 300 mmHg or 400 mmHg for 6 h resulted in the desired ACS diagnosis criteria with a ΔP value of less than 30 mmHg. The serum analytes, histological damage score, and fibrosis level of the combined injury group were significantly increased compared with control group, while the blood flow was significantly decreased compared with control group. Conclusion: We successfully established a new preclinical ACS-like rat model, by the compression of the lower leg of rats with 300 mmHg pressure for 6 h and blunt trauma by 1.0 kg weight falling. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Standardized Pre-clinical Surgical Animal Model Protocol to Investigate the Cellular and Molecular Mechanisms of Ischemic Flap Healing.
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Aksamitiene, Edita, Heffelfinger, Ryan N., Hoek, Jan B., and Pribitkin, Edmund deAzevedo
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SKIN regeneration ,FREE flaps ,HEALING ,LABORATORY rats ,ANIMAL models in research ,RATTUS norvegicus ,PLASTIC surgery - Abstract
Background: Some of the most complex surgical interventions to treat trauma and cancer include the use of locoregional pedicled and free autologous tissue transfer flaps. While the techniques used for these reconstructive surgery procedures have improved over time, flap complications and even failure remain a significant clinical challenge. Animal models are useful in studying the pathophysiology of ischemic flaps, but when repeatability is a primary focus of a study, conventional in-vivo designs, where one randomized subset of animals serves as a treatment group while a second subset serves as a control, are at a disadvantage instigated by greater subject-to-subject variability. Our goal was to provide a step-by-step methodological protocol for creating an alternative standardized, more economical, and transferable pre-clinical animal research model of excisional full-thickness wound healing following a simulated autologous tissue transfer which includes the primary ischemia, reperfusion, and secondary ischemia events with the latter mimicking flap salvage procedure. Results: Unlike in the most frequently used classical unilateral McFarlane's caudally based dorsal random pattern skin flap model, in the herein described bilateral epigastric fasciocutaneous advancement flap (BEFAF) model, one flap heals under normal and a contralateral flap—under perturbed conditions or both flaps heal under conditions that vary by one within-subjects factor. We discuss the advantages and limitations of the proposed experimental approach and, as a part of model validation, provide the examples of its use in laboratory rat (Rattus norvegicus) axial pattern flap healing studies. Conclusions: This technically challenging but feasible reconstructive surgery model eliminates inter-subject variability, while concomitantly minimizing the number of animals needed to achieve adequate statistical power. BEFAFs may be used to investigate the spatiotemporal cellular and molecular responses to complex tissue injury, interventions simulating clinically relevant flap complications (e.g., vascular thrombosis) as well as prophylactic, therapeutic or surgical treatment (e.g., flap delay) strategies in the presence or absence of confounding risk factors (e.g., substance abuse, irradiation, diabetes) or favorable wound-healing promoting activities (e.g., exercise). Detailed visual instructions in BEFAF protocol may serve as an aid for teaching medical or academic researchers basic vascular microsurgery techniques that focus on precision, tremor management and magnification. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Pharmacological and cell-based treatments to increase local skin flap viability in animal models.
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Berry, Charlotte E., Le, Thalia, An, Nicholas, Griffin, Michelle, Januszyk, Micheal, Kendig, Carter B., Fazilat, Alexander Z., Churukian, Andrew A., Pan, Phoebe M., and Wan, Derrick C.
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DRUG therapy ,TOPICAL drug administration ,ANIMAL models in research ,REPERFUSION injury ,OPERATIVE surgery ,CELL death ,PERFORATOR flaps (Surgery) - Abstract
Local skin flaps are frequently employed for wound closure to address surgical, traumatic, congenital, or oncologic defects. (1) Despite their clinical utility, skin flaps may fail due to inadequate perfusion, ischemia/reperfusion injury (IRI), excessive cell death, and associated inflammatory response. (2) All of these factors contribute to skin flap necrosis in 10–15% of cases and represent a significant surgical challenge. (3, 4) Once flap necrosis occurs, it may require additional surgeries to remove the entire flap or repair the damage and secondary treatments for infection and disfiguration, which can be costly and painful. (5) In addition to employing appropriate surgical techniques and identifying healthy, well-vascularized tissue to mitigate the occurrence of these complications, there is growing interest in exploring cell-based and pharmacologic augmentation options. (6) These agents typically focus on preventing thrombosis and increasing vasodilation and angiogenesis while reducing inflammation and oxidative stress. Agents that modulate cell death pathways such as apoptosis and autophagy have also been investigated. (7) Implementation of drugs and cell lines with potentially beneficial properties have been proposed through various delivery techniques including systemic treatment, direct wound bed or flap injection, and topical application. This review summarizes pharmacologic- and cell-based interventions to augment skin flap viability in animal models, and discusses both translatability challenges facing these therapies and future directions in the field of skin flap augmentation. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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