Advanced stages of papillary and anaplastic thyroid cancer continue to be plagued by a dismal prognosis, which is a result of limited effective therapies for these cancers. Due to the high proportion of thyroid cancers harboring mutations in the MAPK pathway, the MAPK pathway has become a focal point for therapeutic intervention in thyroid cancer. Unfortunately, unlike melanoma, a similar responsiveness to MAPK pathway inhibition has yet to be observed in thyroid cancer patients. To address this issue, we have focused on targeting the non-receptor tyrosine kinase, Src, and we and others have demonstrated that targeting Src results in inhibition of growth, invasion, and migration both in vitro and in vivo, which can be enhanced through the combined inhibition of Src and the MAPK pathway. Therefore, we examined the efficacy of the combination therapy across a panel of thyroid cancer cell lines representing common oncogenic drivers (BRAF, RAS, and PIK3CA). Interestingly, combined inhibition of Src and the MAPK pathway overcomes intrinsic dasatinib resistance in cell lines where both the MAPK and PI3K pathways are inhibited, which we show is likely due to the regulation of the PI3K pathway by Src in these responsive cells. Interestingly, we have mapped downstream phosphorylation of rpS6 as a key biomarker of response, and cells that maintain rpS6 phosphorylation likely represent drug tolerant persisters. Altogether, the combined inhibition of Src and the MAPK pathway holds great promise for improving the overall survival of advanced thyroid cancer patients with BRAF and RAS mutations, and activation of the PI3K pathway and rpS6 phosphorylation represent important biomarkers of response for patients treated with this therapy.
Echolocation is the primary sense used by most bats to navigate their environment. However, the influence of echolocating behaviors upon the morphology of the auditory apparatus remains largely uninvestigated. While it is known that middle ear ossicle size scales positively with body mass across mammals, and that peak call frequency scales negatively with body mass among bats, there are still large gaps in our understanding of the degree to which allometry or ecology influences the morphology of the chiropteran auditory apparatus. To investigate this, we used μCT datasets to quantify three morphological components of the inner and middle ear: ossicle size, ossicle shape, and cochlear spirality. These data were collected across 27 phyllostomid species, spanning a broad range of body sizes, habitats, and dietary categories, and the relationships between these variables and ear morphology were assessed using a comparative phylogenetic approach. Ossicle size consistently scaled with strong negative allometry relative to body mass. Cochlear spirality was significantly (p = .025) associated with wing aspect ratio (a proxy for habitat use) but was not associated with body mass. From a morphological perspective, the malleus and incus exhibited some variation in kind with diet and call frequency, while stapes morphology is more closely tied to body size. Future work will assess these relationships within other chiropteran lineages, and investigate potential morphological differences in the middle and inner ear of echolocating‐vs‐non‐echolocating taxa.
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