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  • Our sample is representative of mRCC treated with sunitinib

    2023-03-17

    Our sample is representative of mRCC treated with sunitinib. However, the results from CCC setting have limited inference due to small exploratory sample (n = 51). Additionally, the significance of survival differences in CCC according to AXL staining is tangential. Unfortunately, we were unable to define risk criteria according Motzer et al. [24] and Heng et al. [23] for all patients due to paucity of clinical data. Therefore, further studies are warranted to extend and validate the present findings.
    Conclusion
    Acknowledgments
    Introduction Ischemic stroke, a devastating neurological disease, is the third leading cause of mortality and morbidity worldwide (Lakhan et al., 2009). Following Z-VEID-FMK ischemia, microglia and astrocytes are activated via Toll-like receptors (TLRs) (Liu et al., 2011), leading to up-regulation of nuclear factor kappa B (NF-κB) (Zwagerman et al., 2010). NF-κB has been well-documented to be a key regulator of both cell survival and inflammatory genes (Shih et al., 2015, Harari and Liao, 2010). NF-κB-induced inflammation has been shown to be via TLR-mediated signaling, which ultimately promotes production of proinflammatory cytokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (Shih et al., 2015). TLRs are critical in mediating inflammation, and therefore TLRs signaling is tightly regulated (Wang et al., 2009). Several TLRs signaling suppressors have been described in immune cells (Liew et al., 2005). Recent studies revealed that Tyro3, Axl, and Mer (TAM receptors) play a pivotal role in negatively regulating innate immunity via the inhibition of the TLR-mediated inflammatory response and the promotion of phagocytic clearance of apoptotic cells (Wang et al., 2009). Tyro3, Axl, and Mer receptors make up the TAM family of tyrosine kinase receptors which are expressed on myeloid-derived hematopoietic cells. TAM receptors have been shown to suppress TLRs signaling, thereby preventing over-stimulation (Sun et al., 2010). One of the ligands for TAMs is Growth-arrest-specific protein 6 (Gas6), which has the highest affinity for Axl. Gas6/Axl signaling pathway has been suggested to play a critical role in various diseases and in reducing inflammation (Manfioletti et al., 1993). Gas6 has been shown to reduce the release of proinflammatory cytokines (Alciato et al., 2010). TAM receptors attenuate inflammation via downstream signaling including suppressor of cytokine signaling 1 (SOCS1), SOCS3, and Twist, which inhibit both TLR and cytokine-driven immune responses (Sun et al., 2010). In the absence of TAM receptors, inflammation is uncontrolled, leading to reduced clearance of apoptotic cells, auto-immune disease (Lu and Lemke, 2001), greater response to endotoxin (Camenisch et al., 1999), and increased inflammatory cytokines (Deng et al., 2012). Since the only drug of Food and Drug Administration-approved pharmacological treatment for acute ischemic stroke is tissue plasminogen activator (tPA), which is only administered to 2–5% of stroke patients (Brainin et al., 2007), it is important to continue searching for novel therapeutics. Developments of effective anti-inflammatory drugs are urgently needed for the therapies of ischemic stroke. However, whether rGas6 attenuates the inflammation induced by cerebral ischemia/reperfusion injury remains unclear. The present study aims to investigate the neuroprotective effect and potential molecular mechanisms of rGas6 in a rat MCAO model.
    Materials and methods
    Results As shown in Fig. 1, Gas6 expression increased 6h after MCAO, but then significantly decreased by 12h after MCAO, remaining significantly lower than MCAO for up to 72h after injury (Fig. 1A and B). A similar trend was observed for Axl expression levels; Axl was increased at 6h before decreasing below sham levels at 12 and 24h post-ictus (Fig. 1A and C). Proinflammatory cytokines IL-1β, IL-6 and TNF-α were significantly increased at 6h and remained elevated for up to 72h post-MCAO (Fig. 1A, D–F).