| 1. |
- Liu, Anbu, et al.
(author)
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DDR1/2 enhance KIT activation and imatinib resistance of primary and secondary KIT mutants in gastrointestinal stromal tumors
- 2024
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In: Molecular Carcinogenesis. - 0899-1987. ; 63:1, s. 75-93
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Journal article (peer-reviewed)abstract
- Gastrointestinal stromal tumors (GISTs) are predominantly initiated by KIT mutations. In this study, we observed that discoidin domain receptors 1 and 2 (DDR1 and DDR2) exhibited high expression in GISTs, were associated with KIT, and enhanced the activation of both wild-type KIT and primary KIT mutants. Inhibition of DDR1/2 led to a reduction in the activation of KIT and its downstream signaling molecules, ultimately impairing GIST cell survival and proliferation in vitro. Consequently, treatment of mice carrying germline KIT/V558A mutation with DDR1/2 inhibitor significantly impeded tumor growth, and the combined use of DDR1/2 inhibitor and imatinib, the first-line targeted therapeutic agent for GISTs, markedly enhanced tumor growth suppression. In addition, DDR1/2 inhibition resulted in decreased KIT expression, while KIT inhibition led to upregulation of DDR1/2 expression in GISTs. The presence of DDR1/2 also decreased the sensitivity of wild-type KIT or primary KIT mutants to imatinib, indicating a possible role for DDR1/2 in promoting GIST survival during KIT-targeted therapy. The development of drug-resistant secondary KIT mutations is a primary factor contributing to GIST recurrence following targeted therapy. Similar to primary KIT mutants, DDR1/2 can associate with and enhance the activation of secondary KIT mutants, further diminishing their sensitivity to imatinib. In summary, our data demonstrate that DDR1/2 contribute to KIT activation in GISTs and strengthen resistance to imatinib for both primary and secondary KIT mutants, providing a rationale for further exploration of DDR1/2 targeting in GIST treatment.
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| 2. |
- Zhang, Shidong, et al.
(author)
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Simple and complex polymer electrolyte fuel cell stack models : A comparison
- 2018. - 13
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In: ECS Transactions. - : The Electrochemical Society. - 1938-6737 .- 1938-5862. - 9781607685395 ; 86, s. 287-300
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Conference paper (peer-reviewed)abstract
- In this paper, two distinct polymer electrolyte fuel cell stack models are constructed: a detailed numerical model (DNM) employing a fine-scale computational mesh and a coarse-mesh approach based on a distributed resistance analogy (DRA) where diffusion terms in the transport equations are replaced by rate terms. Both methods are applied to a 5-cell, high-temperature polymer electrolyte fuel cell stack with an active area of 200 cm2 per cell. The polarization curve and local current density distributions from both the DRA and DNM are compared with experimental data, finding good agreement. Temperature, pressure, Nernst potential, and species distributions are also exhibited. The DNM displays details of fine-scale local extrema not captured by the DRA; however, the latter requires orders of magnitude less computer processor power and memory for execution. Both methods provide much finer-scale results than present experimental techniques.
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